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Toxins, Volume 15, Issue 8 (August 2023) – 38 articles

Cover Story (view full-size image): Mycolactone, a toxin produced by Mycobacterium ulcerans, causes the NTD Buruli ulcer by inhibiting peptide translocation through the Sec61 translocon. Only one of two isoforms (B) is cytotoxic. This work probes the roles of cellular localization versus association in isomer specificity. Simulations reveal that stronger membrane affinity increases the local concentration of isomer B. Concomitantly, mycolactone B interacts more potently with the translocon through patch residues involved in signal recognition during co-translation and through gating elements during post-translational translocation. Thus, isomer specificity is a consequence of both localization and association revealing molecular features that may benefit the development of Buruli ulcer diagnostics and Sec61 therapeutics. View this paper
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13 pages, 3029 KiB  
Article
Quercetin Alleviates Lipopolysaccharide-Induced Cell Oxidative Stress and Inflammatory Responses via Regulation of the TLR4-NF-κB Signaling Pathway in Bovine Rumen Epithelial Cells
by Maocheng Jiang, Kexin Wang, Yinghao Huang, Xuelei Zhang, Tianyu Yang, Kang Zhan and Guoqi Zhao
Toxins 2023, 15(8), 512; https://doi.org/10.3390/toxins15080512 - 21 Aug 2023
Cited by 3 | Viewed by 1391
Abstract
Subacute rumen acidosis (SARA) will cause an increase in endotoxin, which will have a negative effect on the bovine rumen epithelial cells (BREC). Flavonoids are effective in treating inflammation caused by endotoxin. Quercetin is a vital flavonoid widely occurring in fruits and vegetables [...] Read more.
Subacute rumen acidosis (SARA) will cause an increase in endotoxin, which will have a negative effect on the bovine rumen epithelial cells (BREC). Flavonoids are effective in treating inflammation caused by endotoxin. Quercetin is a vital flavonoid widely occurring in fruits and vegetables and has received significant interest as a prospective anti-inflammatory antioxidant. Nonetheless, quercetin’s protective machinery against such damage to BREC induced by lipopolysaccharide (LPS) remains unclear. A combined quercetin and LPS-induced BREC inflammation model was utilized to elucidate the effect of quercetin protecting BREC from LPS-induced injury. After treating BREC with different doses of LPS (1, 5, and 10 μg/mL) for 6 h or 24 h, the mRNA expression of inflammatory factors was detected. Our experimental results show the establishment of the BREC inflammation model via mRNA high expression of pro-inflammatory cytokines in BREC following 6 h treatment with 1 µg/mL LPS. The promotive effect of 80 μg/mL quercetin on BREC growth via the cell counting kit-8 (CCK8) assay was observed. The expression of pro-inflammatory cytokines and chemokines, notably tumor necrosis factor α (TNF-α), Interleukin 1β (IL-1β), IL-6, CC-motif chemokine ligand 2 (CCL2), CCL20, CCL28, and CXC motif chemokine 9 (CXCL9), etc., was significantly reduced by quercetin supplementation. We also analyzed the mRNA detection of related pathways by qRT-PCR. Our validation studies demonstrated that quercetin markedly curbed the mRNA expression of the toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein (MyD88) and the nuclear factor-κB (NF-κB) in LPS-treated BREC. In addition, western blot result outcomes confirmed, as expected, that LPS significantly activated phosphorylation of p44/42 extracellular regulated protein kinases (ERK1/2) and NF-κB. Unexpectedly, this effect was reversed by adding quercetin. To complement western blot results, we assessed p-ERK1/2 and p-p65 protein expression using immunofluorescence, which gave consistent results. Therefore, quercetin’s capacity to bar the TLR4-mediated NF-κB and MAPK signaling pathways may be the cause of its anti-inflammatory effects on LPS-induced inflammatory reactions in BREC. According to these results, quercetin may be utilized as an anti-inflammatory medication to alleviate inflammation brought on by high-grain feed, and it also lays out a conceptual foundation regarding the development and utilization of quercetin in the later stage. Full article
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15 pages, 341 KiB  
Review
Modified Mycotoxins and Multitoxin Contamination of Food and Feed as Major Analytical Challenges
by Ksenija Nešić, Kristina Habschied and Krešimir Mastanjević
Toxins 2023, 15(8), 511; https://doi.org/10.3390/toxins15080511 - 19 Aug 2023
Cited by 4 | Viewed by 1455
Abstract
Mycotoxins, as natural products of molds, are often unavoidable contaminants of food and feed, to which the increasingly evident climate changes contribute a large part. The consequences are more or less severe and range from economic losses to worrying health problems to a [...] Read more.
