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Toxins
Volume 16
Issue 12
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Toxins, Volume 16, Issue 12 (December 2024) – 51 articles

Cover Story (view full-size image): Epsilon toxin (ETX) from Clostridium perfringens is a pore-forming toxin (PFT) capable of crossing the blood–brain barrier and binding to myelin structures. In vitro assays demonstrate that ETX impairs oligodendrocytes, leading to demyelination. The myelin and lymphocyte protein (MAL) is widely recognized as the receptor for ETX, as its presence is essential for ETX-mediated pore formation in host-cell plasma membranes. Certain cells produce extracellular vesicles (EVs) to mitigate pore formation by some PFTs. In this study, we observed that ETX induces EV formation in HeLa cells overexpressing the MAL-GFP protein. Notably, the MAL protein and ETX oligomers are present in these EVs, providing valuable insights into the mode of action of ETX and its interaction with its receptor. View this paper
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12 pages, 1541 KiB  
Communication
Machine Learning for Predicting Zearalenone Contamination Levels in Pet Food
by Zhenlong Wang, Wei An, Jiaxue Wang, Hui Tao, Xiumin Wang, Bing Han and Jinquan Wang
Toxins 2024, 16(12), 553; https://doi.org/10.3390/toxins16120553 - 23 Dec 2024
Viewed by 790
Abstract
Zearalenone (ZEN) has been detected in both pet food ingredients and final products, causing acute toxicity and chronic health problems in pets. Therefore, the early detection of mycotoxin contamination in pet food is crucial for ensuring the safety and well-being of animals. This [...] Read more.
Zearalenone (ZEN) has been detected in both pet food ingredients and final products, causing acute toxicity and chronic health problems in pets. Therefore, the early detection of mycotoxin contamination in pet food is crucial for ensuring the safety and well-being of animals. This study aims to develop a rapid and cost-effective method using an electronic nose (E-nose) and machine learning algorithms to predict whether ZEN levels in pet food exceed the regulatory limits (250 µg/kg), as set by Chinese pet food legislation. A total of 142 pet food samples from various brands, collected between 2021 and 2023, were analyzed for ZEN contamination via liquid chromatography–tandem mass spectrometry. Additionally, the “AIR PEN 3” E-nose, equipped with 10 metal oxide sensors, was employed to identify volatile compounds in the pet food samples, categorized into 10 different groups. Machine learning algorithms, including liner regression, k-nearest neighbors, support vector machines, random forests, XGBoost, and multi-layer perceptron (MLP), were used to classify the samples based on their volatile profiles. The MLP algorithm showed the highest discrimination accuracy at 86.6% in differentiating between pet food samples above and below the ZEN threshold. Other algorithms showed moderate accuracy, ranging from 77.1% to 84.8%. The ensemble model, which combined the predictions from all classifiers, further improved the classification performance, achieving the highest accuracy at 90.1%. These results suggest that the combination of E-nose technology and machine learning provides a rapid, cost-effective approach for screening ZEN contamination in pet food at the market entry stage. Full article
(This article belongs to the Special Issue Toxicity Assessment, Rapid Detection and Control of Foodborne Mycotoxins: Advances and Prospects)
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7 pages, 269 KiB  
Article
Food Confusion Between Edible and Poisonous Plants: A 22-Year Retrospective of the Southeastern France Poison Control Center
by Romain Torrents, Julien Reynoard, Mathieu Glaizal, Corinne Schmitt, Katharina Von Fabeck, Audrey Boulamery, Luc De Haro and Nicolas Simon
Toxins 2024, 16(12), 552; https://doi.org/10.3390/toxins16120552 - 21 Dec 2024
Viewed by 571
Abstract
Objective: In some regions of the globe, accidental food confusion regarding plants can cause severe poisoning events and deaths. The aim of this study was to report on those confusions from the Marseille Poison Control Centre’s (PCC) experience from 2002 to 2023. Results: [...] Read more.
Objective: In some regions of the globe, accidental food confusion regarding plants can cause severe poisoning events and deaths. The aim of this study was to report on those confusions from the Marseille Poison Control Centre’s (PCC) experience from 2002 to 2023. Results: Over 22 years, 2197 food confusion events were managed with 321 different species. The most frequently involved plant was Nerium oleander (289 cases, 13.1%), then Cucurbitaceae genus (3.3%), Colchicum autumnale (3.3%), Prunus amygdalus (3%), Mahinot esculenta (3%), Cytisus laburnum (2.6%), Aesculus hippocastanum (2.5%) and Narcissus Jonquilla (2%). Many botanical confusion events were also reported (n = 1386, 63%), but with fewer than five identical species. Only one death was reported for this review, in an event involving Aconitum napellus. Two antidotes were used for all the series: Datura genus and Prunus dulcis. Discussion: The most implicated plant was Nerium oleander. This is explained by its distribution. This rate is very low compared to that of suicide attempts with this plant. Many cases were symptomatic (53.6%), but very few of them described severe symptoms (only 0.5% severe poisonings). Few patients needed to be admitted to intensive care (0.4%), and even fewer needed an antidote (two cases). Only one death occurred, involving Aconitum napellus. Food confusions were more common than suicide attempts with plants, but seem to be less severe. However, death and serious complications can occur, so it is important to identify and manage the plants concerned. Material and Methods: For each food confusion event managed between 2002 and 2023 at the Southeastern France PCC based in Marseille, we performed a retrospective review. This PCC is responsible for the Provence–Alpes–Côte d’Azur Region, Corsica Island and Indian Ocean French overseas territories. For each case, severity was calculated with the Poison Severity Score (PSS). Full article
(This article belongs to the Section Plant Toxins)
19 pages, 2438 KiB  
Review
Lesser-Known Cyanotoxins: A Comprehensive Review of Their Health and Environmental Impacts
by Molham Al Haffar, Ziad Fajloun, Sami Azar, Jean-Marc Sabatier and Ziad Abi Khattar
Toxins 2024, 16(12), 551; https://doi.org/10.3390/toxins16120551 - 19 Dec 2024
Viewed by 1274
Abstract
Cyanobacteria, also known as blue-green algae, are a diverse phylum of photosynthetic, Gram-negative bacteria and one of the largest microbial taxa. These organisms produce cyanotoxins, which are secondary metabolites that can have significant impacts on both human health and the environment. While toxins [...] Read more.
Cyanobacteria, also known as blue-green algae, are a diverse phylum of photosynthetic, Gram-negative bacteria and one of the largest microbial taxa. These organisms produce cyanotoxins, which are secondary metabolites that can have significant impacts on both human health and the environment. While toxins like Microcystins and Cylindrospermopsins are well-documented and have been extensively studied, other cyanotoxins, including those produced by Lyngbya and Nostoc, remain underexplored. These lesser-known toxins can cause various health issues in humans, including neurotoxicity, hepatotoxicity, and dermatotoxicity, each through distinct mechanisms. Moreover, recent studies have shown that cyanobacteria can be aerosolized and transmitted through the air over long distances, providing an additional route for human exposure to their harmful effects. However, it remains an area that requires much more investigation to accurately assess the health risks and develop appropriate public health guidelines. In addition to direct exposure to toxins, cyanobacteria can lead to harmful algal blooms, which pose further risks to human and wildlife health, and are a global concern. There is limited knowledge about these lesser-known cyanotoxins, highlighting the need for further research to understand their clinical manifestations and improve society’s preparedness for the associated health risks. This work aims to review the existing literature on these underexplored cyanotoxins, which are associated with human intoxication, elucidate their clinical relevance, address significant challenges in cyanobacterial research, and provide guidance on mitigating their adverse effects. Full article
(This article belongs to the Special Issue Advances in Cyanotoxins: Latest Developments in Risk Assessment)
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14 pages, 1375 KiB  
Article
The Effect of Purified Opharin Isolated from the Venom of King Cobra (Ophiophagus hannah) in Modulating Macrophage Inflammatory Responses and Vascular Integrity
by Tuchakorn Lertwanakarn, Armando Reyes, Emelyn Salazar, Martha Barrientos, Elda E. Sanchez and Montamas Suntravat
Toxins 2024, 16(12), 550; https://doi.org/10.3390/toxins16120550 - 19 Dec 2024
Viewed by 686
Abstract
King cobra (Ophiophagus hannah) venom comprises a diverse array of proteins and peptides. However, the roles and properties of these individual components are still not fully understood. Among these, Cysteine-rich secretory proteins (CRiSPs) are recognized but not fully characterized. This study [...] Read more.
