Toxins

38 pages, 7473 KiB

Open AccessReview

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

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

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

Abstract

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

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

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

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8 pages, 235 KiB

Open AccessReview

Onabotulinumtoxin A for the Treatment of Post-Traumatic Headache: Is It Better than Anti-CGRP Antibodies?

by Lanfranco Pellesi, Dilara Onan and Paolo Martelletti

Toxins 2024, 16(10), 427; https://doi.org/10.3390/toxins16100427 - 2 Oct 2024

Abstract

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the [...] Read more.

Post-traumatic headache (PTH) is a common and debilitating consequence of traumatic brain injury (TBI), often resembling migraine and tension-type headaches. Despite its prevalence, the optimal treatment for PTH remains unclear, with current strategies largely extrapolated from other headache disorders. This review evaluates the use of onabotulinumtoxin A (ONA) and anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) in the treatment of PTH. A comprehensive literature search was conducted on PubMed, including studies published up to September 2024, focusing on the efficacy, safety, and mechanisms of onabotulinumtoxin A and anti-CGRP mAbs in PTH. Both clinical trials and observational studies were reviewed. ONA, widely recognized for its efficacy in chronic migraine, has shown limited benefits in PTH with only one trial involving abobotulinumtoxin A in a cohort of 40 subjects. A phase 2 trial with fremanezumab, an anti-CGRP monoclonal antibody, failed to demonstrate significant efficacy in PTH, raising questions about the utility of targeting CGRP in this condition. ONA may offer advantages over anti-CGRP mAbs, not only in terms of its broader mechanism of action but also in cost-effectiveness and higher patient adherence. Both ONA and anti-CGRP mAbs are potential options for the management of PTH, but the current evidence is insufficient to establish clear guidelines. The negative results from the fremanezumab trial suggest that CGRP inhibition may not be sufficient for treating PTH, whereas onabotulinumtoxin A’s ability to target multiple pain pathways may make it a more promising candidate. Full article

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

10 pages, 619 KiB

Open AccessArticle

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

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

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

Abstract

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

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

(This article belongs to the Section Uremic Toxins)

20 pages, 3372 KiB

Open AccessArticle

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

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

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

Abstract

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

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

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

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19 pages, 3599 KiB

Open AccessArticle

High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance Identifies Impairment of Metabolism by T-2 Toxin, in Relation to Toxicity, in Zebrafish Embryo Model

by Ariel Lawson, Mark Annunziato, Narmin Bashirova, Muhamed N. Hashem Eeza, Jörg Matysik, A. Alia and John. P. Berry

Toxins 2024, 16(10), 424; https://doi.org/10.3390/toxins16100424 - 1 Oct 2024

Abstract

Among the widespread trichothecene mycotoxins, T-2 toxin is considered the most toxic congener. In the present study, we utilized high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), coupled to the zebrafish (Danio rerio) embryo model, as a toxicometabolomics approach to elucidate [...] Read more.

Among the widespread trichothecene mycotoxins, T-2 toxin is considered the most toxic congener. In the present study, we utilized high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR), coupled to the zebrafish (Danio rerio) embryo model, as a toxicometabolomics approach to elucidate the cellular, molecular and biochemical pathways associated with T-2 toxicity. Aligned with previous studies in the zebrafish embryo model, exposure to T-2 toxin was lethal in the high parts-per-billion (ppb) range, with a median lethal concentration (LC₅₀) of 105 ppb. Exposure to the toxins was, furthermore, associated with system-specific alterations in the production of reactive oxygen species (ROS), including decreased ROS production in the liver and increased ROS in the brain region, in the exposed embryos. Moreover, metabolic profiling based on HRMAS NMR revealed the modulation of numerous, interrelated metabolites, specifically including those associated with (1) phase I and II detoxification, and antioxidant pathways; (2) disruption of the phosphocholine lipids of cell membranes; (3) mitochondrial energy metabolism, including apparent disruption of the tricarboxylic acid (TCA) cycle, and the electron transport chain of oxidative phosphorylation, as well as “upstream” effects on carbohydrate, i.e., glucose metabolism; and (4) several compensatory catabolic pathways. Taken together, these observations enabled development of an integrated, system-level model of T-2 toxicity in relation to human and animal health. Full article

