Toxins

19 pages, 3955 KiB

Open AccessArticle

De Novo Assembly of Venom Gland Transcriptome of Tropidolaemus wagleri (Temple Pit Viper, Malaysia) and Insights into the Origin of Its Major Toxin, Waglerin

by Choo Hock Tan, Kae Yi Tan and Nget Hong Tan

Toxins 2023, 15(9), 585; https://doi.org/10.3390/toxins15090585 - 21 Sep 2023

Viewed by 1406

Abstract

The venom proteome of Temple Pit Viper (Tropidolaemus wagleri) is unique among pit vipers, characterized by a high abundance of a neurotoxic peptide, waglerin. To further explore the genetic diversity of its toxins, the present study de novo assembled the venom [...] Read more.

The venom proteome of Temple Pit Viper (Tropidolaemus wagleri) is unique among pit vipers, characterized by a high abundance of a neurotoxic peptide, waglerin. To further explore the genetic diversity of its toxins, the present study de novo assembled the venom gland transcriptome of T. wagleri from west Malaysia. Among the 15 toxin gene families discovered, gene annotation and expression analysis reveal the dominating trend of bradykinin-potentiating peptide/angiotensin-converting enzyme inhibitor-C-type natriuretic peptide (BPP/ACEI-CNP, 76.19% of all-toxin transcription) in the transcriptome, followed by P-III snake venom metalloproteases (13.91%) and other toxins. The transcript TwBNP01 of BPP/ACEI-CNP represents a large precursor gene (209 amino acid residues) containing the coding region for waglerin (24 residues). TwBNP01 shows substantial sequence variations from the corresponding genes of its sister species, Tropidolaemus subannulatus of northern Philippines, and other viperid species which diversely code for proline-rich small peptides such as bradykinin-potentiating peptides (BPPs). The waglerin/waglerin-like peptides, BPPs and azemiopsin are proline-rich, evolving de novo from multiple highly diverged propeptide regions within the orthologous BPP/ACEI-CNP genes. Neofunctionalization of the peptides results in phylogenetic constraints consistent with a phenotypic dichotomy, where Tropidolaemus spp. and Azemiops feae convergently evolve a neurotoxic trait while vasoactive BPPs evolve only in other species. Full article

(This article belongs to the Special Issue Recent Updates in Venomics and Applications)

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20 pages, 5339 KiB

Open AccessArticle

Comparing Traditional and Toxin-Oriented Approaches towards Antivenom Production against Bitis arietans Snake Venom

by Felipe Raimondi Guidolin, Kemily Stephanie de Godoi, Angela Alice Amadeu Megale, Cristiane Castilho Fernandes da Silva, Roberto Tadashi Kodama, Daniela Cajado-Carvalho, Leo Kei Iwai, Patrick Jack Spencer, Fernanda Calheta Vieira Portaro and Wilmar Dias da Silva

Toxins 2023, 15(9), 584; https://doi.org/10.3390/toxins15090584 - 20 Sep 2023

Viewed by 1441

Abstract

Accidents with snakes are responsible for about 32,000 deaths annually in sub-Saharan Africa, caused mostly by snakes from the genus Bitis, in particular Bitis arietans. B. arietans venom is composed of a complex mixture of toxins, mainly metalloproteases, serine proteases, phospholipases, [...] Read more.

Accidents with snakes are responsible for about 32,000 deaths annually in sub-Saharan Africa, caused mostly by snakes from the genus Bitis, in particular Bitis arietans. B. arietans venom is composed of a complex mixture of toxins, mainly metalloproteases, serine proteases, phospholipases, lectins, and disintegrins. In this work, we compared two approaches to anti-B. arietans antivenom production: immunization with crude snake venom (“traditional approach”) and immunization with selected key toxins isolated from the snake venom (“toxin oriented” approach). Fractions from B. arietans venom were isolated by size exclusion chromatography. Crude venom and samples containing serine proteases or metalloproteases were selected for the immunization of BALB/c mice. Anti-B. arietans and anti-serine proteases plasmas showed a similar recognition profile and higher titers and affinity than the anti-metalloproteases plasma. Cross-recognition of other Bitis venoms was observed, but with low intensity. Although the plasma of all experimental groups inhibited the enzymatic activity of B. arietans venom in vitro, in vivo protection was not achieved. Our results have shown limitations in both approaches considered. Based on this, we proposed a model of polyclonal, species-specific, monovalent antivenoms that could be used as a base to produce customizable polyvalent sera for use in sub-Saharan Africa. Full article

(This article belongs to the Special Issue Antivenom for Venomous Bites Treatment: Assessment of Antivenom Quality, Efficacy and Safety, and Development of Next Generation Antivenoms)

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18 pages, 2656 KiB

Open AccessSystematic Review

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

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

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

Cited by 6 | Viewed by 2101

Abstract

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

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

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

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38 pages, 3353 KiB

Open AccessReview

Understanding the Risks of Diffusion of Cyanobacteria Toxins in Rivers, Lakes, and Potable Water

by Amin Mahmood Thawabteh, Hani A Naseef, Donia Karaman, Sabino A. Bufo, Laura Scrano and Rafik Karaman

Toxins 2023, 15(9), 582; https://doi.org/10.3390/toxins15090582 - 20 Sep 2023

Cited by 6 | Viewed by 2835

Abstract

Blue-green algae, or cyanobacteria, may be prevalent in our rivers and tap water. These minuscule bacteria can grow swiftly and form blooms in warm, nutrient-rich water. Toxins produced by cyanobacteria can pollute rivers and streams and harm the liver and nervous system in [...] Read more.

Blue-green algae, or cyanobacteria, may be prevalent in our rivers and tap water. These minuscule bacteria can grow swiftly and form blooms in warm, nutrient-rich water. Toxins produced by cyanobacteria can pollute rivers and streams and harm the liver and nervous system in humans. This review highlights the properties of 25 toxin types produced by 12 different cyanobacteria genera. The review also covered strategies for reducing and controlling cyanobacteria issues. These include using physical or chemical treatments, cutting back on fertilizer input, algal lawn scrubbers, and antagonistic microorganisms for biocontrol. Micro-, nano- and ultrafiltration techniques could be used for the removal of internal and extracellular cyanotoxins, in addition to powdered or granular activated carbon, ozonation, sedimentation, ultraviolet radiation, potassium permanganate, free chlorine, and pre-treatment oxidation techniques. The efficiency of treatment techniques for removing intracellular and extracellular cyanotoxins is also demonstrated. These approaches aim to lessen the risks of cyanobacterial blooms and associated toxins. Effective management of cyanobacteria in water systems depends on early detection and quick action. Cyanobacteria cells and their toxins can be detected using microscopy, molecular methods, chromatography, and spectroscopy. Understanding the causes of blooms and the many ways for their detection and elimination will help the management of this crucial environmental issue. Full article

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18 pages, 4439 KiB

Open AccessArticle

Patulin Stimulates Progenitor Leydig Cell Proliferation but Delays Its Differentiation in Male Rats during Prepuberty

by Huitao Li, Ming Su, Hang Lin, Jingjing Li, Shaowei Wang, Lei Ye, Xingwang Li and Renshan Ge

Toxins 2023, 15(9), 581; https://doi.org/10.3390/toxins15090581 - 20 Sep 2023

Viewed by 1064

Abstract

Patulin is a mycotoxin with potential reproductive toxicity. We explored the impact of patulin on Leydig cell (LC) development in male rats. Male Sprague Dawley rats (21 days postpartum) were gavaged patulin at doses of 0.5, 1, and 2 mg/kg/day for 7 days. [...] Read more.