King cobra (Ophiophagus hannah) venom comprises a diverse array of proteins and peptides. However, the roles and properties of these individual components are still not fully understood. Among these, Cysteine-rich secretory proteins (CRiSPs) are recognized but not fully characterized. This study investigates the biological effects of Opharin, the CRiSP from king cobra venom (KCV). The effects of Opharin on cytokine production, specifically on IL-1β, IL-6, IL-8, TNF-α, and IL-10 release, were evaluated over 24 h in monocyte-derived macrophage (MDM) cells. Notably, the levels of these inflammatory cytokines were significantly increased over 24 h, with values higher than those observed in cells treated with crude KCV at most time points. Additionally, the in vivo Miles assay in mice revealed that Opharin increased vascular permeability by 26% compared to the negative control group. These findings highlight the Opharin’s role in severe inflammatory and vascular responses observed in king cobra envenomation. Still, further research is essential to elucidate the pharmacological and toxicological effects of venom components, ultimately enhancing the clinical management of envenomation. Full article
(This article belongs to the Special Issue Advances in Venom Research: Biological Activities, Therapeutic Potential, and Molecular Mechanism)
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14 pages, 4733 KiB  
Article
Rice Straw-Derived Biochar Mitigates Microcystin-LR-Induced Hepatic Histopathological Injury and Oxidative Damage in Male Zebrafish via the Nrf2 Signaling Pathway
by Wang Lin, Fen Hu, Wansheng Zou, Suqin Wang, Pengling Shi, Li Li, Jifeng Yang and Pinhong Yang
Toxins 2024, 16(12), 549; https://doi.org/10.3390/toxins16120549 - 18 Dec 2024
Viewed by 826
Abstract
Microcystin-leucine arginine (MC-LR) poses a serious threat to aquatic animals during cyanobacterial blooms. Recently, biochar (BC), derived from rice straw, has emerged as a potent adsorbent for eliminating hazardous contaminants from water. To assess the joint hepatotoxic effects of environmentally relevant concentrations of [...] Read more.
Microcystin-leucine arginine (MC-LR) poses a serious threat to aquatic animals during cyanobacterial blooms. Recently, biochar (BC), derived from rice straw, has emerged as a potent adsorbent for eliminating hazardous contaminants from water. To assess the joint hepatotoxic effects of environmentally relevant concentrations of MC-LR and BC on fish, male adult zebrafish (Danio rerio) were sub-chronically co-exposed to varying concentrations of MC-LR (0, 1, 5, and 25 μg/L) and BC (0 and 100 μg/L) in a fully factorial experiment. After 30 days exposure, our findings suggested that the existence of BC significantly decreased MC-LR bioavailability in liver. Furthermore, histopathological analysis revealed that BC mitigated MC-LR-induced hepatic lesions, which were characterized by mild damage, such as vacuolization, pyknotic nuclei, and swollen mitochondria. Compared to the groups exposed solely to MC-LR, decreased malondialdehyde (MDA) and increased catalase (CAT) and superoxide dismutase (SOD) were noticed in the mixture groups. Concurrently, significant changes in the mRNA expression levels of Nrf2 pathway genes (cat, sod1, gstr, keap1a, nrf2a, and gclc) further proved that BC reduces the oxidative damage induced by MC-LR. These findings demonstrate that BC decreases MC-LR bioavailability in the liver, thereby alleviating MC-LR-induced hepatotoxicity through the Nrf2 signaling pathway in zebrafish. Our results also imply that BC could serve as a potentially environmentally friendly material for mitigating the detrimental effects of MC-LR on fish. Full article
(This article belongs to the Special Issue Toxic Cyanobacterial Bloom Detection and Removal: What's New?)
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12 pages, 4369 KiB  
Communication
Brefeldin A—A Major Pathogenic Factor of Peanut Pod Rot from Fusarium neocosmosporiellum
by Huiling Wang, Xiaohan Wang, Huiling Han, Quanlin Yu, Xinmiao Tan, Junlong Liu, Yiting Zhao and Weiming Sun
Toxins 2024, 16(12), 548; https://doi.org/10.3390/toxins16120548 - 18 Dec 2024
Viewed by 589
Abstract
Fusarium neocosmosporiellum is the main pathogen of peanut pod rot in China. To investigate the type of F. neocosmosporiellum toxin and its pathogenic mechanism, a macrolide, brefeldin A, was isolated. The structure of the compound was identified by 1D and 2D nuclear magnetic [...] Read more.
Fusarium neocosmosporiellum is the main pathogen of peanut pod rot in China. To investigate the type of F. neocosmosporiellum toxin and its pathogenic mechanism, a macrolide, brefeldin A, was isolated. The structure of the compound was identified by 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization–mass spectrometry (HR-ESI-MS). At the same time, the content of the compound in healthy and diseased peanut capsules was detected, and its plant toxicity to radish, mung bean, rice, and peanut seed radicle elongation and pathogenicity to peanut pod rot were evaluated. The results showed that brefeldin A at 50 μg/mL could significantly inhibit the radicle elongation of rice seeds. Brefeldin A was detected only in pods with peanut rot. Injecting 2 mg/mL brefeldin A solution into peanut pods caused the severe decay of peanut pods at the R3R4 stage, which is consistent with the symptoms of peanut rot. Full article
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10 pages, 290 KiB  
Article
Ochratoxin A and AFM1 in Cheese and Cheese Substitutes: LC-MS/MS Method Validation, Natural Occurrence, and Risk Assessment
by María Agustina Pavicich, Stefano Compagnoni, Celine Meerpoel, Katleen Raes and Sarah De Saeger
Toxins 2024, 16(12), 547; https://doi.org/10.3390/toxins16120547 - 18 Dec 2024
Viewed by 740
Abstract
Cheese is vulnerable to contamination with mycotoxins, particularly ochratoxin A (OTA) and aflatoxin M1 (AFM1). This study aims to develop and validate an analytical method for the detection and quantification of OTA and AFM1 in cheese and to assess their prevalence and associated [...] Read more.
Cheese is vulnerable to contamination with mycotoxins, particularly ochratoxin A (OTA) and aflatoxin M1 (AFM1). This study aims to develop and validate an analytical method for the detection and quantification of OTA and AFM1 in cheese and to assess their prevalence and associated risks. A liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was validated for detecting these mycotoxins in 41 cheese samples, including firm-ripened, spreadable, and plant-based alternatives. The results showed that OTA was detected exclusively in grated Parmigiano Reggiano cheese, while AFM1 was found in both Parmigiano Reggiano and Pecorino cheeses. This study goes beyond analytical method development by providing a preliminary exposure assessment and risk characterization for OTA and AFM1 in cheese, bridging the gap between analytical chemistry and public health implications. This study identified potential health risks associated with OTA, particularly for children and adolescents categorized as high consumers of Parmigiano Reggiano cheese. The findings underscore the need for monitoring of OTA and AFM1 in cheese and further research to establish regulatory limits for these contaminants. Full article
(This article belongs to the Special Issue Advances in Contamination, Detection and Risk Assessment of Mycotoxins)
14 pages, 2413 KiB  
Systematic Review
Treatment with OnabotulinumtoxinA for Oromandibular Dystonia: A Systematic Review and Meta-Analysis
by Kazuya Yoshida and Ryuji Kaji
Toxins 2024, 16(12), 546; https://doi.org/10.3390/toxins16120546 - 16 Dec 2024
Viewed by 826
Abstract
Oromandibular dystonia (OMD) is a focal dystonia characterized by contractions of the masticatory, lingual, and other muscles of the stomatognathic system. We conducted a systematic review and meta-analysis to elucidate the impact and safety of botulinum toxin in OMD. The eligibility criteria were [...] Read more.