(This article belongs to the Section Mycotoxins)

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Graphical abstract

13 pages, 2076 KiB

Open AccessArticle

Real-World Use of Intradetrusor Botulinum Toxin Injections: A Population-Based Study from France

by Alain Ruffion, Pierre Karam, Anne Forestier and Pierre Denys

Toxins 2024, 16(10), 423; https://doi.org/10.3390/toxins16100423 - 1 Oct 2024

Abstract

In recent decades, intradetrusor injections of botulinum toxin A (BoNT-A) have been widely applied to treat incontinence in both idiopathic overactive bladder (iOAB) and neurogenic detrusor overactivity incontinence (NDOI). This analysis, based on the French National Hospital Discharge Database (PMSI), aims to describe [...] Read more.

In recent decades, intradetrusor injections of botulinum toxin A (BoNT-A) have been widely applied to treat incontinence in both idiopathic overactive bladder (iOAB) and neurogenic detrusor overactivity incontinence (NDOI). This analysis, based on the French National Hospital Discharge Database (PMSI), aims to describe real-world trends in intradetrusor BoNT-A use between 2014 and 2022. Among 32,864 patients who received at least one intradetrusor BoNT-A injection, 18,320 (55.7%) had conditions coded under iOAB, 13,376 (40.7%) under NDOI, and 1168 (3.6%) under other indications. The overall mean interval between two intradetrusor BoNT-A injections was 9.7 months, ranging from 8.7 months in patients with multiple sclerosis (MS) to 11.5 months in patients with cerebral pathologies. The median number of injections was two (quartile 1–quartile 3, 1–4) in patients with spina bifida, whereas it was five (2–10) in those with MS. Only 31% of patients with iOAB received more than two intradetrusor BoNT-A injections. Regardless of its indication, BoNT-A was well tolerated. Adverse events occurring during or requiring hospitalization included infections (3.8%), hematuria (0.53%), and bleeding episodes necessitating transfusions (0.11%), all recorded within the initial month following BoNT-A injection. Our analysis of the PMSI database highlights a broad spectrum of intradetrusor BoNT-A injection practices. Full article

(This article belongs to the Special Issue Application of Botulinum Neurotoxin in Lower Urinary Tract Dysfunctions: Where Are We Now? II)

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25 pages, 3146 KiB

Open AccessReview

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

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

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

Abstract

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

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

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

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11 pages, 802 KiB

Open AccessArticle

Presence of Ochratoxin a Residues in Blood Serum of Slaughtered Pigs in Greece

by Mikela Vlachou, Andreana Pexara, Nikolaos Solomakos, Alexander Govaris, Dimitrios Palaiogiannis, Vassilis Athanasiadis and Stavros I. Lalas

Toxins 2024, 16(10), 421; https://doi.org/10.3390/toxins16100421 - 30 Sep 2024

Abstract

This study aimed to assess the presence of ochratoxin A (OTA) residues in the blood serum of slaughtered pigs in Greece. Samples were obtained from 1695 healthy slaughtered pigs originating from 113 different farms located in 21 geographic regional units in 8 different [...] Read more.

This study aimed to assess the presence of ochratoxin A (OTA) residues in the blood serum of slaughtered pigs in Greece. Samples were obtained from 1695 healthy slaughtered pigs originating from 113 different farms located in 21 geographic regional units in 8 different geographic regions of Greece and were analyzed using an immunosorbent assay (ELISA) and high-performance liquid chromatography with fluorescence detector (HPLC-FD). OTA contamination assessment showed that 782 (46.1%) and 1233 (72.7%) samples were OTA-positive, with a concentration range of 0.20–5.38 μg/L and 0.15–5.96 µg/L according to ELISA and HPLC-FD analysis, respectively. Also, 88 (77.9%) and 108 (95.6%) of farms were found to be OTA-positive by ELISA and HPLC-FD analysis, respectively. The highest OTA serum positivity rate (>98%) and toxin level (5.96 µg/L) determined by HPLC-FD were observed in the Thessaly region, whereas a high prevalence of up to 100% (range 75–100%) was found on farms in the Crete Island region. The detection of OTA in the serum of slaughtered pigs in different regions in Greece poses a risk for animal and human health and highlights the need for constant OTA monitoring in the swine industry and pork meat production facilities. Full article