Patulin is a mycotoxin with potential reproductive toxicity. We explored the impact of patulin on Leydig cell (LC) development in male rats. Male Sprague Dawley rats (21 days postpartum) were gavaged patulin at doses of 0.5, 1, and 2 mg/kg/day for 7 days. Patulin markedly lowered serum testosterone at ≥0.5 mg/kg and progesterone at 1 and 2 mg/kg, while increasing LH levels at 2 mg/kg. Patulin increased the CYP11A1⁺ (cholesterol side-chain cleavage, a progenitor LC biomarker) cell number and their proliferation at 1 and 2 mg/kg. Additionally, patulin downregulated Lhcgr (luteinizing hormone receptor), Scarb1 (high-density lipoprotein receptor), and Cyp17a1 (17α-hydroxylase/17,20-lyase) at 1 and 2 mg/kg. It increased the activation of pAKT1 (protein kinase B), pERK1/2 (extracellular signal-related kinases 1 and 2), pCREB (cyclic AMP response binding protein), and CCND1 (cyclin D1), associated with cell cycle regulation, in vivo. Patulin increased EdU incorporation into R2C LC and stimulated cell cycle progression in vitro. Furthermore, patulin showed a direct inhibitory effect on 11β-HSD2 (11β-hydroxysteroid dehydrogenase 2) activity, which eliminates the adverse effects of glucocorticoids. This study provides insights into the potential mechanisms via which patulin affects progenitor LC development in young male rats. Full article

(This article belongs to the Special Issue Toxicology of Mycotoxins: Experimental Forward)

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15 pages, 366 KiB

Open AccessArticle

Effects of a Multi-Component Mycotoxin-Detoxifying Agent on Oxidative Stress, Health and Performance of Sows

by Vasileios G. Papatsiros, Christos Eliopoulos, Nikolaos Voulgarakis, Dimitrios Arapoglou, Insaf Riahi, Meritxell Sadurní and Georgios I. Papakonstantinou

Toxins 2023, 15(9), 580; https://doi.org/10.3390/toxins15090580 - 19 Sep 2023

Cited by 1 | Viewed by 1579

Abstract

This in vivo study aimed to investigate the effects of a multi-component mycotoxin-detoxifying agent, containing clays (bentonite, sepiolite), phytogenic feed additives (curcumin, silymarin) and postbiotics (yeast cell wall, hydrolyzed yeast) on the antioxidant capacity, health and reproductive performance of pregnant and lactating sows [...] Read more.

This in vivo study aimed to investigate the effects of a multi-component mycotoxin-detoxifying agent, containing clays (bentonite, sepiolite), phytogenic feed additives (curcumin, silymarin) and postbiotics (yeast cell wall, hydrolyzed yeast) on the antioxidant capacity, health and reproductive performance of pregnant and lactating sows challenged by mycotoxins. Eighty (80) primiparous sows (mean age 366 ± 3 days) per each of the two trial farms were divided into two groups in each farm: a) T1 (control group): 40 sows received the contaminated feed and b) T2 group (experimental group): 40 sows received the contaminated feed plus the mycotoxin-detoxifying agent, one month before farrowing until the end of the lactation period. Thiobarbituric acid reactive substances (TBARS), protein carbonyls (CARBS) and total antioxidant capacity (TAC) were evaluated as biomarkers of oxidative stress. Clinical and reproductive parameters were recorded. Our results indicate that the administration of a multi-component mycotoxin-detoxifying agent’s administration in sow feed has beneficial effects on oxidative stress biomarkers and can improve sows’ health and performance. Full article

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

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13 pages, 3412 KiB

Open AccessArticle

Lactobacillus fermentum Alleviates the Colorectal Inflammation Induced by Low-Dose Sub-Chronic Microcystin-LR Exposure

by Yue Yang, Cong Wen, Shuilin Zheng, Fengmei Song, Ying Liu, Xueqiong Yao, Yan Tang, Xiangling Feng, Jihua Chen and Fei Yang

Toxins 2023, 15(9), 579; https://doi.org/10.3390/toxins15090579 - 19 Sep 2023

Viewed by 1089

Abstract

Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics [...] Read more.

Microcystin-LR (MC-LR) contamination is a worldwide environmental problem that poses a grave threat to the water ecosystem and public health. Exposure to MC-LR has been associated with the development of intestinal injury, but there are no effective treatments for MC-LR-induced intestinal disease. Probiotics are “live microorganisms that are beneficial to the health of the host when administered in sufficient quantities”. It has been demonstrated that probiotics can prevent or treat a variety of human diseases; however, their ability to mitigate MC-LR-induced intestinal harm has not yet been investigated. The objective of this study was to determine whether probiotics can mitigate MC-LR-induced intestinal toxicity and its underlying mechanisms. We first evaluated the pathological changes in colorectal tissues using an animal model with sub-chronic exposure to low-dose MC-LR, HE staining to assess colorectal histopathologic changes, qPCR to detect the expression levels of inflammatory factors in colorectal tissues, and WB to detect the alterations on CSF1R signaling pathway proteins in colorectal tissues. Microbial sequencing analysis and screening of fecal microorganisms differential to MC-LR treatment in mice. To investigate the role of microorganisms in MC-LR-induced colorectal injury, an in vitro model of MC-LR co-treatment with microorganisms was developed. Our findings demonstrated that MC-LR treatment induced an inflammatory response in mouse colorectal tissues, promoted the expression of inflammatory factors, activated the CSF1R signaling pathway, and significantly decreased the abundance of Lactobacillus. In a model of co-treatment with MC-LR and Lactobacillus fermentum (L. fermentum), it was discovered that L. fermentum substantially reduced the incidence of the colorectal inflammatory response induced by MC-LR and inhibited the protein expression of the CSF1R signaling pathway. This is the first study to suggest that L. fermentum inhibits the CSF1R signaling pathway to reduce the incidence of MC-LR-induced colorectal inflammation. This research may provide an excellent experimental foundation for the development of strategies for the prevention and treatment of intestinal diseases in MC-LR. Full article

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14 pages, 6384 KiB

Open AccessArticle

Antifungal Activity of Ageritin, a Ribotoxin-like Protein from Cyclocybe aegerita Edible Mushroom, against Phytopathogenic Fungi

by Sara Ragucci, Stefany Castaldi, Nicola Landi, Rachele Isticato and Antimo Di Maro

Toxins 2023, 15(9), 578; https://doi.org/10.3390/toxins15090578 - 18 Sep 2023

Cited by 1 | Viewed by 1211

Abstract

Ageritin from poplar mushrooms is a specific endonuclease that hydrolyzes a single phosphodiester bond located in the sarcin-ricin loop (SRL) of the large rRNA, thereby blocking protein synthesis. Considering the possible biotechnological use of this enzyme, here we report its antifungal activity against [...] Read more.