Mycotoxins, as natural products of molds, are often unavoidable contaminants of food and feed, to which the increasingly evident climate changes contribute a large part. The consequences are more or less severe and range from economic losses to worrying health problems to a fatal outcome. One of the best preventive approaches is regular monitoring of food and feed for the presence of mycotoxins. However, even under conditions of frequent, comprehensive, and conscientious controls, the desired protection goal may not be achieved. In fact, it often happens that, despite favorable analytical results that do not indicate high mycotoxin contamination, symptoms of their presence occur in practice. The most common reasons for this are the simultaneous presence of several different mycotoxins whose individual content does not exceed the detectable or prescribed values and/or the alteration of the form of the mycotoxin, which renders it impossible to be analytically determined using routine methods. When such contaminated foods enter a living organism, toxic effects occur. This article aims to shed light on the above problems in order to pay more attention to them, work to reduce their impact, and, eventually, overcome them. Full article
(This article belongs to the Section Mycotoxins)
30 pages, 2031 KiB  
Review
The Need for Next-Generation Antivenom for Snakebite Envenomation in India
by Muralidharan Vanuopadath, Karthika Rajan, Aswathy Alangode, Sudarslal Sadasivan Nair and Bipin Gopalakrishnan Nair
Toxins 2023, 15(8), 510; https://doi.org/10.3390/toxins15080510 - 18 Aug 2023
Cited by 2 | Viewed by 2088
Abstract
The limitations posed by currently available antivenoms have emphasized the need for alternative treatments to counteract snakebite envenomation. Even though exact epidemiological data are lacking, reports have indicated that most global snakebite deaths are reported in India. Among the many problems associated with [...] Read more.
The limitations posed by currently available antivenoms have emphasized the need for alternative treatments to counteract snakebite envenomation. Even though exact epidemiological data are lacking, reports have indicated that most global snakebite deaths are reported in India. Among the many problems associated with snakebite envenomation, issues related to the availability of safer and more efficient antivenoms are of primary concern. Since India has the highest number of global snakebite deaths, efforts should be made to reduce the burden associated with snakebite envenoming. Alternative methods, including aptamers, camel antivenoms, phage display techniques for generating high-affinity antibodies and antibody fragments, small-molecule inhibitors, and natural products, are currently being investigated for their effectiveness. These alternative methods have shown promise in vitro, but their in vivo effectiveness should also be evaluated. In this review, the issues associated with Indian polyvalent antivenoms in neutralizing venom components from geographically distant species are discussed in detail. In a nutshell, this review gives an overview of the current drawbacks of using animal-derived antivenoms and several alternative strategies that are currently being widely explored. Full article
(This article belongs to the Special Issue Snake Venom-Omics and Next Generation Antivenom)
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12 pages, 593 KiB  
Review
Botulinum Toxin—A High-Dosage Effect on Functional Outcome and Spasticity-Related Pain in Subjects with Stroke
by Domenico Intiso, Antonello Marco Centra, Michele Gravina, Angelo Chiaramonte, Michelangelo Bartolo and Filomena Di Rienzo
Toxins 2023, 15(8), 509; https://doi.org/10.3390/toxins15080509 - 18 Aug 2023
Cited by 1 | Viewed by 1332
Abstract
Stroke patients can develop spasticity and spasticity-related pain (SRP). These disorders are frequent and can contribute to functional limitations and disabling conditions. Many reports have suggested that higher doses than initially recommended of BTX-A can be used effectively and safely, especially in the [...] Read more.