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18 pages, 2659 KiB

Open AccessArticle

SYNCHRONIZE: Real-World Retrospective Safety Analysis of Patients Treated with OnabotulinumtoxinA for More than One Therapeutic Indication

by Grace Forde, Benjamin M. Brucker, Kimberly Becker Ifantides, Atul T. Patel, Angeli Mayadev, Theodore Brown, Ziyad Ayyoub, Kenneth Martinez, Ritu Singh, Mariana Nelson, Simona Battucci, Irina Yushmanova, Ahunna Ukah and Christopher Rhyne

Toxins 2024, 16(10), 420; https://doi.org/10.3390/toxins16100420 - 29 Sep 2024

Abstract

OnabotulinumtoxinA (onabotA) is approved in the US for 12 therapeutic indications. Real-world data on onabotA multi-indication use are limited, often leading to delayed or reduced treatment. This study provides real-world evidence on the safety of onabotA when treating multiple indications concomitantly. SYNCHRONIZE was [...] Read more.

OnabotulinumtoxinA (onabotA) is approved in the US for 12 therapeutic indications. Real-world data on onabotA multi-indication use are limited, often leading to delayed or reduced treatment. This study provides real-world evidence on the safety of onabotA when treating multiple indications concomitantly. SYNCHRONIZE was a multicenter, retrospective, chart-review study evaluating onabotA’s safety for adults treated for ≥2 therapeutic indications within a 3-month period. The primary outcome was treatment-emergent adverse events (TEAEs) within 6 months post-treatment. A total of 279 patients were included. The most common concomitant indications treated were cervical dystonia and chronic migraine (43.4%). The average 3-month cumulative dose for multiple indications was 282.2 U. The treatment interval for multiple indications was ≤24 h for most patients (62.4%). Overall, 28.7% of patients reported ≥1 TEAE with no apparent trends in TEAEs and dose interval or cumulative dose. Reported TEAEs included UTI (5.7%), neck pain (5.0%), and headache (4.3%). No patient had a lack of effect according to clinical objective measurements. SYNCHRONIZE described the real-world safety of onabotA for patients treated concomitantly for ≥2 indications within a 3-month period. TEAEs were generally consistent with the known safety profiles of individual indications. No new safety signals were identified). Full article

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14 pages, 3852 KiB

Open AccessArticle

Cloning of Three Aflatoxin B1 Oxidases of the Dipeptidyl Peptidase III Family and Evaluation of Their Potential for Practical Applications as Decontamination Enzymes

by Igor Sinelnikov, Ivan Zorov, Yury Denisenko, Kristina Demidova, Alexandra Rozhkova and Larisa Shcherbakova

Toxins 2024, 16(10), 419; https://doi.org/10.3390/toxins16100419 - 27 Sep 2024

Abstract

Aflatoxin B1 (AFB1) produced by some Aspergillus species belongs to the most dangerous contaminants of animal feeds. Development of safe and cost efficient decontamination methods saving feed quality and nutritional value are of paramount importance. The use of recombinant AFB1-detoxifying microbial enzymes represents [...] Read more.

Aflatoxin B1 (AFB1) produced by some Aspergillus species belongs to the most dangerous contaminants of animal feeds. Development of safe and cost efficient decontamination methods saving feed quality and nutritional value are of paramount importance. The use of recombinant AFB1-detoxifying microbial enzymes represents a promising biotechnological approach meeting the aforementioned requirements. In this study, three AFB1-degrading oxidases (AFOs) from edible basidiomycetes Cantharellus cibarius, Lentinula edodes and Pleurotus eryngii as well as AFO from Armillaria tabescens were expressed in E. coli Rosetta (DE3) and purified by immobilized metal-chelate chromatography. The stabilizing effect of the addition of glycerol and β-mercaptoethanol during protein extraction is shown. The catalytic constants of the recombinant AFOs (rAFOs) and other characteristics, which might be important for their practical application (and optimal temperature and pH, thermolability, regulation of the activity by metal ions and chelating agents, storage stability) were investigated. Among the obtained enzymes, rAFO from P. eryngii (Pe-AFO), which was characterized by the highest specific activity, thermostability and pH stability (especially at acidic pH range), the lowest K_m, and relative resistance to the inhibition by phytate, showed the best AFB1-degrading efficacy. However, Pe-AFO and all other rAFOs significantly decreased the target activity during heating above 45 °C, storage frozen or lyophilization. Full article