Ageritin from poplar mushrooms is a specific endonuclease that hydrolyzes a single phosphodiester bond located in the sarcin-ricin loop (SRL) of the large rRNA, thereby blocking protein synthesis. Considering the possible biotechnological use of this enzyme, here we report its antifungal activity against virulent fungi affecting crops of economic interest. Our results show that ageritin (200 µg/plug; ~13.5 nmole) inhibits the growth of Botrytis cinerea (57%), Colletotrichum truncatum (42%), and Alternaria alternata (57%), when tested on potato dextrose agar plates. At the same time, no effect was observed against Trichoderma harzianum (a fungus promoting beneficial effects in plants). To verify whether the antifungal action of ageritin against B. cinerea and T. harzianum was due to ribosome damage, we tested ageritin in vitro on partially isolated B. cinerea and T. harzianum ribosomes. Interestingly, ageritin was able to release the Endo’s fragment from both tested fungal ribosomes. We therefore decided to test the antifungal effect of ageritin on B. cinerea and T. harzianum using a different growth condition (liquid medium). Differently from the result in solid medium, ageritin can inhibit both B. cinerea and T. harzianum fungal growth in liquid medium in a concentration-dependent manner up to 35.7% and 38.7%, respectively, at the highest concentration tested (~200 µg/mL; 12 µM), and the analysis of RNA isolated from ageritin-treated cells revealed the presence of Endo’s fragment, highlighting its ability to cross the fungal cell wall and reach the ribosomes. Overall, these data highlight that the efficacy of antifungal treatment to prevent or treat a potential fungal disease may depend not only on the fungal species but also on the conditions of toxin application. Full article

(This article belongs to the Section Uremic Toxins)

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21 pages, 1833 KiB

Open AccessReview

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

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

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

Cited by 2 | Viewed by 2079

Abstract

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

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

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

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21 pages, 1338 KiB

Open AccessReview

Occurrence of Mycotoxins in Dried Fruits Worldwide, with a Focus on Aflatoxins and Ochratoxin A: A Review

by Miguel Ángel González-Curbelo and Bulent Kabak

Toxins 2023, 15(9), 576; https://doi.org/10.3390/toxins15090576 - 18 Sep 2023

Cited by 5 | Viewed by 3723

Abstract

Dried fruits are popular and nutritious snacks consumed worldwide due to their long shelf life and concentrated nutrient content. However, fruits can be contaminated with various toxigenic fungal species during different stages, including cultivation, harvesting, processing, drying, and storage. Consequently, these products may [...] Read more.

Dried fruits are popular and nutritious snacks consumed worldwide due to their long shelf life and concentrated nutrient content. However, fruits can be contaminated with various toxigenic fungal species during different stages, including cultivation, harvesting, processing, drying, and storage. Consequently, these products may contain high levels of mycotoxins. This risk is particularly pronounced in developed countries due to the impact of climate change. Several factors contribute to mycotoxin production, including the type of fruit, geographical location, climate conditions, harvest treatments, and storage management practices. The main mycotoxins in dried fruits are aflatoxins (AFs) and ochratoxin A (OTA), which can induce human health problems and economic losses. Mycotoxin contamination can vary significantly depending on the geographic origin of dried fruits (vine fruits, figs, dates, apricots, prunes, and mulberries). The aim of this review was to fill the knowledge gap by consolidating data from various regions to understand the global picture and identify regions with higher contamination risks. By consolidating research from various origins and stages of the supply chain, the review intends to shed light on potential contamination events during pre-harvest, drying, storage, and trading, while also highlighting the effects of storage conditions and climate change on mycotoxin contamination. Full article

(This article belongs to the Special Issue Mycotoxin Spectrum in Food and Feed)

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23 pages, 5002 KiB

Open AccessArticle

The Role of Mycotoxins in Interactions between Fusarium graminearum and F. verticillioides Growing in Saprophytic Cultures and Co-Infecting Maize Plants

by Mohammed Sherif, Nadine Kirsch, Richard Splivallo, Katharina Pfohl and Petr Karlovsky

Toxins 2023, 15(9), 575; https://doi.org/10.3390/toxins15090575 - 18 Sep 2023

Cited by 2 | Viewed by 1427

Abstract

Fusarium graminearum (FG) and Fusarium verticillioides (FV) co-occur in infected plants and plant residues. In maize ears, the growth of FV is stimulated while FG is suppressed. To elucidate the role of mycotoxins in these effects, we used FG [...] Read more.

Fusarium graminearum (FG) and Fusarium verticillioides (FV) co-occur in infected plants and plant residues. In maize ears, the growth of FV is stimulated while FG is suppressed. To elucidate the role of mycotoxins in these effects, we used FG mutants with disrupted synthesis of nivalenol (NIV) and deoxynivalenol (DON) and a FV mutant with disrupted synthesis of fumonisins to monitor fungal growth in mixed cultures in vitro and in co-infected plants by real-time PCR. In autoclaved grains as well as in maize ears, the growth of FV was stimulated by FG regardless of the production of DON or NIV by the latter, whereas the growth of FG was suppressed. In autoclaved grains, fumonisin-producing FV suppressed FG more strongly than a fumonisin-nonproducing strain, indicating that fumonisins act as interference competition agents. In co-infected maize ears, FG suppression was independent of fumonisin production by FV, likely due to heterogeneous infection and a lower level of fumonisins in planta. We conclude that (i) fumonisins are agents of interference competition of FV, and (ii) trichothecenes play no role in the interaction between FG and FV. We hypothesize the following: (i) In vitro, FG stimulates the FV growth by secreting hydrolases that mobilize nutrients. In planta, suppression of plant defense by FG may additionally play a role. (ii) The biological function of fumonisin production in planta is to protect kernels shed on the ground by accumulating protective metabolites before competitors become established. Therefore, to decipher the biological function of mycotoxins, the entire life history of mycotoxin producers must be considered. Full article

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

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13 pages, 2955 KiB

Open AccessArticle

Long-Term Exposure to Microcystin-LR Induces Gastric Toxicity by Activating the Mitogen-Activated Protein Kinase Signaling Pathway

by Ying Liu, Yafang Li, Qinmei Tan, Yilin Lv, Yan Tang, Yue Yang, Xueqiong Yao and Fei Yang

Toxins 2023, 15(9), 574; https://doi.org/10.3390/toxins15090574 - 18 Sep 2023

Cited by 1 | Viewed by 1238

Abstract

Previous studies have primarily concentrated on the hepatotoxicity of MC-LR, whereas its gastric toxicity effects and mechanisms of long-term exposure under low dosage remain unknown. Herein, the gastric tissue from C57BL/6 mice fed with drinking water contaminated by low-dose MC-LR (including 1, 60, [...] Read more.