Stroke patients can develop spasticity and spasticity-related pain (SRP). These disorders are frequent and can contribute to functional limitations and disabling conditions. Many reports have suggested that higher doses than initially recommended of BTX-A can be used effectively and safely, especially in the case of severe spasticity; however, whether the treatment produces any benefit on the functional outcome and SRP is unclear. Studies published between January 1989 and December 2022 were retrieved from MEDLINE/PubMed, Embase, and Cochrane Central Register. Only obabotulinumtoxinA (obaBTX-A), onabotulinumtoxinA, (onaBTX-A), and incobotulinumtoxinA (incoBTX-A) were considered. The term “high dosage” indicates ≥600 U. Nine studies met the inclusion criteria. Globally, 460 subjects were treated with BTX-A high dose, and 301 suffered from stroke. Studies had variable method designs, sample sizes, and aims. Only five (55.5%) reported data about the functional outcome after BTX-A injection. Functional measures were also variable, and the improvement was observed predominantly in the disability assessment scale (DAS). SRP pain was quantified by visual analog scale (VAS) and only three studies reported the BTX-A effect. There is no scientific evidence that this therapeutic strategy unequivocally improves the functionality of the limbs. Although no clear-cut evidence emerges, certain patients with spasticity might obtain goal-oriented improvement from high-dose BTX-A. Likewise, data are insufficient to recommend high BTX dosage in SRP. Full article
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17 pages, 7408 KiB  
Article
A Multi-Layer-Controlled Strategy for Cloning and Expression of Toxin Genes in Escherichia coli
by Jessie Vandierendonck, Yana Girardin, Pieter De Bruyn, Henri De Greve and Remy Loris
Toxins 2023, 15(8), 508; https://doi.org/10.3390/toxins15080508 - 18 Aug 2023
Cited by 1 | Viewed by 1963
Abstract
Molecular cloning and controlled expression remain challenging when the target gene encodes a protein that is toxic to the host. We developed a set of multi-layer control systems to enable cloning of genes encoding proteins known to be highly toxic in Escherichia coli [...] Read more.
Molecular cloning and controlled expression remain challenging when the target gene encodes a protein that is toxic to the host. We developed a set of multi-layer control systems to enable cloning of genes encoding proteins known to be highly toxic in Escherichia coli and other bacteria. The different multi-layer control systems combine a promoter–operator system on a transcriptional level with a riboswitch for translational control. Additionally, replicational control is ensured by using a strain that reduces the plasmid copy number. The use of weaker promoters (such as PBAD or PfdeA) in combination with the effective theophylline riboswitch is essential for cloning genes that encode notoriously toxic proteins that directly target translation and transcription. Controlled overexpression is possible, allowing the system to be used for evaluating in vivo effects of the toxin. Systems with a stronger promoter can be used for successful overexpression and purification of the desired protein but are limited to toxins that are more moderate and do not interfere with their own production. Full article
(This article belongs to the Section Bacterial Toxins)
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14 pages, 1389 KiB  
Article
Expression of Cholera Toxin (CT) and the Toxin Co-Regulated Pilus (TCP) by Variants of ToxT in Vibrio cholerae Strains
by Donghyun Lee, Hunseok Choi, Seonghyeon Son, Jonghyun Bae, Jayun Joo, Dong Wook Kim and Eun Jin Kim
Toxins 2023, 15(8), 507; https://doi.org/10.3390/toxins15080507 - 17 Aug 2023
Cited by 2 | Viewed by 1619
Abstract
The expression of the two major virulence genes of Vibrio choleraetcpA (the major subunit of the toxin co-regulated pilus) and ctxAB (cholera toxin)—is regulated by the ToxR regulon, which is triggered by environmental stimuli during infection within the human small intestine. [...] Read more.