(This article belongs to the Special Issue Detection, Control and Contamination of Mycotoxins (Volume II))

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21 pages, 1531 KiB

Open AccessArticle

Aflatoxins Levels in Concentrate Feeds Collected from Specialized Dairy Farms and Local Markets in Selected Urban Centers of Eastern Ethiopia

by Angassa Tesfaye, Mohammed Yusuf Kurtu, Yesihak Yusuf Mummed and Abdi Mohammed

Toxins 2024, 16(10), 418; https://doi.org/10.3390/toxins16100418 - 27 Sep 2024

Abstract

Aflatoxin constitutes a significant concern for food and feed safety, posing detrimental health risks to both animals and humans. This study aimed to examine the prevalence and concentration of aflatoxins in maize feed, total mixed ration, and wheat bran collected from specialized dairy [...] Read more.

Aflatoxin constitutes a significant concern for food and feed safety, posing detrimental health risks to both animals and humans. This study aimed to examine the prevalence and concentration of aflatoxins in maize feed, total mixed ration, and wheat bran collected from specialized dairy farms and local markets in three major urban centers in eastern Ethiopia. A total of 180 feed samples were collected from September 2021 to January 2022 in Chiro town, Dire Dawa city, and Harar city. These samples underwent thorough extraction and immunoaffinity clean-up before aflatoxin analysis using HPLC/FLD. The results revealed that AFB₁, AFB₂, AFG₁, AFG₂, and TAF contamination was detected in 72.2%, 66.1%, 71.1%, 68.7%, and 82.8% of the feed samples, respectively. The corresponding mean levels of each aflatoxin were 28.15 ± 3.50, 3.3 ± 0.40, 19.87 ± 1.87, 2.7 ± 0.32, and 54.01 ± 4.72 µg/kg, respectively. The occurrence and levels of aflatoxin varied across different study sites and feed types. Notably, feeds from Dire Dawa city exhibited significantly higher mean levels of AFB₁ (43.98 ± 5.3 µg/kg), AFB₂ (5.69 ± 0.6 µg/kg), AFG₁ (32.25 ± 2.7 µg/kg), and AFG₂ (5.01 ± 0.5 µg/kg) than feeds from other urban centers did. Additionally, a significantly higher occurrence of AFB₁ (29.4%) and AFG₁ (28.3%) was detected in feed from Dire Dawa city. Similarly, the total mixed ration (TMR) displayed significantly higher levels of AFB₁ (50.67 ± 5.2 µg/kg), AFB₂ (4.74 ± 0.6 µg/kg), AFG₁ (32.87 ± 2.6 µg/kg), and AFG₂ (3.86 ± 0.5 µg/kg) compared to the other feed types. Moreover, a significantly higher occurrence of AFB₁ (30.7%) and AFG₁ (28.7%) was detected in the TMR. Furthermore, a moderate correlation was observed between the count of aflatoxigenic Aspergillus species and the levels of TAF in the feed samples. Overall, this study underscores the widespread presence of aflatoxin contamination in dairy feeds in eastern Ethiopia, highlighting the urgent need for stringent monitoring and mitigation measures to ensure food and feed safety, as well as public health. Full article

(This article belongs to the Section Mycotoxins)