Oromandibular dystonia (OMD) is a focal dystonia characterized by contractions of the masticatory, lingual, and other muscles of the stomatognathic system. We conducted a systematic review and meta-analysis to elucidate the impact and safety of botulinum toxin in OMD. The eligibility criteria were full-length original articles that provided data evaluating the efficacy and adverse effects of onabotulinumtoxinA injections in patients with OMD. PubMed and Embase were searched for articles published before 31 May 2023. We analyzed cases that showed a favorable response (>0% improvement), moderate or greater response (>50% improvement), and adverse effects. A fixed-model meta-analysis of 26 studies involving 1103 patients revealed that an overall favorable effect of onabotulinumtoxinA injection was observed in 96.2% (95% confidence interval [CI], 95–97.5%, p < 0.00001) of patients, with significant heterogeneity (p < 0.00001, I2 = 85%). A moderate response (>50% improvement) was observed in 88.9% of patients (95% CI, 87–90.8%, p < 0.00001) with significant heterogeneity (p < 0.00001, I2 = 85%). Adverse effects were detected in 17.8% of patients, and the most common event was dysphagia (10.1%). Our systematic review found that onabotulinumtoxinA injection was effective, with a low rate of side effects. Further randomized controlled trials are required to clarify the evidence-based efficacy and adverse effects. Full article
(This article belongs to the Special Issue Botulinum Toxin Therapy for Diseases in the Oral and Maxillofacial Regions)
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10 pages, 1876 KiB  
Article
The Choice of Anti-Inflammatory Influences the Elimination of Protein-Bound Uremic Toxins
by Víctor Joaquín Escudero-Saiz, Elena Cuadrado-Payán, María Rodriguez-Garcia, Gregori Casals, Lida María Rodas, Néstor Fontseré, María del Carmen Salgado, Carla Bastida, Nayra Rico, José Jesús Broseta and Francisco Maduell
Toxins 2024, 16(12), 545; https://doi.org/10.3390/toxins16120545 - 16 Dec 2024
Viewed by 666
Abstract
Pain is a frequent and disturbing symptom among hemodialysis patients. Protein-bound uremic toxins (PBUTs) are related to cardiovascular and overall mortality, and they are difficult to remove with current hemodialysis treatments. The PBUT displacers, such as furosemide, tryptophan, or ibuprofen, may be promising [...] Read more.
Pain is a frequent and disturbing symptom among hemodialysis patients. Protein-bound uremic toxins (PBUTs) are related to cardiovascular and overall mortality, and they are difficult to remove with current hemodialysis treatments. The PBUT displacers, such as furosemide, tryptophan, or ibuprofen, may be promising new strategies for improving their clearance. This study aims to compare ibuprofen versus other analgesic drugs in PBUT removal. A prospective study was carried out in 23 patients. Patients underwent four dialysis sessions with routine dialysis parameters, except for analgesic drugs administered (lysine acetylsalicylic acid, acetaminophen, dexketoprofen, and ibuprofen). The reduction ratios (RRs) of a wide range of molecular weight molecules were assessed, including total p-cresyl sulfate and total indoxyl-sulfate. There were no complications related to the administered drug, and pain was controlled independently of the drug. There were no differences in the RR of small-size and medium-sized molecules between all four study treatments. However, indoxyl sulfate and p-cresyl sulfate RRs when ibuprofen was administered were significantly higher than lysine acetylsalicylic acid, acetaminophen, and dexketoprofen treatments. In conclusion, patients with pain may benefit from treatment with ibuprofen instead of lysine acetylsalicylic acid, paracetamol, or dexketoprofen, since in addition to improving pain, it increases the removal of PBUTs. Full article
(This article belongs to the Section Uremic Toxins)
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18 pages, 4767 KiB  
Article
The Ability of AST-120 to Lower the Serum Indoxyl Sulfate Level Improves Renal Outcomes and the Lipid Profile in Diabetic and Nondiabetic Animal Models of Chronic Kidney Disease: A Meta-Analysis
by Hande O. Altunkaynak, Eda Karaismailoglu and Ziad A. Massy
Toxins 2024, 16(12), 544; https://doi.org/10.3390/toxins16120544 - 16 Dec 2024
Viewed by 968
Abstract
The therapeutic benefit of the oral adsorbent drug AST-120 in chronic kidney disease (CKD) is related to an indoxyl sulfate (IS)-lowering action. Diabetes and dyslipidemia might worsen kidney damage in CKD. However, it is not known whether AST-120 influences lipid abnormalities as well [...] Read more.
The therapeutic benefit of the oral adsorbent drug AST-120 in chronic kidney disease (CKD) is related to an indoxyl sulfate (IS)-lowering action. Diabetes and dyslipidemia might worsen kidney damage in CKD. However, it is not known whether AST-120 influences lipid abnormalities as well as renal function in patients with CKD and diabetes. The objective of the present meta-analysis was to evaluate the efficacy of AST-120 treatment in CKD using data from preclinical studies. Mixed-effect or random-effect models were used to estimate the standardized mean difference (SMD) and the 95% confidence interval (CI). Publication bias was assessed with a funnel plot and Egger’s test. The potential influence of some variables (the dose and duration of AST-120 treatment, the animal species, and the CKD model’s diabetic status) was evaluated in subgroup analyses. Treatment with AST-120 was associated with a significantly lower IS level in animals with CKD (SMD = −1.75; 95% CI = −2.00, −1.49; p < 0.001). Significant improvements in markers of renal function and the lipid profile were also observed. In subgroup analyses of the cholesterol level, the diabetic status, the AST-120 dose, and the animal species were found to be influential factors. AST-120 lowered serum IS and triglyceride levels and improved renal function in animal models of CKD independent of diabetes status. However, AST-120’s ability to lower the total cholesterol level was more prominent in animals with diabetic CKD. Full article
(This article belongs to the Special Issue The Role of Uremic Toxins in Comorbidities of Chronic Kidney Disease)
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15 pages, 23082 KiB  
Article
Reduction in Renal Heme Oxygenase-1 Is Associated with an Aggravation of Kidney Injury in Shiga Toxin-Induced Murine Hemolytic-Uremic Syndrome
by Antonio N. Mestekemper, Wiebke Pirschel, Nadine Krieg, Maria K. Paulmann, Christoph Daniel, Kerstin Amann and Sina M. Coldewey
Toxins 2024, 16(12), 543; https://doi.org/10.3390/toxins16120543 - 14 Dec 2024
Viewed by 950
Abstract
Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the [...] Read more.
Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by Hmox1) in HUS has not yet been investigated. We hypothesized that HO-1, also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced Hmox1 gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced Hmox1 gene deletion (Hmox1R26Δ/Δ) and control mice (Hmox1lox/lox). This HO-1 induction was significantly lower (−43%) in Hmox1R26Δ/Δ mice compared to Hmox1lox/lox mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase (p = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase (p = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS. Full article
(This article belongs to the Section Bacterial Toxins)
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12 pages, 543 KiB  
Article
Microcystins Exposure and the Risk of Metabolic Syndrome: A Cross-Sectional Study in Central China
by Shuidong Feng, Yuke Zeng, Fengmei Song, Minxue Shen and Fei Yang
Toxins 2024, 16(12), 542; https://doi.org/10.3390/toxins16120542 - 14 Dec 2024
Viewed by 639
Abstract
A growing body of evidence indicates that microcystins (MCs) exposure may cause metabolic diseases. However, studies exploring the effects of MCs exposure on the risk of metabolic syndrome (MetS) in humans are currently lacking, and the underlying mechanisms remain unclear. Here, we conducted [...] Read more.