The expression of the two major virulence genes of Vibrio choleraetcpA (the major subunit of the toxin co-regulated pilus) and ctxAB (cholera toxin)—is regulated by the ToxR regulon, which is triggered by environmental stimuli during infection within the human small intestine. Special culture methods are required to induce the expression of virulence genes in V. cholerae in the laboratory setting. In the present study, induction of the expression of virulence genes by two point mutations (65th and 139th amino acids) in toxT, which is produced by the ToxR regulon and activates the transcription of the virulence genes in V. cholerae, under laboratory culture conditions has been investigated. Each of the four toxT alleles assessed displayed different transcriptional activator functions in a given V. cholerae strain. Although the ToxR regulon has been known to not be expressed by El Tor biotype V. cholerae strains cultured under standard laboratory conditions, the variant toxT alleles that we assessed in this study enabled the expression virulence genes in El Tor biotype strains grown under simple culture conditions comprising shake culture in LB medium, suggesting that the regulation of virulence gene expression may be regulated more complexly than previously thought and may involve additional factors beyond the production of ToxT by the ToxR regulon. Full article
(This article belongs to the Special Issue Cholera Toxin)
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20 pages, 11391 KiB  
Article
Of Seven New K+ Channel Inhibitor Peptides of Centruroides bonito, α-KTx 2.24 Has a Picomolar Affinity for Kv1.2
by Kashmala Shakeel, Timoteo Olamendi-Portugal, Muhammad Umair Naseem, Baltazar Becerril, Fernando Z. Zamudio, Gustavo Delgado-Prudencio, Lourival Domingos Possani and Gyorgy Panyi
Toxins 2023, 15(8), 506; https://doi.org/10.3390/toxins15080506 - 15 Aug 2023
Cited by 1 | Viewed by 1143
Abstract
Seven new peptides denominated CboK1 to CboK7 were isolated from the venom of the Mexican scorpion Centruroides bonito and their primary structures were determined. The molecular weights ranged between 3760.4 Da and 4357.9 Da, containing 32 to 39 amino acid residues with three [...] Read more.
Seven new peptides denominated CboK1 to CboK7 were isolated from the venom of the Mexican scorpion Centruroides bonito and their primary structures were determined. The molecular weights ranged between 3760.4 Da and 4357.9 Da, containing 32 to 39 amino acid residues with three putative disulfide bridges. The comparison of amino acid sequences with known potassium scorpion toxins (KTx) and phylogenetic analysis revealed that CboK1 (α-KTx 10.5) and CboK2 (α-KTx 10.6) belong to the α-KTx 10.x subfamily, whereas CboK3 (α-KTx 2.22), CboK4 (α-KTx 2.23), CboK6 (α-KTx 2.21), and CboK7 (α-KTx 2.24) bear > 95% amino acid similarity with members of the α-KTx 2.x subfamily, and CboK5 is identical to Ce3 toxin (α-KTx 2.10). Electrophysiological assays demonstrated that except CboK1, all six other peptides blocked the Kv1.2 channel with Kd values in the picomolar range (24–763 pM) and inhibited the Kv1.3 channel with comparatively less potency (Kd values between 20–171 nM). CboK3 and CboK4 inhibited less than 10% and CboK7 inhibited about 42% of Kv1.1 currents at 100 nM concentration. Among all, CboK7 showed out-standing affinity for Kv1.2 (Kd = 24 pM), as well as high selectivity over Kv1.3 (850-fold) and Kv1.1 (~6000-fold). These characteristics of CboK7 may provide a framework for developing tools to treat Kv1.2-related channelopathies. Full article
(This article belongs to the Special Issue Cross-Talk between Toxins and Channels)
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12 pages, 2449 KiB  
Article
Geographic Variability, Seasonality, and Increase in ASPCA Animal Poison Control Center Harmful Blue-Green Algae Calls—United States and Canada, 2010–2022
by Rebecca A. Bloch, Grace Faulkner, Elizabeth D. Hilborn, Tina Wismer, Nicole Martin and Sarah Rhea
Toxins 2023, 15(8), 505; https://doi.org/10.3390/toxins15080505 - 15 Aug 2023
Cited by 1 | Viewed by 1549
Abstract
Harmful cyanobacteria (blue-green algae) exposures can cause illness or death in humans and animals. We characterized American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC) harmful blue-green algae (HBGA) call data, compared it to a measure of [...] Read more.