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24 pages, 400 KiB

Open AccessReview

History and Toxinology of Palytoxins

by Harriet L. Hammond and Chad J. Roy

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

Abstract

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

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

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

15 pages, 3079 KiB

Open AccessArticle

Effects of Propolis Supplementation on Gut Microbiota and Uremic Toxin Profiles of Patients Undergoing Hemodialysis

by Larissa Fonseca, Marcia Ribeiro, Júnia Schultz, Natália A. Borges, Ludmila Cardozo, Viviane O. Leal, Marcelo Ribeiro-Alves, Bruna R. Paiva, Paulo E. C. Leite, Carmen L. Sanz, Fernanda Kussi, Lia S. Nakao, Alexandre Rosado, Peter Stenvinkel and Denise Mafra

Toxins 2024, 16(10), 416; https://doi.org/10.3390/toxins16100416 - 25 Sep 2024

Abstract

Background: Propolis possesses many bioactive compounds that could modulate the gut microbiota and reduce the production of uremic toxins in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). This clinical trial aimed to evaluate the effects of propolis on the gut microbiota [...] Read more.

Background: Propolis possesses many bioactive compounds that could modulate the gut microbiota and reduce the production of uremic toxins in patients with chronic kidney disease (CKD) undergoing hemodialysis (HD). This clinical trial aimed to evaluate the effects of propolis on the gut microbiota profile and uremic toxin plasma levels in HD patients. These are secondary analyses from a previous double-blind, randomized clinical study, with 42 patients divided into two groups: the placebo and propolis group received 400 mg of green propolis extract/day for eight weeks. Indole-3 acetic acid (IAA), indoxyl sulfate (IS), and p-cresyl sulfate (p-CS) plasma levels were evaluated by reversed-phase liquid chromatography, and cytokines were investigated using the multiplex assay (Bio-Plex Magpix^®). The fecal microbiota composition was analyzed in a subgroup of patients (n = 6) using a commercial kit for fecal DNA extraction. The V4 region of the 16S rRNA gene was then amplified by the polymerase chain reaction (PCR) using short-read sequencing on the Illumina NovaSeq PE250 platform in a subgroup. Forty-one patients completed the study, 20 in the placebo group and 21 in the propolis group. There was a positive correlation between IAA and TNF-α (r = 0.53, p = 0.01), IL-2 (r = 0.66, p = 0.002), and between pCS and IL-7 (r = 0.46, p = 0.04) at the baseline. No significant changes were observed in the values of uremic toxins after the intervention. Despite not being significant, microbial evenness and observed richness increased following the propolis intervention. Counts of the Fusobacteria species showed a positive correlation with IS, while counts of Firmicutes, Lentisphaerae, and Proteobacteria phyla were negatively correlated with IS. Two months of propolis supplementation did not reduce the plasma levels of uremic toxins (IAA, IS, and p-CS) or change the fecal microbiota. Full article

(This article belongs to the Section Uremic Toxins)

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16 pages, 6101 KiB

Open AccessArticle

Enhancing the Cytotoxicity and Apoptotic Efficacy of Parasporin-2-Derived Variants (Mpp46Aa1) on Cancer Cell Lines

by Juan S. Alarcón-Aldana, Lydia Visser, Nohora J. Rueda-Forero, Efraín H. Pinzón-Reyes, Paola Rondón-Villarreal and Miguel O. Suárez-Barrera

Toxins 2024, 16(10), 415; https://doi.org/10.3390/toxins16100415 - 25 Sep 2024

Abstract

Parasporin PS2Aa1, recently renamed Mpp46Aa1, is an anti-cancer protein known for its selectivity against various human cancer cell lines. We genetically modified native PS2Aa1 to create a library of approximately 100 mutants. From this library, we selected promising mutants based on their half-maximal [...] Read more.

Parasporin PS2Aa1, recently renamed Mpp46Aa1, is an anti-cancer protein known for its selectivity against various human cancer cell lines. We genetically modified native PS2Aa1 to create a library of approximately 100 mutants. From this library, we selected promising mutants based on their half-maximal inhibitory concentration (IC₅₀) and sequence variations. In this study, Variant 3–35, with the G257V substitution, demonstrated increased cytotoxicity and selectivity against the colon cancer cell line SW480. Conversely, Variant N65, featuring substitutions N92D, K175R, and S218G, yielded the most favorable results against the cancer cell lines SW-620, MOLT-4, and Jurkat. The caspase 3/7 and 9, Annexin V-Cy3 and 6-GFDA activities, and, most notably, mitochondrial membrane permeabilization assays confirmed the apoptotic marker elevation. These findings indicate that residues 92, 175, 218, and 257 may play a critical role in the cytotoxic activity and selectivity. We successfully obtained genetically improved variants with substitutions at these key amino acid positions. Additionally, we conducted molecular dynamic simulations to explore the potential interactions between PS2Aa1 and the CD59 GPI-anchored protein. The simulation results revealed that residues 57, 92, and 101 were consistently present, suggesting their possible significance in the interactions between parasporin and the CD59 protein. Full article