A growing body of evidence indicates that microcystins (MCs) exposure may cause metabolic diseases. However, studies exploring the effects of MCs exposure on the risk of metabolic syndrome (MetS) in humans are currently lacking, and the underlying mechanisms remain unclear. Here, we conducted a cross-sectional study in central China to explore the effect of serum MCs on MetS, and assessed the mediation effects of the inflammation biomarker, white blood cell (WBC) level, in this relationship. The relationships among MCs and WBC level and risk of MetS were assessed using binary logistic and linear regression. Mediation analysis was used to explore possible mechanisms underlying those associations by employing R software (version 4.3.1). Compared to the lowest quartile of MCs, the highest quartile had an increased risk of MetS (odds ratio [OR] = 2.10, 95% confidence interval [CI]: 1.19, 3.70), with a dose–response relationship (p for trend < 0.05). WBCs mediated 11.14% of the association between serum MCs and triglyceride (TG) levels, but did not mediate the association of MCs exposure with MetS. This study firstly reveals that MCs exposure is an independent risk factor for MetS in a dose–response manner, and suggests that WBC level could partially mediate the association of MCs exposure with TG levels. Full article
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17 pages, 1482 KiB  
Article
Assessment of the Effects of Anatoxin-a In Vitro: Cytotoxicity and Uptake
by Cristina Plata-Calzado, Ana I. Prieto, Ana M. Cameán and Angeles Jos
Toxins 2024, 16(12), 541; https://doi.org/10.3390/toxins16120541 - 13 Dec 2024
Viewed by 924
Abstract
Anatoxin-a (ATX-a) is a cyanotoxin whose toxicological profile has been underinvestigated in comparison to other cyanotoxins such as microcystins (MCs) or cylindrospermopsin (CYN). However, its wide distribution, occurrence, and toxic episodes justify more attention. It is classified as a neurotoxin, but it has [...] Read more.
Anatoxin-a (ATX-a) is a cyanotoxin whose toxicological profile has been underinvestigated in comparison to other cyanotoxins such as microcystins (MCs) or cylindrospermopsin (CYN). However, its wide distribution, occurrence, and toxic episodes justify more attention. It is classified as a neurotoxin, but it has also been reported to affect other organs and systems. Thus, the aim of this study was to establish, as a first tier in its toxicological evaluation, its cytotoxicity in a wide range of cell lines representative of potential target organs (N2a, SH-SY5Y, HepG2, Caco2, L5178Y Tk+/−, THP-1 and Jurkat). As limited effects were observed after exposure to up to 200 µg/mL of ATX-a for 24 h (only Jurkat and THP-1 cells showed reduced cell viability), cell uptake experiments were performed by ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS). The results showed that the immune system cells had the highest percentage of ATX-a in the intracellular fraction, followed by neuronal cells and finally Caco-2 and HepG2 cells. Moreover, the expression of genes related to cell death mechanisms in THP-1 cells was also analyzed by polymerase chain reaction (PCR) and showed no changes under the conditions tested. Further research is required on ATX-a’s toxic effects and toxicokinetics to contribute to its risk assessment. Full article
(This article belongs to the Special Issue Advances in Cyanotoxins: Latest Developments in Risk Assessment)
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17 pages, 19758 KiB  
Article
The Protein Engineering of Zearalenone Hydrolase Results in a Shift in the pH Optimum of the Relative Activity of the Enzyme
by Anna Dotsenko, Igor Sinelnikov, Ivan Zorov, Yury Denisenko, Aleksandra Rozhkova and Larisa Shcherbakova
Toxins 2024, 16(12), 540; https://doi.org/10.3390/toxins16120540 - 13 Dec 2024
Viewed by 823
Abstract
An acidic shift in the pH profile of Clonostachys rosea zearalenone hydrolase (ZHD), the most effective and well-studied zearalenone-specific lactone hydrolase, is required to extend the range of applications for the enzyme as a decontamination agent in the feed and food production industries. [...] Read more.
An acidic shift in the pH profile of Clonostachys rosea zearalenone hydrolase (ZHD), the most effective and well-studied zearalenone-specific lactone hydrolase, is required to extend the range of applications for the enzyme as a decontamination agent in the feed and food production industries. Amino acid substitutions were engineered in the active center of the enzyme to decrease the pKa values of the catalytic residues E126 and H242. The T216K substitution provided a shift in the pH optimum by one unit to the acidic region, accompanied by a notable expansion in the pH profile under acidic conditions. The engineered enzyme demonstrated enhanced activity within the pH range of 3–5 and improved the activity within the pH ranging from 6 to 10. The D31N and D31A substitutions also resulted in a two-unit shift in the pH optimum towards acidic conditions, although this was accompanied by a significant reduction in the enzyme activity. The D31S substitution resulted in a shift in the pH profile towards the alkaline region. The alterations in the enzyme properties observed following the T216K substitution were consistent with the conditions required for the ZHD application as decontamination enzymes at acidic pH values (from 3.0 to 6.0). Full article
(This article belongs to the Special Issue Occurrence, Toxicity, Metabolism, Analysis and Control of Mycotoxins)
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20 pages, 3277 KiB  
Article
Variations in Kojic Acid Production and Corn Infection Among Aspergillus flavus Isolates Suggest a Potential Role as a Virulence Factor
by Rebecca R. Sweany, Matthew K. Gilbert, Carol H. Carter-Wientjes, Geromy G. Moore and Matthew D. Lebar
Toxins 2024, 16(12), 539; https://doi.org/10.3390/toxins16120539 - 13 Dec 2024
Viewed by 1075
Abstract
Kojic acid is a secondary metabolite with strong chelating and antioxidant properties produced by Aspergillus flavus and A. oryzae. Although antioxidants and chelators are important virulence factors for plant pathogens, the ecological role of kojic acid remains unclear. We previously observed a [...] Read more.
Kojic acid is a secondary metabolite with strong chelating and antioxidant properties produced by Aspergillus flavus and A. oryzae. Although antioxidants and chelators are important virulence factors for plant pathogens, the ecological role of kojic acid remains unclear. We previously observed a greater gene expression of antioxidants, especially kojic acid, by non-aflatoxigenic A. flavus when co-cultured with aflatoxigenic A. flavus. Aflatoxin production was also reduced. In this study, we investigated kojic acid production in 22 A. flavus isolates from Louisiana and compared them to four common A. flavus strains in liquid medium and on corn kernels. Corn kernel infection was assessed by quantifying the maize beta tubulin DNA content of the kernels using drop digital PCR (ddPCR). Maize beta tubulin DNA content decreased with increased corn kernel infection. Greater kojic acid production by A. flavus isolates coincided with greater levels of corn kernel infection. All isolates produced 60 and 700 times more kojic acid than aflatoxin and cyclopiazonic acid (a known virulence factor), respectively, which varied among sclerotial size categories. A. flavus strains with small sclerotia, which were rarely isolated from corn, produced the least kojic acid and infected corn kernels the least, while medium and large sclerotia strains—mainly isolated from corn—produced the most kojic acid and were more infectious. Non-aflatoxigenic isolates from Louisiana produced the most kojic acid. These results suggest that kojic acid is a potential virulence factor and may increase the pathogenic success of medium and large sclerotia-producing A. flavus, which could ultimately lead to more effective A. flavus biocontrol strains. Further studies are required to determine the effects that kojic acid has on the redox environment during corn infection and how the altered redox environment decreases aflatoxin production. Full article
(This article belongs to the Special Issue Toxicity, Mitigation and Chemical Analysis of Aflatoxins and Other Toxic Metabolites Produced by Aspergillus)
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16 pages, 14718 KiB  
Article
Repair of Retrorsine-Induced DNA Damage in Rat Livers: Insights Gained from Transcriptomic and Proteomic Studies
by Yun Long, Yiwei Wang, Zijing Song, Xin He, Yisheng He and Ge Lin
Toxins 2024, 16(12), 538; https://doi.org/10.3390/toxins16120538 - 13 Dec 2024
Viewed by 717
Abstract
Pyrrolizidine alkaloids (PAs) are common phytotoxins that are found worldwide. Upon hepatic metabolic activation, the reactive PA metabolites covalently bind to DNAs and form DNA adducts, causing mutagenicity and tumorigenicity in the liver. However, the molecular basis of the formation and removal of [...] Read more.