Previous studies have primarily concentrated on the hepatotoxicity of MC-LR, whereas its gastric toxicity effects and mechanisms of long-term exposure under low dosage remain unknown. Herein, the gastric tissue from C57BL/6 mice fed with drinking water contaminated by low-dose MC-LR (including 1, 60, and 120 μg/L) was investigated. The results obtained showed that exposure to different concentrations of MC-LR resulted in significant shedding and necrosis of gastric epithelial cells in mice, and a down-regulation of tight junction markers, including ZO-1, Claudin1, and Occludin in the stomach, which might lead to increased permeability of the gastric mucosa. Moreover, the protein expression levels of p-RAF/RAF, p-ERK1/2/ERK1/2, Pink1, Parkin, and LC3-II/LC-3-I were increased in the gastric tissue of mice exposed to 120 μg/L of MC-LR, while the protein expression level of P62 was significantly decreased. Furthermore, we found that pro-inflammatory factors, including IL-6 and TNF-ɑ, were dramatically increased, while the anti-inflammatory factor IL-10 was significantly decreased in the gastric tissue of MC-LR-exposed mice. The activation of the MAPK signaling pathway and mitophagy might contribute to the development of gastric damage by promoting inflammation. We first reported that long-term exposure to MC-LR induced gastric toxicity by activating the MAPK signaling pathway, providing a new insight into the gastric toxic mechanisms caused by MC-LR. Full article

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24 pages, 3192 KiB

Open AccessArticle

Single-Domain Antibody Multimers for Detection of Botulinum Neurotoxin Serotypes C, D, and Their Mosaics in Endopep-MS

by Michiel M. Harmsen, Jan C. Cornelissen, Fimme J. van der Wal, Jan H. W. Bergervoet and Miriam Koene

Toxins 2023, 15(9), 573; https://doi.org/10.3390/toxins15090573 - 17 Sep 2023

Viewed by 1169

Abstract

Botulinum neurotoxins (BoNTs) are highly toxic proteins that require high-affinity immunocapture reagents for use in endopeptidase-based assays. Here, 30 novel and 2 earlier published llama single-domain antibodies (VHHs) against the veterinary-relevant BoNT serotypes C and D were yeast-produced. These VHHs recognized 10 independent [...] Read more.

Botulinum neurotoxins (BoNTs) are highly toxic proteins that require high-affinity immunocapture reagents for use in endopeptidase-based assays. Here, 30 novel and 2 earlier published llama single-domain antibodies (VHHs) against the veterinary-relevant BoNT serotypes C and D were yeast-produced. These VHHs recognized 10 independent antigenic sites, and many cross-reacted with the BoNT/DC and CD mosaic variants. As VHHs are highly suitable for genetically linking to increase antigen-binding affinity, 52 VHH multimers were produced and their affinity for BoNT/C, D, DC, and CD was determined. A selection of 15 multimers with high affinity (K_D < 0.1 nM) was further shown to be resilient to a high salt wash that is used for samples from complex matrices and bound native BoNTs from culture supernatants as shown by Endopep-MS. High-affinity multimers suitable for further development of a highly sensitive Endopep-MS assay include four multimers that bind both BoNT/D and CD with K_D of 14–99 pM, one multimer for BoNT/DC (65 pM) that also binds BoNT/C (75 pM), and seven multimers for BoNT/C (<1–19 pM), six of which also bind BoNT/DC with lower affinity (93–508 pM). In addition to application in diagnostic tests, these VHHs could be used for the development of novel therapeutics for animals or humans. Full article

(This article belongs to the Collection Rapid Detection of Bacterial Toxins)

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10 pages, 583 KiB

Open AccessArticle

Serum Trimethylamine N-Oxide Level Is Positively Associated with Aortic Stiffness Measured by Carotid–Femoral Pulse Wave Velocity in Patients Undergoing Maintenance Hemodialysis

by Po-Yu Huang, Bang-Gee Hsu, Yu-Hsien Lai, Chih-Hsien Wang and Jen-Pi Tsai

Toxins 2023, 15(9), 572; https://doi.org/10.3390/toxins15090572 - 17 Sep 2023

Cited by 1 | Viewed by 1188

Abstract

Trimethylamine N-oxide (TMAO) is a biomarker that is effective in predicting major adverse cardiovascular (CV) events. Age-related vascular problems are significantly affected by aortic stiffness (AS), which is independently linked to CV morbidity and mortality. This study aimed to determine the association [...] Read more.

Trimethylamine N-oxide (TMAO) is a biomarker that is effective in predicting major adverse cardiovascular (CV) events. Age-related vascular problems are significantly affected by aortic stiffness (AS), which is independently linked to CV morbidity and mortality. This study aimed to determine the association between serum TMAO levels and carotid–femoral pulse wave velocity (cfPWV) in patients receiving hemodialysis (HD) therapy. In total, 115 patients with HD were enrolled in this study. The AS group included patients whose cfPWV was >10 m/s. Using high-performance liquid chromatography and mass spectrometry, the levels of serum TMAO were measured. The AS group included 42 (36.5%) patients, and compared with the non-AS group, the rates of diabetes, hypertension, older age, systolic blood pressure, serum glucose, and TMAO levels were high. In the multivariate logistic regression analysis, serum TMAO and age were independently linked with AS after correcting for the factors significantly associated with AS. Following multivariate stepwise linear regression analysis, serum TMAO in these individuals was found to be strongly correlated with cfPWV values (p < 0.001). In patients on chronic HD, serum TMAO level is an independent measure of AS and strongly correlated with cfPWV. Full article

(This article belongs to the Special Issue Toxicity of Uremic Compounds: Recent Research & Development)

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15 pages, 3143 KiB

Open AccessArticle

Antifungal and Antiaflatoxigenic Activities of Massoia Essential Oil and C10 Massoia Lactone against Aflatoxin-Producing Aspergillus flavus

by Yubin Lee, Soo Jean Park, Kyeongnam Kim, Tae-Oh Kim and Sung-Eun Lee

Toxins 2023, 15(9), 571; https://doi.org/10.3390/toxins15090571 - 16 Sep 2023

Cited by 1 | Viewed by 1315

Abstract

Fungal infection and mycotoxin contamination are major hazards to the safe storage and distribution of foods and feeds consumed by humans and livestock. This study investigated the antifungal and antiaflatoxigenic activities of massoia essential oil (MEO) and its major constituent, C10 massoia lactone [...] Read more.