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15 pages, 1341 KiB

Open AccessArticle

Effect of Temperature, Relative Humidity, and Incubation Time on the Mycotoxin Production by Fusarium spp. Responsible for Dry Rot in Potato Tubers

by Maria Gutiérrez-Pozo, Carol Verheecke-Vaessen, Sofia Kourmpetli, Leon A. Terry and Angel Medina

Toxins 2024, 16(10), 414; https://doi.org/10.3390/toxins16100414 - 24 Sep 2024

Abstract

Potato is the fourth most consumed crop in the world. More than half of the crop is stored for three to nine months at cold temperatures (3–10 °C) for the fresh and seed market. One of the main causes of fresh potato waste [...] Read more.

Potato is the fourth most consumed crop in the world. More than half of the crop is stored for three to nine months at cold temperatures (3–10 °C) for the fresh and seed market. One of the main causes of fresh potato waste in the retail supply chain is the processing of fungal and bacterial rots during storage. Dry rot is a fungal disease that mainly affects the potato crop during storage and is responsible for 1% of tuber losses in the UK. It is produced by Fusarium spp., such as Fusarium sambucinum and F. oxysporum, which can lead to the accumulation of mycotoxins in the potato tuber. Little is known about the impact of environmental factors on the accumulation of mycotoxins in potato tubers. Understanding the ecophysiology of these fungi is key to mitigating their occurrence under commercial storage conditions. Therefore, this work aimed to elucidate the effect of three different temperatures (5, 10, and 15 °C) and two different water activities (a_w; 0.97, 0.99) on the ecophysiology and mycotoxin accumulation of F. sambucinum and F. oxysporum in a potato-based semi-synthetic medium. The mycotoxin accumulation was then studied in vivo, in potato tubers cultivated under organic farming conditions, stored for 40 days at 8.5 °C. Results showed that higher temperatures and a_w enhanced fungal growth, lag time, and mycotoxin accumulation in vitro. Growth rate was 2 and 3.6 times higher when the temperature increased from 5 to 10 and 15 °C, respectively. Six different mycotoxins (T-2, HT-2, diacetoxyscirpenol, 15-acetoxyscirpenol, neosolaniol, and beauvericin) were detected in vitro and in vivo. T-2 was the most abundant mycotoxin detected in vitro, observing 10⁶ ng of T-2/g media after 21 days of incubation at 10 °C and 0.99 a_w. Due to the long period of time that potato tubers spend in storage, the fluctuations of environmental factors, such as temperature and relative humidity, could promote the development of fungal rot, as well as mycotoxin accumulation. This could result in important food and economic losses for the potato market and a threat to food safety. Full article

(This article belongs to the Collection Editorial Board Members’ Collection Series: Fungal Metabolites: From Toxins to Therapeutics)

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15 pages, 2730 KiB

Open AccessReview

Ultrasound-Guided Botulinum Toxin-A Injections into the Masseter Muscle for Both Medical and Aesthetic Purposes

by Marius Nicolae Popescu, Cristina Beiu, Carmen Andrada Iliescu, Andreea Racoviță, Mihai Berteanu, Mădălina Gabriela Iliescu, Ana Maria Alexandra Stănescu, Diana Sabina Radaschin and Liliana Gabriela Popa

Toxins 2024, 16(10), 413; https://doi.org/10.3390/toxins16100413 - 24 Sep 2024

Abstract

With the increasing use of Botulinum toxin type A (BoNT-A) injections in the masseter muscles for both medical and aesthetic purposes, there is a constant need to continually enhance the efficacy of these treatments and reduce the risk of potential adverse events. This [...] Read more.