Pyrrolizidine alkaloids (PAs) are common phytotoxins that are found worldwide. Upon hepatic metabolic activation, the reactive PA metabolites covalently bind to DNAs and form DNA adducts, causing mutagenicity and tumorigenicity in the liver. However, the molecular basis of the formation and removal of PA-derived DNA adducts remains largely unexplored. In the present study, Sprague Dawley (SD) rats were exposed to retrorsine (RTS), a representative PA, at a human-relevant dose of 3.3 mg/kg/day for 28 days. The rats were divided into three groups: control, RTS-28 (sacrificed after continuous RTS exposure), and RTS-161 (sacrificed at 133 days post-RTS-exposure). The multi-omics analyses demonstrated the involvement of homologous recombination (HR) and non-homologous end joining (NHEJ) repair pathways as a response to PA-induced DNA damage. Additionally, the characteristic guanine adducts induced by RTS exposure were in accordance with the higher expression of XPA and XPC, indicating that nucleotide excision repair (NER) and base excision repair (BER) also contributed to repairing RTS-induced DNA damage. Furthermore, we also showed that DNA damage persisted after PA exposure, and mutagenically related repair errors might occur due to the prolonged genotoxic effects. The present study lays the foundation for bridging PA-derived DNA adducts, DNA damage, DNA repair, and the follow-up mutagenesis and carcinogenesis associated with PA exposure. Full article
(This article belongs to the Special Issue Plant Toxin Emergency)
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19 pages, 5894 KiB  
Article
Application of Pulsed Electric Field During Malting: Impact on Fusarium Species Growth and Mycotoxin Production
by Nela Prusova, Marcel Karabin, Lukas Jelinek, Jana Chrpova, Jaroslava Ovesna, Pavel Svoboda, Tereza Dolezalova, Adam Behner, Jana Hajslova and Milena Stranska
Toxins 2024, 16(12), 537; https://doi.org/10.3390/toxins16120537 - 12 Dec 2024
Cited by 1 | Viewed by 748
Abstract
The increasing contamination of cereals by micromycetes and mycotoxins during malting still poses an unresolved food safety problem. This study characterises the potential of the novel, rapidly developing food production technology of Pulsed Electric Field (PEF) to reduce the viability of Fusarium fungi [...] Read more.
The increasing contamination of cereals by micromycetes and mycotoxins during malting still poses an unresolved food safety problem. This study characterises the potential of the novel, rapidly developing food production technology of Pulsed Electric Field (PEF) to reduce the viability of Fusarium fungi and the production of mycotoxins during malting. Barley, artificially inoculated with four Fusarium species, was treated by PEF with two different intensities and then malted using a standard Pilsner-type technology. Concentrations of fungi were quantified by RT-PCR, expression of fungal growth-related genes was assessed using mRNA sequencing, and mycotoxin levels were analysed by U-HPLC-HRMS/MS. Despite the different trends for micromycetes and mycotoxins after application of variously intense PEF conditions, significant reductions were generally observed. The greatest decrease was for F. sporotrichioides and F. poae, where up to six fold lower levels were achieved for malts produced from the PEF-treated barley when compared to the control. For F. culmorum and F. graminearum, up to a two-fold reduction in the PEF-generated malts was observed. These reductions mostly correlated with a decrease in relevant mycotoxins, specifically type A trichothecenes. Full article
(This article belongs to the Section Mycotoxins)
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17 pages, 1879 KiB  
Article
Degradation of Cylindrospermopsin Spiked in Natural Water (Paranoá Lake, Brasília, Brazil) by Fenton Process: A Bench–Scale Study
by Matheus Almeida Ferreira, Cristina Celia Silveira Brandão and Yovanka Pérez Ginoris
Toxins 2024, 16(12), 536; https://doi.org/10.3390/toxins16120536 - 12 Dec 2024
Viewed by 600
Abstract
The frequency and intensity of harmful cyanobacterial blooms have increased in the last decades, posing a risk to public health since conventional water treatments do not effectively remove extracellular cyanotoxins. Consequently, advanced technologies such as the Fenton process are required to ensure water [...] Read more.
The frequency and intensity of harmful cyanobacterial blooms have increased in the last decades, posing a risk to public health since conventional water treatments do not effectively remove extracellular cyanotoxins. Consequently, advanced technologies such as the Fenton process are required to ensure water safety. The cyanotoxin cylindrospermopsin (CYN) demands special attention, as it is abundant in the extracellular fraction and has a high toxicological potential. Hence, this study aimed to assess the application of the Fenton process for the oxidation of CYN spiked in natural water from Paranoá Lake (Brasília, Brazil). The H2O2/Fe(II) molar ratio was evaluated from 0.2 to 3.4, with an optimum molar ratio of 0.4, achieving a CYN degradation efficiency of 97.8% when using 100 µM of H2O2 and 250 µM of Fe(II). The CYN degradation efficiency, using 75 µM of H2O2 and 187.5 µM of Fe(II), decreased by increasing the initial pH (from 96.2% at pH 2 to 23.0% at pH 9) and the initial CYN concentration (from 93.7% at 0.05 µM of CYN to 85.0% at 0.2 µM of CYN). At the optimum H2O2/Fe(II) molar ratio of 0.4, the hydroxy radical scavengers tested (124.3 µM C of algogenic organic matter, 5 mg L−1 of humic acid, and 513.3 µM of methanol) did not considerably affect the CYN degradation, reaching a maximum CYN degradation reduction from 98.3% to 82.2%. Full article
(This article belongs to the Special Issue Toxic Cyanobacterial Bloom Detection and Removal: What's New?)
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15 pages, 2588 KiB  
Communication
Quantification of Staphylococcal Enterotoxin A Variants at Low Level in Dairy Products by High-Resolution Top-Down Mass Spectrometry
by Nina Aveilla, Cécile Feraudet-Tarisse, Dominique Marcé, Abdelhak Fatihi, François Fenaille, Jacques-Antoine Hennekinne, Stéphanie Simon, Yacine Nia and François Becher
Toxins 2024, 16(12), 535; https://doi.org/10.3390/toxins16120535 - 11 Dec 2024
Viewed by 760
Abstract
Food poisoning outbreaks frequently involve staphylococcal enterotoxins (SEs). SEs include 33 distinct types and multiple sequence variants per SE type. Various mass spectrometry methods have been reported for the detection of SEs using a conventional bottom-up approach. However, the bottom-up approach cannot differentiate [...] Read more.
Food poisoning outbreaks frequently involve staphylococcal enterotoxins (SEs). SEs include 33 distinct types and multiple sequence variants per SE type. Various mass spectrometry methods have been reported for the detection of SEs using a conventional bottom-up approach. However, the bottom-up approach cannot differentiate between all sequence variants due to partial sequence coverage, and it requires a long trypsin digestion time. While the alternative top-down approach can theoretically identify any sequence modifications, it generally provides lower sensitivity. In this study, we optimized top-down mass spectrometry conditions and incorporated a fully 15N-labeled SEA spiked early in the protocol to achieve sensitivity and repeatability comparable to bottom-up approaches. After robust immunoaffinity purification of the SEA, mass spectrometry signals were acquired on a Q-Orbitrap instrument operated in full-scan mode and targeted acquisition by parallel reaction monitoring (PRM), enabling the identification of sequence variants and precise quantification of SEA. The protocol was evaluated in liquid and solid dairy products and demonstrated detection limits of 0.5 ng/mL or ng/g in PRM and 1 ng/mL or ng/g in full-scan mode for milk and Roquefort cheese. The top-down method was successfully applied to various dairy products, allowing discrimination of contaminated versus non-contaminated food, quantification of SEA level and identification of the variant involved. Full article
(This article belongs to the Section Bacterial Toxins)
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21 pages, 4145 KiB  
Article
Assessing the Potential Synergistic/Antagonistic Effects of Citrinin and Cannabidiol on SH-SY5Y, HepG2, HEK293 Cell Lines, and Human Lymphocytes
by Dubravka Rašić, Antonio Zandona, Maja Katalinić, Martin Češi and Nevenka Kopjar
Toxins 2024, 16(12), 534; https://doi.org/10.3390/toxins16120534 - 11 Dec 2024
Viewed by 829
Abstract
The increasing use of Cannabis sativa products for medicinal, dietary, and recreational purposes has raised concerns about mycotoxin contamination in cannabis and hemp. Mycotoxins persist in these products’ post-processing, posing health risks via multiple exposure routes. This study investigated cytotoxic and genotoxic interactions [...] Read more.