Fungal infection and mycotoxin contamination are major hazards to the safe storage and distribution of foods and feeds consumed by humans and livestock. This study investigated the antifungal and antiaflatoxigenic activities of massoia essential oil (MEO) and its major constituent, C10 massoia lactone (C10), against aflatoxin B (AFB)-producing Aspergillus flavus ATCC 22546. Their antifungal activities were evaluated using a disc diffusion assay, agar dilution method, and a mycelial growth inhibition assay with the AFB analysis using liquid chromatography triple quadrupole mass spectrometry. MEO and C10 exhibited similar antifungal and antiaflatoxigenic activities against A. flavus. C10 was a primary constituent in MEO and represented up to 45.1% of total peak areas analyzed by gas chromatography–mass spectrometry, indicating that C10 is a major compound contributing to the antifungal and antiaflatoxigenic activities of MEO. Interestingly, these two materials increased AFB production in A. flavus by upregulating the expression of most genes related to AFB biosynthesis by 3- to 60-fold. Overall, MEO and C10 could be suitable candidates as natural preservatives to control fungal infection and mycotoxin contamination in foods and feeds as Generally Recognized As Safe (GRAS) in the Flavor and Extract Manufacturers Association of the United States (FEMA), and MEO is a more suitable substance than C10 because of its wider range of uses and higher allowed concentration than C10. Full article

(This article belongs to the Section Mycotoxins)

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22 pages, 3072 KiB

Open AccessReview

New Strategies for Biocontrol of Bacterial Toxins and Virulence: Focusing on Quorum-Sensing Interference and Biofilm Inhibition

by Hua Zhang, Zhen Zhang, Jing Li and Guangyong Qin

Toxins 2023, 15(9), 570; https://doi.org/10.3390/toxins15090570 - 15 Sep 2023

Cited by 4 | Viewed by 1969

Abstract

The overuse of antibiotics and the emergence of multiple-antibiotic-resistant pathogens are becoming a serious threat to health security and the economy. Reducing antimicrobial resistance requires replacing antibiotic consumption with more biocontrol strategies to improve the immunity of animals and humans. Probiotics and medicinal [...] Read more.

The overuse of antibiotics and the emergence of multiple-antibiotic-resistant pathogens are becoming a serious threat to health security and the economy. Reducing antimicrobial resistance requires replacing antibiotic consumption with more biocontrol strategies to improve the immunity of animals and humans. Probiotics and medicinal plants have been used as alternative treatments or preventative therapies for a variety of diseases caused by bacterial infections. Therefore, we reviewed some of the anti-virulence and bacterial toxin-inhibiting strategies that are currently being developed; this review covers strategies focused on quenching pathogen quorum sensing (QS) systems, the disruption of biofilm formation and bacterial toxin neutralization. It highlights the probable mechanism of action for probiotics and medicinal plants. Although further research is needed before a definitive statement can be made on the efficacy of any of these interventions, the current literature offers new hope and a new tool in the arsenal in the fight against bacterial virulence factors and bacterial toxins. Full article

(This article belongs to the Section Bacterial Toxins)

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14 pages, 1284 KiB

Open AccessArticle

Development of a Generic PBK Model for Human Biomonitoring with an Application to Deoxynivalenol

by Sylvia Notenboom, Rudolf T. Hoogenveen, Marco J. Zeilmaker, Annick D. Van den Brand, Ricardo Assunção and Marcel J. B. Mengelers

Toxins 2023, 15(9), 569; https://doi.org/10.3390/toxins15090569 - 13 Sep 2023

Viewed by 933

Abstract

Toxicokinetic modelling provides a powerful tool in relating internal human exposure (i.e., assessed through urinary biomarker levels) to external exposure. Chemical specific toxicokinetic models are available; however, this specificity prevents their application to similar contaminants or to other routes of exposure. For this [...] Read more.

Toxicokinetic modelling provides a powerful tool in relating internal human exposure (i.e., assessed through urinary biomarker levels) to external exposure. Chemical specific toxicokinetic models are available; however, this specificity prevents their application to similar contaminants or to other routes of exposure. For this reason, we investigated whether a generic physiological-based kinetic (PBK) model might be a suitable alternative for a biokinetic model of deoxynivalenol (DON). IndusChemFate (ICF) was selected as a generic PBK model, which could be fit for purpose. Being suited for simulating multiple routes of exposure, ICF has particularly been used to relate the inhalation and dermal exposure of industrial chemicals to their urinary excretion. For the first time, the ICF model was adapted as a generic model for the human biomonitoring of mycotoxins, thereby extending its applicability domain. For this purpose, chemical-specific data for DON and its metabolites were collected directly from the literature (distribution and metabolism) or indirectly (absorption and excretion) by fitting the ICF model to previously described urinary excretion data. The obtained results indicate that this generic model can be used to model the urinary excretion of DON and its glucuronidated metabolites following dietary exposure to DON. Additionally, the present study establishes the basis for further development of the model to include an inhalation exposure route alongside the oral exposure route. Full article

(This article belongs to the Special Issue Human Biomonitoring and Risk Assessment of Mycotoxins)

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18 pages, 871 KiB

Open AccessReview

Recombination in Bacterial Genomes: Evolutionary Trends

by Anton E. Shikov, Iuliia A. Savina, Anton A. Nizhnikov and Kirill S. Antonets

Toxins 2023, 15(9), 568; https://doi.org/10.3390/toxins15090568 - 12 Sep 2023

Cited by 1 | Viewed by 1406

Abstract

Bacterial organisms have undergone homologous recombination (HR) and horizontal gene transfer (HGT) multiple times during their history. These processes could increase fitness to new environments, cause specialization, the emergence of new species, and changes in virulence. Therefore, comprehensive knowledge of the impact and [...] Read more.

Bacterial organisms have undergone homologous recombination (HR) and horizontal gene transfer (HGT) multiple times during their history. These processes could increase fitness to new environments, cause specialization, the emergence of new species, and changes in virulence. Therefore, comprehensive knowledge of the impact and intensity of genetic exchanges and the location of recombination hotspots on the genome is necessary for understanding the dynamics of adaptation to various conditions. To this end, we aimed to characterize the functional impact and genomic context of computationally detected recombination events by analyzing genomic studies of any bacterial species, for which events have been detected in the last 30 years. Genomic loci where the transfer of DNA was detected pertained to mobile genetic elements (MGEs) housing genes that code for proteins engaged in distinct cellular processes, such as secretion systems, toxins, infection effectors, biosynthesis enzymes, etc. We found that all inferences fall into three main lifestyle categories, namely, ecological diversification, pathogenesis, and symbiosis. The latter primarily exhibits ancestral events, thus, possibly indicating that adaptation appears to be governed by similar recombination-dependent mechanisms. Full article

(This article belongs to the Special Issue Prospective of Cry-Proteins in Application and Overcoming of Pest Resistance)

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11 pages, 335 KiB

Open AccessArticle

Incidence of Aflatoxins and Ochratoxin A in Wheat and Corn from Albania

by Dritan Topi, Janja Babič, Breda Jakovac-Strajn and Gabrijela Tavčar-Kalcher

Toxins 2023, 15(9), 567; https://doi.org/10.3390/toxins15090567 - 12 Sep 2023

Cited by 3 | Viewed by 1402

Abstract

In this study, aflatoxins (AFs) and ochratoxin A (OTA) were analyzed in grains, specifically wheat and corn, from Albania. To summarize, 71 wheat and 45 corn samples from different growing areas were collected. The multi-toxin analytical procedure involved sample extraction and liquid chromatography–tandem [...] Read more.