Harmful cyanobacteria (blue-green algae) exposures can cause illness or death in humans and animals. We characterized American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC) harmful blue-green algae (HBGA) call data, compared it to a measure of harmful algal bloom public awareness, and considered its suitability as a public health information source. ASPCA APCC dog and cat “HBGA exposure” calls made 1 January 2010–31 December 2022 were included. We calculated annual HBGA call percentages and described calls (species, month, origin, exposure route). We characterized public awareness by quantifying Nexis Uni® (LexisNexis Academic; New York, NY, USA)-indexed news publications (2010–2022) pertaining to “harmful algal bloom(s)”. Call percentage increased annually, from 0.005% (2010) to 0.070% (2022). Of 999 HBGA calls, 99.4% (n = 993) were dog exposures. Over 65% (n = 655) of calls were made July–September, largely from the New England (n = 154 (15.4%)) and Pacific (n = 129 (12.9.%)) geographic divisions. Oral and dermal exposures predominated (n = 956 (95.7%)). Harmful algal bloom news publications increased overall, peaking in 2019 (n = 1834). Higher call volumes in summer and in the New England and Pacific geographic divisions drove HBGA call increases; public awareness might have contributed. Dogs and humans have similar exposure routes. ASPCA APCC HBGA call data could serve as a public health information source. Full article
(This article belongs to the Special Issue Unveiling the Toxic Effects of Harmful Algal Blooms)
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29 pages, 6193 KiB  
Article
A Novel Therapeutic Formulation for the Improved Treatment of Indian Red Scorpion (Mesobuthus tamulus) Venom-Induced Toxicity-Tested in Caenorhabditis elegans and Rodent Models
by Bhabana Das, Dev Madhubala, Saurov Mahanta, Aparup Patra, Upasana Puzari, Mojibur R. Khan and Ashis K. Mukherjee
Toxins 2023, 15(8), 504; https://doi.org/10.3390/toxins15080504 - 14 Aug 2023
Cited by 1 | Viewed by 2229
Abstract
Indian Red Scorpion (Mesobuthus tamulus) stings are a neglected public health problem in tropical and sub-tropical countries, including India. The drawbacks of conventional therapies using commercial anti-scorpion antivenom (ASA) and α1-adrenoreceptor antagonists (AAA) have prompted us to search for an adequate [...] Read more.
Indian Red Scorpion (Mesobuthus tamulus) stings are a neglected public health problem in tropical and sub-tropical countries, including India. The drawbacks of conventional therapies using commercial anti-scorpion antivenom (ASA) and α1-adrenoreceptor antagonists (AAA) have prompted us to search for an adequate formulation to improve treatment against M. tamulus stings. Novel therapeutic drug formulations (TDF) of low doses of commercial ASA, AAA, and ascorbic acid have remarkably improved in neutralising the in vivo toxic effects of M. tamulus venom (MTV) tested in Caenorhabditis elegans and Wistar strain albino rats in vivo models. The neutralisation of MTV-induced production of free radicals, alteration of the mitochondrial transmembrane potential, and upregulated expression of genes involved in apoptosis, detoxification, and stress response in C. elegans by TDF surpassed the same effect shown by individual components of the TDF. Further, TDF efficiently neutralized the MTV-induced increase in blood glucose level within 30 to 60 min post-treatment, organ tissue damage, necrosis, and pulmonary oedema in Wistar rats, indicating its clinical application for effecting treating M. tamulus envenomation. This study demonstrates for the first time that C. elegans can be a model organism for screening the neutralization potency of the drug molecules against a neurotoxic scorpion venom. Full article
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19 pages, 10885 KiB  
Article
Deciphering the Hazardous Effects of AFB1 and T-2 Toxins: Unveiling Toxicity and Oxidative Stress Mechanisms in PK15 Cells and Mouse Kidneys
by Shuai Xiao, Yingxin Wu, Suisui Gao, Mingxia Zhou, Zhiwei Liu, Qianbo Xiong, Lihuang Jiang, Guoxiang Yuan, Linfeng Li and Lingchen Yang
Toxins 2023, 15(8), 503; https://doi.org/10.3390/toxins15080503 - 14 Aug 2023
Cited by 4 | Viewed by 1238
Abstract
In China, animal feeds are frequently contaminated with a range of mycotoxins, with Aflatoxin B1 (AFB1) and T-2 toxin (T-2) being two highly toxic mycotoxins. This study investigates the combined nephrotoxicity of AFB1 and T-2 on PK15 cells and murine renal tissues and [...] Read more.