The increasing use of Cannabis sativa products for medicinal, dietary, and recreational purposes has raised concerns about mycotoxin contamination in cannabis and hemp. Mycotoxins persist in these products’ post-processing, posing health risks via multiple exposure routes. This study investigated cytotoxic and genotoxic interactions between cannabidiol (CBD) and the mycotoxin citrinin (CIT) using human cell models: SH-SY5Y, HepG2, HEK293, and peripheral blood lymphocytes. IC50 values and membrane disruption were initially assessed, followed by an evaluation of genotoxicity in lymphocytes using the Comet Assay and Cytokinesis Blocked Micronucleus Cytome Assay. Obtained findings demonstrate that cell-type sensitivity varied across treatments, with combined CBD and CIT exposure exhibiting distinct interactions. Lactate dehydrogenase (LDH) release remained minimal, suggesting cytotoxicity did not stem from membrane disruption but likely involved intracellular pathways. In lymphocytes, CBD alone produced negligible cyto/genotoxic effects and weak antiproliferative responses, whereas CIT displayed clear toxic impacts. DNA damage indicates that CIT may induce genome instability through indirect mechanisms rather than direct DNA interaction, with evidence of potential aneuploidic effects from the CBMN Cyt Assay. Combined exposure led to a reduction in CIT-induced DNA and cytogenetic damage, suggesting CIT’s potential interference with the beneficial properties of CBD. These results provide a foundation for further toxicological assessments and highlight the necessity of standardized mycotoxin monitoring in cannabis-derived products. Full article
(This article belongs to the Special Issue Occurrence, Toxicity, Metabolism, Analysis and Control of Mycotoxins)
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20 pages, 3411 KiB  
Article
Veratridine Induces Vasorelaxation in Mouse Cecocolic Mesenteric Arteries
by Joohee Park, Christina Sahyoun, Jacinthe Frangieh, Léa Réthoré, Coralyne Proux, Linda Grimaud, Emilie Vessières, Jennifer Bourreau, César Mattei, Daniel Henrion, Céline Marionneau, Ziad Fajloun, Claire Legendre and Christian Legros
Toxins 2024, 16(12), 533; https://doi.org/10.3390/toxins16120533 - 10 Dec 2024
Viewed by 1112
Abstract
The vegetal alkaloid toxin veratridine (VTD) is a selective voltage-gated Na+ (NaV) channel activator, widely used as a pharmacological tool in vascular physiology. We have previously shown that NaV channels, expressed in arteries, contribute to vascular tone in mouse [...] Read more.
The vegetal alkaloid toxin veratridine (VTD) is a selective voltage-gated Na+ (NaV) channel activator, widely used as a pharmacological tool in vascular physiology. We have previously shown that NaV channels, expressed in arteries, contribute to vascular tone in mouse mesenteric arteries (MAs). Here, we aimed to better characterize the mechanisms of action of VTD using mouse cecocolic arteries (CAs), a model of resistance artery. Using wire myography, we found that VTD induced vasorelaxation in mouse CAs. This VTD-induced relaxation was insensitive to prazosin, an α1-adrenergic receptor antagonist, but abolished by atropine, a muscarinic receptor antagonist. Indeed, VTD–vasorelaxant effect was totally inhibited by the NaV channel blocker tetrodotoxin (0.3 µM), the NO synthase inhibitor L-NNA (20 µM), and low extracellular Na+ concentration (14.9 mM) and was partially blocked by the NCX1 antagonist SEA0400 (45.4% at 1 µM). Thus, we assumed that the VTD-induced vasorelaxation in CAs was due to acetylcholine release by parasympathetic neurons, which induced NO synthase activation mediated by the NCX1-Ca2+ entry mode in endothelial cells (ECs). We demonstrated NCX1 expression in ECs by RT-qPCR and immunohisto- and western immunolabelling. VTD did not induce an increase in intracellular Ca2+ ([Ca2+]i), while SEA0400 partially blocked acetylcholine-triggered [Ca2+]i elevations in Mile Sven 1 ECs. Altogether, these results illustrate that VTD activates NaV channels in parasympathetic neurons and then vasorelaxation in resistance arteries, which could explain arterial hypotension after VTD intoxication. Full article
(This article belongs to the Special Issue Toxins: From the Wild to the Lab)
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14 pages, 3562 KiB  
Article
Venom from Loxosceles Spiders Collected in Southeastern and Northeastern Brazilian Regions Cause Hemotoxic Effects on Human Blood Components
by Rafaela Silva-Magalhães, Ayla Mel Gomes dos Santos, Ana Luiza Silva-Araújo, Pamella Luize Peres-Damásio, Valéria Gonçalves de Alvarenga, Luciana Souza de Oliveira, Eladio Flores Sanchez, Carlos Chávez-Olórtegui, Luana Silveira da Rocha Nowicki Varela, Ana Luiza Bittencourt Paiva and Clara Guerra-Duarte
Toxins 2024, 16(12), 532; https://doi.org/10.3390/toxins16120532 - 10 Dec 2024
Viewed by 782
Abstract
Spiders of the genus Loxosceles represent a public health problem in Brazil due to the severity of the cutaneous and systemic effects that may result from their bite. In the systemic form of loxoscelism, hemolytic anemia, thrombocytopenia, and disseminated intravascular coagulation can occur. [...] Read more.
Spiders of the genus Loxosceles represent a public health problem in Brazil due to the severity of the cutaneous and systemic effects that may result from their bite. In the systemic form of loxoscelism, hemolytic anemia, thrombocytopenia, and disseminated intravascular coagulation can occur. Despite the seriousness of Loxosceles accidents, the venom of some species has not yet been properly characterized considering these hemotoxic effects, such as that of Loxosceles amazonica, Loxosceles aff. Variegata, and Loxosceles similis. To better understand their toxic potential, this study aimed to characterize the hematotoxic properties of these Loxosceles venoms. The crude venom was obtained from specimens of L. amazonica, L. aff. Variegata, and L. similis available from Funed’s arachnidary. In washed platelets, L. aff. variegata inhibited platelet aggregation induced by collagen and convulxin, whereas L. amazonica and L. similis venoms were able to induce platelet aggregation. In the in vitro hemolysis assays, all venoms experimentally induced direct hemolysis of human erythrocytes in a concentration-dependent manner, with different intensities. Furthermore, evidence suggest that the ABO and Rh systems may influence hemolytic activity. Finally, the studied Loxosceles venoms degraded fibrinogen, suggesting possible alterations in the coagulation cascade. Based in the here-presented preliminary study, in vivo assays in model animals are needed to verify the real toxic potential of these species’ venom, building up knowledge to elucidate the action of Loxosceles venoms in blood. Full article
(This article belongs to the Special Issue Brown Spider Venom Toxins: Biological Activities, Molecular Mechanisms, Cell Biology, Biotechnological Applications, and Targets for the Therapeutic Management of Loxoscelism)
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26 pages, 8285 KiB  
Article
Image Analysis and Untargeted Metabolomics Reveal Potential Phytotoxins from Fusarium venenatum Against Major Parasitic Weed Phelipanche ramosa (L.) Pomel
by Ana Bendejacq-Seychelles, Lisa Martinez, Anaïs Corréard, Jean Chrisologue Totozafy, Christian Steinberg, Jean-Bernard Pouvreau, Carole Reibel, Grégory Mouille, Samuel Mondy, Lucie Poulin and Stéphanie Gibot-Leclerc
Toxins 2024, 16(12), 531; https://doi.org/10.3390/toxins16120531 - 10 Dec 2024
Viewed by 883
Abstract
Branched broomrape (Phelipanche ramosa (L.) Pomel), an obligate parasitic weed with a wide host range, is known for its devasting effects on many crops worldwide. Soil fungi, notably Fusarium sp., are described as pathogenic to broomrape, while the hypothesis of the phytotoxicity [...] Read more.