In this study, aflatoxins (AFs) and ochratoxin A (OTA) were analyzed in grains, specifically wheat and corn, from Albania. To summarize, 71 wheat and 45 corn samples from different growing areas were collected. The multi-toxin analytical procedure involved sample extraction and liquid chromatography–tandem mass spectrometry (LC–MS/MS). The incidence of AF was 18% in the analyzed wheat and 71% in the corn samples. The concentration of AFs was much higher in the corn samples than in the wheat samples. The maximum permitted levels for aflatoxin B1 (AFB1) and total AFs were not exceeded in the wheat samples, while they were exceeded in 36% of the corn samples. In the wheat samples, the AFB1 concentration varied between 0.2 and 0.4 µg kg⁻¹. However, the highest concentrations in the corn samples were 2057, 2944, and 3550 µg kg⁻¹. OTA was present in only three corn samples and one wheat sample. However, all contaminated samples exceeded the maximum permitted levels. This report reveals the presence of AFs and OTA in grain commodities, specifically wheat and corn, grown in Albania. Full article

(This article belongs to the Special Issue Looking Forward: Mycotoxins Occurrence and Detection in Food and Feed)

12 pages, 2143 KiB

Open AccessArticle

Longitudinal Assessment of Botulinum Toxin Treatment for Lateral Trunk Flexion and Pisa Syndrome in Parkinson’s Disease: Real-life, Long-Term Study

by Claudia Ledda, Elisa Panero, Ugo Dimanico, Mattia Parisi, Marialuisa Gandolfi, Michele Tinazzi, Christian Geroin, Francesco Marchet, Giuseppe Massazza, Leonardo Lopiano and Carlo Alberto Artusi

Toxins 2023, 15(9), 566; https://doi.org/10.3390/toxins15090566 - 11 Sep 2023

Cited by 1 | Viewed by 1203

Abstract

Lateral trunk flexion (LTF) and its severe form, called Pisa syndrome (PS), are highly invalidating axial postural abnormalities associated with Parkinson’s disease (PD). Management strategies for LTF lack strong scientific evidence. We present a real-life, longitudinal study evaluating long-term efficacy of botulinum toxin [...] Read more.

Lateral trunk flexion (LTF) and its severe form, called Pisa syndrome (PS), are highly invalidating axial postural abnormalities associated with Parkinson’s disease (PD). Management strategies for LTF lack strong scientific evidence. We present a real-life, longitudinal study evaluating long-term efficacy of botulinum toxin (BoNT) injections in axial muscles to reduce LTF and PS in PD. A total of 13 PD patients with LTF > 5° received ultrasound- and electromyography-guided BoNT injections every 4 months. Seven untreated matched PD patients with LTF served as controls and their changes in posture after 18 months were compared with those of seven patients continuing BoNT over 12 months. 53.8% of patients continued the BoNT injections for at least 12 months. Various individual LTF responses were observed. Overall, BoNT-treated patients obtained a not statistically significant improvement of LTF of 17 ± 41% (p = 0.237). In comparison, the seven untreated PD patients suffered a deterioration in LTF over 12 months by 36 ± 45% (p = 0.116), showing a significantly different trajectory of posture change (p = 0.026). In conclusion, repeated BoNT injections in axial muscles showed varying effects in managing PD-associated LTF, suggesting that: (a) a relevant number of patients with LTF can benefit from BoNT; (b) long-term treatment could prevent LTF worsening; (c) an instrumented, personalized approach is important; and (d) there is a need for prospective, long-term studies. Full article

(This article belongs to the Special Issue Botulinum Neurotoxin as a Novel Therapy for Parkinson’s Disease)

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15 pages, 578 KiB

Open AccessReview

Ochratoxin A: Overview of Prevention, Removal, and Detoxification Methods

by Lijuan Ding, Meihua Han, Xiangtao Wang and Yifei Guo

Toxins 2023, 15(9), 565; https://doi.org/10.3390/toxins15090565 - 08 Sep 2023

Cited by 10 | Viewed by 3619

Abstract

Ochratoxins are the secondary metabolites of Penicillium and Aspergillus, among which ochratoxin A (OTA) is the most toxic molecule. OTA is widely found in food and agricultural products. Due to its severe nephrotoxicity, immunotoxicity, neurotoxicity, and teratogenic mutagenesis, it is essential to [...] Read more.

Ochratoxins are the secondary metabolites of Penicillium and Aspergillus, among which ochratoxin A (OTA) is the most toxic molecule. OTA is widely found in food and agricultural products. Due to its severe nephrotoxicity, immunotoxicity, neurotoxicity, and teratogenic mutagenesis, it is essential to develop effective, economical, and environmentally friendly methods for OTA decontamination and detoxification. This review mainly summarizes the application of technology in OTA prevention, removal, and detoxification from physical, chemical, and biological aspects, depending on the properties of OTA, and describes the advantages and disadvantages of each method from an objective perspective. Overall, biological methods have the greatest potential to degrade OTA. This review provides some ideas for searching for new strains and degrading enzymes. Full article

(This article belongs to the Special Issue Last Studies on Mycotoxins’ Fate during Food and Herbal Medicine Processing)

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11 pages, 2154 KiB

Open AccessArticle

Hepatorenal Toxicity after 7-Day Oral Administration of Low-Dose Tetrodotoxin and Its Distribution in the Main Tissues in Mice

by Yaqian Zhong, Xiaojun Zhang, Qiyu Yang and Qianfeng Wang

Toxins 2023, 15(9), 564; https://doi.org/10.3390/toxins15090564 - 08 Sep 2023

Viewed by 1098

Abstract

Tetrodotoxin (TTX) is a highly toxic compound detected in various edible marine animals even in European waters. To characterize the hazard by oral exposure to TTX, its tissue distribution was evaluated after single (75 μg/kg) or 7-day (25–125 μg/kg) oral administration in mice. [...] Read more.