With the increasing use of Botulinum toxin type A (BoNT-A) injections in the masseter muscles for both medical and aesthetic purposes, there is a constant need to continually enhance the efficacy of these treatments and reduce the risk of potential adverse events. This review provides an in-depth analysis of the masseter muscle’s anatomical structure and essential landmarks and emphasizes the advantages of ultrasound (US) guidance in improving the precision of BoNT-A injections compared to conventional blind methods. The review is supplemented with comprehensive figures, including graphics, clinical images, and ultrasound visuals, to support the discussion. Potential complications such as paradoxical bulging, inadvertent injections into the risorius muscle or parotid gland, facial paralysis, and the risk of bone resorption are examined. Future research should aim at refining injection techniques and assessing the long-term effects of repeated treatments to ensure optimal patient care and safety. Full article

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

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28 pages, 4713 KiB

Open AccessArticle

A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning

by Loïs Lequesne, Julie Dano, Audrey Rouaix, Camille Kropp, Marc Plaisance, Stéphanie Gelhaye, Marie-Lou Lequesne, Paloma Piquet, Arnaud Avril, François Becher, Maria Lucia Orsini Delgado and Stéphanie Simon

Toxins 2024, 16(10), 412; https://doi.org/10.3390/toxins16100412 - 24 Sep 2024

Abstract

Ricin is a highly potent toxin that has been used in various attempts at bioterrorism worldwide. Although a vaccine for preventing ricin poisoning (RiVax™) is in clinical development, there are currently no commercially available prophylaxis or treatments for ricin intoxication. Numerous studies have [...] Read more.

Ricin is a highly potent toxin that has been used in various attempts at bioterrorism worldwide. Although a vaccine for preventing ricin poisoning (RiVax™) is in clinical development, there are currently no commercially available prophylaxis or treatments for ricin intoxication. Numerous studies have highlighted the potential of passive immunotherapy using anti-ricin monoclonal antibodies (mAbs) and have shown promising results in preclinical models. In this article, we describe the neutralizing and protective efficacy of a new generation of high-affinity anti-ricin mAbs, which bind and neutralize very efficiently both ricin isoforms D and E in vitro through cytotoxicity cell assays. In vivo, protection assay revealed that one of these mAbs (RicE5) conferred over 90% survival in a murine model challenged intranasally with a 5 LD₅₀ of ricin and treated by intravenous administration of the mAbs 6 h post-intoxication. Notably, a 35% survival rate was observed even when treatment was administered 24 h post-exposure. Moreover, all surviving mice exhibited long-term immunity to high ricin doses. These findings offer promising results for the clinical development of a therapeutic candidate against ricin intoxication and may also pave the way for novel vaccination strategies against ricin or other toxins. Full article

(This article belongs to the Section Plant Toxins)

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13 pages, 3203 KiB

Open AccessArticle

Brevetoxin Aptamer Selection and Biolayer Interferometry Biosensor Application

by Bo Hu, Sheng-Qun Ouyang, Yu-Ping Zhu, Xiao-Ling Lu, Zhe Ning, Bing-Hua Jiao, Liang-Hua Wang, Hao-Bing Yu and Xiao-Yu Liu

Toxins 2024, 16(10), 411; https://doi.org/10.3390/toxins16100411 - 24 Sep 2024

Abstract

Brevetoxins (PbTxs) are very potent marine neurotoxins that can cause an illness clinically described as neurologic shellfish poisoning (NSP). These toxins are cyclic polyether in chemistry and have increased their geographical distribution in the past 2 decades. However, the ethical problems as well [...] Read more.