Branched broomrape (Phelipanche ramosa (L.) Pomel), an obligate parasitic weed with a wide host range, is known for its devasting effects on many crops worldwide. Soil fungi, notably Fusarium sp., are described as pathogenic to broomrape, while the hypothesis of the phytotoxicity of fusaric acid produced by F. verticillioides for parasitic weeds of the genus Orobanche has been proposed. Using image analysis and untargeted metabolomics, this study investigated fungal metabolites phytotoxic for P. ramosa and produced by the F. venenatum MIAE02836 strain, isolated from symptomatic broomrapes and identified as a promising candidate for broomrape biocontrol. Phytotoxicity tests of crude extracts from the fungus alone or in interaction with broomrape on P. ramosa microcalli and quantification of necrosis by image analysis confirmed the phytotoxic potential of F. venenatum MIAE02836 metabolites towards the early developmental stages of P. ramosa. Data analysis of a non-targeted metabolomics approach revealed numerous metabolites produced by F. venenatum MIAE02836. Four of them, accumulated during interaction with the parasitic plant, are known for their phytotoxic potential: maculosin, cyclo(Leu-Phe), phenylalanyl-D-histidine and anguidine. These results suggest that combining image acquisition of the microcalli screening test and untargeted metabolomic approach is an interesting and relevant method to characterize phytotoxic fungal metabolites. Full article
(This article belongs to the Section Mycotoxins)
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6 pages, 189 KiB  
Editorial
Botulinum Toxin and Migraine: Goals and Perspectives
by Maria Pia Prudenzano
Toxins 2024, 16(12), 530; https://doi.org/10.3390/toxins16120530 - 10 Dec 2024
Viewed by 802
Abstract
This Special Issue aims to provide an updated overview of the current state and future perspectives of botulinum toxin treatment for migraine [...] Full article
(This article belongs to the Special Issue Botulinum Toxin and Migraine: Goals and Perspectives)
14 pages, 1043 KiB  
Article
Integrating Telemedicine in Botulinum Toxin Type-A Treatment for Spasticity Management: Perspectives and Challenges from Italian Healthcare Professionals
by Stefania Spina, Salvatore Facciorusso, Nicoletta Cinone, Luigi Santoro, Anna Castagna, Marina Ramella, Franco Molteni, Andrea Santamato and The Collaborative Working Group
Toxins 2024, 16(12), 529; https://doi.org/10.3390/toxins16120529 - 7 Dec 2024
Viewed by 998
Abstract
(1) Background: Telemedicine is a vital tool for enhancing healthcare accessibility and outcomes at reduced costs. This study aimed to assess the usability of the Maia Connected Care telemedicine platform for managing spasticity in patients receiving botulinum toxin type-A, focusing on the perspectives [...] Read more.
(1) Background: Telemedicine is a vital tool for enhancing healthcare accessibility and outcomes at reduced costs. This study aimed to assess the usability of the Maia Connected Care telemedicine platform for managing spasticity in patients receiving botulinum toxin type-A, focusing on the perspectives of Italian physiatrists with expertise in this treatment. (2) Methods: Conducted from March 2023 to June 2023, this multicenter survey involved 15 Italian physicians who used the platform for teleconsultations. Data collected included demographic details, responses to the Telemedicine Usability Questionnaire, and physician insights on patient satisfaction, treatment effectiveness, and implementation challenges in telehealth. (3) Results: The platform demonstrated high usability, with strong physician satisfaction due to its user-friendly interface and quality of interactions. A majority expressed willingness to continue telehealth for spasticity management, noting its effectiveness in improving patient satisfaction and outcomes. Challenges included replicating the depth of in-person consultations and addressing issues like reimbursement and telehealth standardization. (4) Conclusions: This study highlights telemedicine’s potential for spasticity management and clinician satisfaction, while underscoring the need for improvements in simulating in-person experiences and addressing systemic issues. The absence of patient perspectives represents a limitation, advocating for future research to optimize telemedicine practices and evaluate long-term clinical impacts. Full article
(This article belongs to the Section Bacterial Toxins)
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39 pages, 6873 KiB  
Review
Exploring Mycolactone—The Unique Causative Toxin of Buruli Ulcer: Biosynthetic, Synthetic Pathways, Biomarker for Diagnosis, and Therapeutic Potential
by Gideon Atinga Akolgo, Kingsley Bampoe Asiedu and Richard Kwamla Amewu
Toxins 2024, 16(12), 528; https://doi.org/10.3390/toxins16120528 - 6 Dec 2024
Viewed by 1507
Abstract
Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of [...] Read more.
Mycolactone is a complex macrolide toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer. The aim of this paper is to review the chemistry, biosynthetic, and synthetic pathways of mycolactone A/B to help develop an understanding of the mode of action of these polyketides as well as their therapeutic potential. The synthetic work has largely been driven by the desire to afford researchers enough (≥100 mg) of the pure toxins for systematic biological studies toward understanding their very high biological activities. The review focuses on pioneering studies of Kishi which elaborate first-, second-, and third-generation approaches to the synthesis of mycolactones A/B. The three generations focused on the construction of the key intermediates required for the mycolactone synthesis. Synthesis of the first generation involves assignment of the relative and absolute stereochemistry of the mycolactones A and B. This was accomplished by employing a linear series of 17 chemical steps (1.3% overall yield) using the mycolactone core. The second generation significantly improved the first generation in three ways: (1) by optimizing the selection of protecting groups; (2) by removing needless protecting group adjustments; and (3) by enhancing the stereoselectivity and overall synthetic efficiency. Though the synthetic route to the mycolactone core was longer than the first generation, the overall yield was significantly higher (8.8%). The third-generation total synthesis was specifically aimed at an efficient, scalable, stereoselective, and shorter synthesis of mycolactone. The synthesis of the mycolactone core was achieved in 14 linear chemical steps with 19% overall yield. Furthermore, a modular synthetic approach where diverse analogues of mycolactone A/B were synthesized via a cascade of catalytic and/or asymmetric reactions as well as several Pd-catalyzed key steps coupled with hydroboration reactions were reviewed. In addition, the review discusses how mycolactone is employed in the diagnosis of Buruli ulcer with emphasis on detection methods of mass spectrometry, immunological assays, RNA aptamer techniques, and fluorescent-thin layer chromatography (f-TLC) methods as diagnostic tools. We examined studies of the structure–activity relationship (SAR) of various analogues of mycolactone. The paper highlights the multiple biological consequences associated with mycolactone such as skin ulceration, host immunomodulation, and analgesia. These effects are attributed to various proposed mechanisms of actions including Wiskott–Aldrich Syndrome protein (WASP)/neural Wiskott–Aldrich Syndrome protein (N-WASP) inhibition, Sec61 translocon inhibition, angiotensin II type 2 receptor (AT2R) inhibition, and inhibition of mTOR. The possible application of novel mycolactone analogues produced based on SAR investigations as therapeutic agents for the treatment of inflammatory disorders and inflammatory pain are discussed. Additionally, their therapeutic potential as anti-viral and anti-cancer agents have also been addressed. Full article
(This article belongs to the Section Mycotoxins)
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20 pages, 2006 KiB  
Article
Biological and Chemical Management of Aspergillus carbonarius and Ochratoxin A in Vineyards
by Maria K. Iliadi, Maria Varveri and Dimitrios I. Tsitsigiannis
Toxins 2024, 16(12), 527; https://doi.org/10.3390/toxins16120527 - 6 Dec 2024
Viewed by 848
Abstract
Ochratoxin A (OTA) is a widely distributed mycotoxin and potent carcinogen produced by several fungal genera, but mainly by Aspergillus carbonarius. Grape contamination occurs in vineyards during the period between veraison and pre-harvest, and it is the main cause of OTA’s presence [...] Read more.