Tetrodotoxin (TTX) is a highly toxic compound detected in various edible marine animals even in European waters. To characterize the hazard by oral exposure to TTX, its tissue distribution was evaluated after single (75 μg/kg) or 7-day (25–125 μg/kg) oral administration in mice. Moreover, TTX liver and renal toxicity was evaluated after 7-day oral administration. The elimination cycle of a single oral dose of TTX (75 µg/kg) was found to be approximately 168 h (7 days). Daily oral administration of TTX at doses of 25, 75, and 125 µg/kg for 7 consecutive days revealed dose-dependent toxic effects on the liver and kidney. Histopathological examination showed increased inflammatory cell infiltration in the liver and kidney with higher TTX doses, along with disorganization of the hepatic cord and renal tubular cell arrangement. The study results indicated that TTX had more hepatotoxicity than nephrotoxicity in mice. These findings provide insights into the unintentional ingestion of a low dose of TTX in mammals, including humans, and emphasize the importance of food safety. Full article

(This article belongs to the Special Issue Advances in Marine Toxins: Characterization, Analysis and Surveillance)

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27 pages, 3347 KiB

Open AccessReview

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

by Sonal Gupta and Sabine Pellett

Toxins 2023, 15(9), 563; https://doi.org/10.3390/toxins15090563 - 08 Sep 2023

Cited by 3 | Viewed by 3990

Abstract

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

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

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

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10 pages, 556 KiB

Open AccessArticle

Multi-Mycotoxin Analysis in Italian Grains Using Ultra-High-Performance Chromatography Coupled to Quadrupole Orbitrap Mass Spectrometry

by Juliane Lima da Silva, Sonia Lombardi, Luigi Castaldo, Elena Morelli, Jaqueline Garda-Buffon, Luana Izzo and Alberto Ritieni

Toxins 2023, 15(9), 562; https://doi.org/10.3390/toxins15090562 - 08 Sep 2023

Viewed by 1107

Abstract

Mycotoxins are a major source of contamination in cereals, posing risks to human health and causing significant economic losses to the industry. A comprehensive strategy for the analysis of 21 mycotoxins in Italian cereal grain samples (n = 200) was developed using [...] Read more.

Mycotoxins are a major source of contamination in cereals, posing risks to human health and causing significant economic losses to the industry. A comprehensive strategy for the analysis of 21 mycotoxins in Italian cereal grain samples (n = 200) was developed using a simple and quick sample preparation method combined with ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry (UHPLC Q-Orbitrap HRMS). The proposed method showed some advantages, such as multi-mycotoxin analyses with simple sample preparation, fast determination, and high sensitivity. The analysis of the sample revealed the presence of 11 mycotoxins, with α-zearalenol being the most frequently detected, while deoxynivalenol exhibited the highest contamination level. Furthermore, co-occurrence was identified in 15.5% of the samples under analysis. Among these, 13% of the samples reported the simultaneous presence of two mycotoxins, while 2.5% showed the co-occurrence of three mycotoxins. Currently, there has been a renewed interest in guaranteeing the quality and safety of products intended for human consumption. This study holds significant value due to its ability to simultaneously detect multiple mycotoxins within a complex matrix. Furthermore, it provides findings regarding the occurrence and co-occurrence of emerging mycotoxins that currently lack regulation under the existing European Commission Regulation. Full article

(This article belongs to the Special Issue Analysis of Contaminants of Toxicologic Concern in Food, Feed and Nutraceuticals – In Memory of Prof. Alberto Ritieni)

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14 pages, 1389 KiB

Open AccessArticle

A Cost-Effectiveness and Budget Impact Analysis of AbobotulinumtoxinA in Greece

by Nikolaos Nomikos, Christos Eleftheriou and Kostas Athanasakis

Toxins 2023, 15(9), 561; https://doi.org/10.3390/toxins15090561 - 08 Sep 2023

Viewed by 1010

Abstract

This study aimed to assess the cost-effectiveness of abobotulinumtoxinA (aboBoNT-A) plus Best Supportive Care (BSC) compared with BSC alone for managing limb spasticity in adult patients in Greece, as well as to conduct a budget impact analysis of the introduction of aboBoNT-A in [...] Read more.

This study aimed to assess the cost-effectiveness of abobotulinumtoxinA (aboBoNT-A) plus Best Supportive Care (BSC) compared with BSC alone for managing limb spasticity in adult patients in Greece, as well as to conduct a budget impact analysis of the introduction of aboBoNT-A in the Greek healthcare system compared to onabotulinumtoxinA (onaBoNT-A). Clinical studies were utilized to extract data on drug efficacy and patients’ utility, while cost data were collected from Greek sources. The results of the study showed that aboBoNT-A plus BSC was a cost-effective treatment option for both upper and lower limb spasticity in adult patients compared to BSC. Additionally, introducing aboBoNT-A into the Greek healthcare system resulted in cost savings in pharmaceutical spending over a 5-year period. The findings suggest that incorporating aboBoNT-A into the Greek healthcare system could improve patient access to treatment and healthcare resource efficiency, as it is a more economical option compared to onaBoNT-A. Full article

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15 pages, 2521 KiB

Open AccessArticle

PnPP-15, a Synthetic Peptide Derived from a Toxin from Phoneutria nigriventer Spider Venom, Alleviates Diabetic Neuropathic Pain and Acts Synergistically with Pregabalin in Mice

by Xavier Maia Mariano, Luana Caroline de Assis Ferreira, Camila Megale Almeida-Leite, Célio José de Castro Junior and Maria Elena de Lima

Toxins 2023, 15(9), 560; https://doi.org/10.3390/toxins15090560 - 07 Sep 2023

Viewed by 1052

Abstract

Diabetic neuropathic pain is one of the complications that affect a wide variety of the diabetic population and is often difficult to treat. Only a small number of patients experience pain relief, which usually comes with onerous side effects and low levels of [...] Read more.

Diabetic neuropathic pain is one of the complications that affect a wide variety of the diabetic population and is often difficult to treat. Only a small number of patients experience pain relief, which usually comes with onerous side effects and low levels of satisfaction. The search for new analgesic drugs is necessary, given the limitations that current drugs present. Combining drugs to treat neuropathic pain has been attracting interest to improve their efficacy compared to single-drug monotherapies while also reducing dose sizes to minimize side effects. The aim of our study was to verify the antinociceptive effect of a synthetic peptide, PnPP-15, alone and combined with pregabalin, in male Swiss diabetic mice using the von Frey method. PnPP-15 is a synthetic peptide derived from PnPP19, a peptide representing a discontinuous epitope of the primary structure of the toxin PnTx2-6 from the venom of the spider Phoneutria nigriventer. The antinociceptive activity of both compounds was dose-dependent and showed synergism, which was verified by isobolographic analysis. Treatment with PnPP-15 did not cause spontaneous or forced motor changes and did not cause any damage or signs of toxicity in the analyzed organs (pancreas, lung, heart, kidney, brain, or liver). In conclusion, PnPP-15 is a great candidate for an analgesic drug against neuropathic pain caused by diabetes and exerts a synergistic effect when combined with pregabalin, allowing for even more efficient treatment. Full article

(This article belongs to the Special Issue Biotechnological Potential of Animal Venom and Toxins)

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14 pages, 3931 KiB

Open AccessArticle

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

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

Toxins 2023, 15(9), 559; https://doi.org/10.3390/toxins15090559 - 07 Sep 2023

Cited by 1 | Viewed by 1457

Abstract

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

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

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

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14 pages, 10916 KiB

Open AccessArticle

Functional Characterization and Toxicological Study of Proanthocyanidins in Weaned Pigs

by Jiahao Liu, Yong Qiao, Bing Yu, Yuheng Luo, Zhiqing Huang, Xiangbing Mao, Jie Yu, Ping Zheng, Hui Yan, Yan Li and Jun He

Toxins 2023, 15(9), 558; https://doi.org/10.3390/toxins15090558 - 07 Sep 2023

Viewed by 1070

Abstract

Proanthocyanidin (PRO) has been implicated in a variety of biological functions, such as antibacterial, antioxidant, and anti-obesity effects. However, little is known about its safety dose for animals. To explore its safety and effect on growth performance and intestinal health, thirty weaned pigs [...] Read more.