Brevetoxins (PbTxs) are very potent marine neurotoxins that can cause an illness clinically described as neurologic shellfish poisoning (NSP). These toxins are cyclic polyether in chemistry and have increased their geographical distribution in the past 2 decades. However, the ethical problems as well as technical difficulties associated with currently employed analysis methods for marine toxins have spurred the quest for suitable alternatives to be applied in a regulatory monitoring regime. In this work, we reported the first instance of concurrent aptamer selection of Brevetoxin-1 (PbTx-1) and Brevetoxin-2 (PbTx-2) and constructed a biolayer interferometry (BLI) biosensor utilizing PbTx-1 aptamer as a specific recognition element. Through an in vitro selection process, we have, for the first time, successfully selected DNA aptamers with high affinity and specificity to PbTx-1 and PbTx-2 from a vast pool of random sequences. Among the selected aptamers, aptamer A5 exhibited the strongest binding affinity to PbTx-1, with an equilibrium dissociation constant (K_D) of 2.56 μM. Subsequently, we optimized aptamer A5 by truncation to obtain the core sequence (A5-S3). Further refinement was achieved through mutations based on the predictions of a QGRS mapper, resulting in aptamer A5-S3G, which showed a significant increase in the K_D value by approximately 100-fold. Utilizing aptamer A5-S3G, we fabricated a label-free, real-time optical BLI aptasensor for the detection of PbTx-1. This aptasensor displayed a broad detection range from 100 nM to 4000 nM PbTx-1, with a linear range between 100 nM and 2000 nM, and a limit of detection (LOD) as low as 4.5 nM. Importantly, the aptasensor showed no cross-reactivity to PbTx-2 or other marine toxins, indicating a high level of specificity for PbTx-1. Moreover, the aptasensor exhibited excellent reproducibility and stability when applied for the detection of PbTx-1 in spiked shellfish samples. We strongly believe that this innovative aptasensor offers a promising alternative to traditional immunological methods for the specific and reliable detection of PbTx-1. Full article

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

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14 pages, 2748 KiB

Open AccessArticle

Identification of New Angiotensin-Converting Enzyme Inhibitory Peptides Isolated from the Hydrolysate of the Venom of Nemopilema nomurai Jellyfish

by Ramachandran Loganathan Mohan Prakash, Deva Asirvatham Ravi, Du Hyeon Hwang, Changkeun Kang and Euikyung Kim

Toxins 2024, 16(9), 410; https://doi.org/10.3390/toxins16090410 - 20 Sep 2024

Abstract

Recently, jellyfish venom has gained attention as a promising reservoir of pharmacologically active compounds, with potential applications in new drug development. In this investigation, novel peptides, isolated from the hydrolysates of Nemopilema nomurai jellyfish venom (NnV), demonstrate potent inhibitory activities against angiotensin-converting enzyme [...] Read more.

Recently, jellyfish venom has gained attention as a promising reservoir of pharmacologically active compounds, with potential applications in new drug development. In this investigation, novel peptides, isolated from the hydrolysates of Nemopilema nomurai jellyfish venom (NnV), demonstrate potent inhibitory activities against angiotensin-converting enzyme (ACE). Proteolytic enzymes—specifically, papain and protamex—were utilized for the hydrolysis under optimized enzymatic conditions, determined by assessing the degree of hydrolysis through the ninhydrin test. Comparative analyses revealed that papain treatment exhibited a notably higher degree of NnV hydrolysis compared to protamex treatment. ACE inhibitory activity was quantified using ACE kit-WST, indicating a substantial inhibitory effect of 76.31% for the papain-digested NnV crude hydrolysate, which was validated by captopril as a positive control. The separation of the NnV-hydrolysate using DEAE sepharose weak-anion-exchange chromatography revealed nine peaks under a 0–1 M NaCl stepwise gradient, with peak no. 3 displaying the highest ACE inhibition of 96%. The further purification of peak no. 3 through ODS-C18 column reverse-phase high-performance liquid chromatography resulted in five sub-peaks (3.1, 3.2, 3.3, 3.4, and 3.5), among which 3.2 exhibited the most significant inhibitory activity of 95.74%. The subsequent analysis of the active peak (3.2) using MALDI–TOF/MS identified two peptides with distinct molecular weights of 896.48 and 1227.651. The peptide sequence determined by MS/MS analysis revealed them as IVGRPLANG and IGDEPRHQYL. The docking studies of the two ACE-inhibitory peptides for ACE molecule demonstrated a binding affinity of −51.4 ± 2.5 and −62.3 ± 3.3 using the HADDOCK scoring function. Full article

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

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