Ochratoxin A (OTA) is a widely distributed mycotoxin and potent carcinogen produced by several fungal genera, but mainly by Aspergillus carbonarius. Grape contamination occurs in vineyards during the period between veraison and pre-harvest, and it is the main cause of OTA’s presence in wine. The aim of the current study was the evaluation of 6 chemical and 11 biological plant protection products (PPPs) and biocontrol agents in commercial vineyards of the two important Greek white wine varieties cv. Malagousia and cv. Savatiano. The PPPs were applied in a 4-year vineyard study as single treatments or/and in combinations as part of IPM systems. Subsequently, nine strains of Aspergillus carbonarius were investigated for their sensitivity against seven active compounds of synthetic fungicides. During the multi-year field trials, various novel management systems, including consortia of biocontrol agents, were revealed to be effective against Aspergillus sour rot and OTA production. However, expected variability was observed in the experimental results, indicating the dynamic character of biological systems and highlighting the possible inconsistency of PPPs’ efficacy in a changing environment. Furthermore, the IPM systems developed effectuated an optimized control of A. carbonarius, leading to 100% inhibition of OTA contamination, showing the importance of using both chemical and biological PPPs for disease management and prevention of fungal fungicide resistance. Finally, the majority of A. carbonarius tested strains were found to be sensitive against the pure active compounds used (fludioxonil, azoxystrobin, chlorothalonil, tebuconazole, cyprodinil, pyrimethanil and boscalid), with only a few exceptions of developed resistance towards boscalid. Full article
(This article belongs to the Special Issue Toxins: 15th Anniversary)
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19 pages, 6558 KiB  
Article
Real-Time Observation of Clickable Cyanotoxin Synthesis in Bloom-Forming Cyanobacteria Microcystis aeruginosa and Planktothrix agardhii
by Rainer Kurmayer and Rubén Morón Asensio
Toxins 2024, 16(12), 526; https://doi.org/10.3390/toxins16120526 - 5 Dec 2024
Viewed by 846
Abstract
Recently, the use of click chemistry for localization of chemically modified cyanopeptides has been introduced, i.e., taking advantage of promiscuous adenylation (A) domains in non-ribosomal peptide synthesis (NRPS), allowing for the incorporation of clickable non-natural amino acids (non-AAs) into their peptide products. In [...] Read more.
Recently, the use of click chemistry for localization of chemically modified cyanopeptides has been introduced, i.e., taking advantage of promiscuous adenylation (A) domains in non-ribosomal peptide synthesis (NRPS), allowing for the incorporation of clickable non-natural amino acids (non-AAs) into their peptide products. In this study, time-lapse experiments have been performed using pulsed feeding of three different non-AAs in order to observe the synthesis or decline of azide- or alkyne-modified microcystins (MCs) or anabaenopeptins (APs). The cyanobacteria Microcystis aeruginosa and Planktothrix agardhii were grown under maximum growth rate conditions (r = 0.35–0.6 and 0.2–0.4 (day−1), respectively) in the presence of non-AAs for 12–168 h. The decline of the azide- or alkyne-modified MC or AP was observed via pulse-feeding. In general, the increase in clickable MC/AP in peptide content reached a plateau after 24–48 h and was related to growth rate, i.e., faster-growing cells also produced more clickable MC/AP. Overall, the proportion of clickable MC/AP in the intracellular fraction correlated with the proportion observed in the dissolved fraction. Conversely, the overall linear decrease in clickable MC/AP points to a rather constant decline via dilution by growth instead of a regulated or induced release in the course of the synthesis process. Full article
(This article belongs to the Special Issue Harmful Algae in a Changing World: Where Did We Come from and Where Are We Going?)
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13 pages, 2371 KiB  
Article
Epsilon Toxin from Clostridium perfringens Induces the Generation of Extracellular Vesicles in HeLa Cells Overexpressing Myelin and Lymphocyte Protein
by Jonatan Dorca-Arévalo, Antonio Santana-Ruiz, Benjamín Torrejón-Escribano, Mireia Martín-Satué and Juan Blasi
Toxins 2024, 16(12), 525; https://doi.org/10.3390/toxins16120525 - 4 Dec 2024
Viewed by 962
Abstract
Epsilon toxin (ETX) from Clostridium perfringens is a pore-forming toxin (PFT) that crosses the blood–brain barrier and binds to myelin structures. In in vitro assays, ETX causes oligodendrocyte impairment, subsequently leading to demyelination. In fact, ETX has been associated with triggering multiple sclerosis. [...] Read more.
Epsilon toxin (ETX) from Clostridium perfringens is a pore-forming toxin (PFT) that crosses the blood–brain barrier and binds to myelin structures. In in vitro assays, ETX causes oligodendrocyte impairment, subsequently leading to demyelination. In fact, ETX has been associated with triggering multiple sclerosis. Myelin and lymphocyte protein (MAL) is widely considered to be the receptor for ETX as its presence is crucial for the effects of ETX on the plasma membrane of host cells that involve pore formation, resulting in cell death. To overcome the pores formed by PFTs, some host cells produce extracellular vesicles (EVs) to reduce the amount of pores inserted into the plasma membrane. The formation of EVs has not been studied for ETX in host cells. Here, we generated a highly sensitive clone from HeLa cells overexpressing the MAL-GFP protein in the plasma membrane. We observed that ETX induces the formation of EVs. Moreover, the MAL protein and ETX oligomers are found in these EVs, which are a very useful tool to decipher and study the mode of action of ETX and characterize the mechanisms involved in the binding of ETX to its receptor. Full article
(This article belongs to the Special Issue Toxin-Host Interaction of Clostridium Toxins)
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Article
Bicistronic Vector Expression of Recombinant Jararhagin-C and Its Effects on Endothelial Cells
by Karla Fernanda Ferraz, Lhiri Hanna De Lucca Caetano, Daniele Pereira Orefice, Paula Andreia Lucas Calabria, Maisa Splendore Della-Casa, Luciana Aparecida Freitas-de-Sousa, Emidio Beraldo-Neto, Sabri Saeed Sanabani, Geraldo Santana Magalhães and Patricia Bianca Clissa
Toxins 2024, 16(12), 524; https://doi.org/10.3390/toxins16120524 - 3 Dec 2024
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Abstract
Jararhagin-C (JarC) is a protein from the venom of Bothrops jararaca consisting of disintegrin-like and cysteine-rich domains. JarC shows a modulating effect on angiogenesis and remodeling of extracellular matrix constituents, improving wound healing in a mouse experimental model. JarC is purified from crude [...] Read more.
Jararhagin-C (JarC) is a protein from the venom of Bothrops jararaca consisting of disintegrin-like and cysteine-rich domains. JarC shows a modulating effect on angiogenesis and remodeling of extracellular matrix constituents, improving wound healing in a mouse experimental model. JarC is purified from crude venom, and the yield is less than 1%. The aim of this work was to obtain the recombinant form of JarC and to test its biological activity. For this purpose, the bicistronic vector pSUMOUlp1 was used. This vector allowed the expression of the recombinant toxin JarC (rJarC) in fusion with the small ubiquitin-related modifier (SUMO) as well as the SUMO protease Ulp1. After expression, this protease was able to efficiently remove SUMO from rJarC inside the bacteria. rJarC free from SUMO was purified at the expected molecular mass and recognized by polyclonal anti-jararhagin antibodies. In terms of biological activity, both the native and recombinant forms showed no toxicity to the HUVEC cell line CRL1730 and were effective in modulating cell migration activity in the experimental in vitro model. These results demonstrate the successful production of rJarC and the preservation of its biological activity, which may facilitate further investigations into the therapeutic potential of this snake venom-derived protein. Full article
(This article belongs to the Special Issue Animals Venom in Drug Discovery: A Valuable Therapeutic Tool)
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