Proanthocyanidin (PRO) has been implicated in a variety of biological functions, such as antibacterial, antioxidant, and anti-obesity effects. However, little is known about its safety dose for animals. To explore its safety and effect on growth performance and intestinal health, thirty weaned pigs were divided into five groups and fed with basal diet containing 0, 30, 300, 600, and 1200 mg/kg PRO for 42 days. Results showed that PRO supplementation at 30 and 300 mg/kg significantly decreased the feed/gain ratio (F:G) and diarrhea rate (p < 0.05). PRO also increased the digestibilities of dry matter, ether extract, gross energy, and ash (p < 0.05). Interestingly, PRO not only elevated the villus height and the ratio of villus height to crypt depth (V/C) in duodenum and jejunum (p < 0.01), but also decreased the crypt depth in the duodenum (p < 0.01). Moreover, PRO supplementation at 30, 300, and 600 mg/kg elevated the expression levels of mucin 1 (MUC1), MUC2, and fatty acid transport protein 1 (FATP-1) in the duodenum (p < 0.05). The expression levels of FATP-4 in jejunum and ileum were also elevated by PRO (p < 0.05). Importantly, histopathological findings of tissues (e.g., heart, liver, kidney, spleen, lungs, pancreas, thymus, mesenteric lymph nodes, stomach, small intestine), serum clinical chemistry, and major hematological parameters were not affected by PRO supplementation. These results suggest that PRO may act as a safe and effective supplement to decrease F:G and improve intestinal health in weaned pigs. Full article

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16 pages, 2873 KiB

Open AccessArticle

Oral and IV Varespladib Rescue Experiments in Juvenile Pigs with Weakness Induced by Australian and Papuan Oxyuranus scutellatus Venoms

by Lyndi L. Gilliam, John Gilliam, Stephen P. Samuel, Rebecca W. Carter, Jerry Ritchey, Tommaso Bulfone, José María Gutiérrez, David J. Williams, Daniela M. Durkin, Sally I. Stephens and Matthew R. Lewin

Toxins 2023, 15(9), 557; https://doi.org/10.3390/toxins15090557 - 07 Sep 2023

Cited by 1 | Viewed by 1085

Abstract

Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, [...] Read more.

Antivenom is currently the standard-of-care treatment for snakebite envenoming, but its efficacy is limited by treatment delays, availability, and in many cases, species specificity. Many of the rapidly lethal effects of envenoming are caused by venom-derived toxins, such as phospholipase A2 (sPLA2); therefore, small molecule direct toxin inhibitors targeting these toxins may have utility as initial and adjunct therapies after envenoming. Varespladib (intravenous, IV) and varespladib-methyl (oral) have been shown to potently inhibit sPLA2s from snake venoms in murine and porcine models, thus supporting their further study as potential treatments for snakebite envenoming. In this pilot study, we tested the ability of these compounds to reverse neurotoxic effects of venom from the Australian and Papuan taipan (Oxyuranus scutellatus) subspecies in juvenile pigs (Sus domesticus). The mean survival time for control animals receiving Australian taipan venom (0.03 mg/kg, n = 3) was 331 min ± 15 min; for those receiving Papuan taipan venom (0.15 mg/kg, n = 3) it was 178 ± 31 min. Thirteen pigs received Australian taipan venom and treatment with either IV or oral varespladib (or with IV to oral transition) and all 13 survived the duration of the study (≥96 h). Eight pigs received Papuan taipan venom followed by treatment: Briefly: Two animals received antivenom immediately and survived to the end of the study. Two animals received antivenom treatment delayed 45 min from envenoming and died within 4 h. Two animals received similarly delayed antivenom treatment and were rescued by varespladib. Two animals were treated with varespladib alone after a 45-min delay. Treatment with varespladib only was effective but required repeat dosing over the course of the study. Findings highlight both the importance of early treatment and, as well, a half-life for the investigational inhibitors now in Phase II clinical trials for snakebite. Varespladib rapidly reversed weakness even when administered many hours post-envenoming and, overall, our results suggest that varespladib and varespladib-methyl could be efficacious tools in the treatment of sPLA2-induced weakness from Oxyuranus envenoming. Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data. Full article

(This article belongs to the Section Animal Venoms)

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22 pages, 680 KiB

Open AccessArticle

The Effect of Mycotoxins and Their Mixtures on Bovine Spermatozoa Characteristics

by Dorit Kalo, Paz Mendelson, Alisa Komsky-Elbaz, Hillary Voet and Zvi Roth

Toxins 2023, 15(9), 556; https://doi.org/10.3390/toxins15090556 - 06 Sep 2023

Viewed by 1052

Abstract

There is growing concern about the effects of mycotoxins on mammalian reproduction. Although the effects of single mycotoxins have been well documented, the impact of their mixtures on spermatozoon quality is less known. Here, frozen-thawed semen (n = 6 bulls) was in-vitro-cultured [...] Read more.

There is growing concern about the effects of mycotoxins on mammalian reproduction. Although the effects of single mycotoxins have been well documented, the impact of their mixtures on spermatozoon quality is less known. Here, frozen-thawed semen (n = 6 bulls) was in-vitro-cultured (2 h) without (control) or with (i) a single mycotoxin [zearalenone (ZEN), ochratoxin A (OTA), toxin 2 (T2), and diacetoxyscirpenol (DAS)] in a dose-response manner; (ii) binary mixtures (OTA + T2, OTA + ZEN, OTA + DAS, ZEN + T2, DAS + T2 and ZEN + DAS); or (iii) ternary mixtures (OTA + DAS + T2, OTA + ZEN + T2, and ZEN + DAS + T2). Then, the spermatozoa quality was characterized according to its plasma- and acrosome-membrane integrity, mitochondrial membrane potential, and oxidation status by a flow cytometer. Exposure to single mycotoxins or binary mixtures did not affect the spermatozoa characteristics. However, exposure to the ternary mixtures, OTA + DAS + T2 and OTA + ZEN + T2, reduced (p < 0.05) the mitochondrial membrane potential relative to the control. In addition, OTA + ZEN + T2 increased (p < 0.05) the proportion of spermatozoa with reactive oxygen species relative to the control. The most suggested interaction effect between the mycotoxins was found to be an additive one. A synergistic interaction, mainly regarding the oxidation status of the spermatozoa, was also found between the mycotoxins. The current study sheds light on the potential risk of exposing spermatozoa to a mycotoxin mixture. Full article

(This article belongs to the Special Issue Effects of Feedborne Mycotoxins on Animal Health 2.0)

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Toxins, Volume 15, Issue 9 (September 2023) – 73 articles

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