In China, animal feeds are frequently contaminated with a range of mycotoxins, with Aflatoxin B1 (AFB1) and T-2 toxin (T-2) being two highly toxic mycotoxins. This study investigates the combined nephrotoxicity of AFB1 and T-2 on PK15 cells and murine renal tissues and their related oxidative stress mechanisms. PK15 cells were treated with the respective toxin concentrations for 24 h, and oxidative stress-related indicators were assessed. The results showed that the combination of AFB1 and T-2 led to more severe cellular damage and oxidative stress compared to exposure to the individual toxins (p < 0.05). In the in vivo study, pathological examination revealed that the kidney tissue of mice exposed to the combined toxins showed signs of glomerular atrophy. The contents of oxidative stress-related indicators were significantly increased in the kidney tissue (p < 0.05). These findings suggest that the combined toxins cause significant oxidative damage to mouse kidneys. The study highlights the importance of considering the combined effects of mycotoxins in animal feed, particularly AFB1 and T-2, which can lead to severe nephrotoxicity and oxidative stress in PK15 cells and mouse kidneys. The findings have important implications for animal feed safety and regulatory policy. Full article
(This article belongs to the Special Issue Effects of Mycotoxins on Animals)
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14 pages, 1933 KiB  
Review
Modulation of Autophagy and Cell Death by Bacterial Outer-Membrane Vesicles
by Camille Pin, Laure David and Eric Oswald
Toxins 2023, 15(8), 502; https://doi.org/10.3390/toxins15080502 - 14 Aug 2023
Cited by 2 | Viewed by 2093
Abstract
Bacteria, akin to eukaryotic cells, possess the ability to release extracellular vesicles, lipidic nanostructures that serve diverse functions in host–pathogen interactions during infections. In particular, Gram-negative bacteria produce specific vesicles with a single lipidic layer called OMVs (Outer Membrane Vesicles). These vesicles exhibit [...] Read more.
Bacteria, akin to eukaryotic cells, possess the ability to release extracellular vesicles, lipidic nanostructures that serve diverse functions in host–pathogen interactions during infections. In particular, Gram-negative bacteria produce specific vesicles with a single lipidic layer called OMVs (Outer Membrane Vesicles). These vesicles exhibit remarkable capabilities, such as disseminating throughout the entire organism, transporting toxins, and being internalized by eukaryotic cells. Notably, the cytosolic detection of lipopolysaccharides (LPSs) present at their surface initiates an immune response characterized by non-canonical inflammasome activation, resulting in pyroptotic cell death and the release of pro-inflammatory cytokines. However, the influence of these vesicles extends beyond their well-established roles, as they also profoundly impact host cell viability by directly interfering with essential cellular machinery. This comprehensive review highlights the disruptive effects of these vesicles, particularly on autophagy and associated cell death, and explores their implications for pathogen virulence during infections, as well as their potential in shaping novel therapeutic approaches. Full article
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12 pages, 1788 KiB  
Article
Okadaic Acid Detection through a Rapid and Sensitive Amplified Luminescent Proximity Homogeneous Assay
by Yuan Qin, Jiayu Li, Jiani Kuang, Sicheng Shen, Xiumei Zhou, Xueqin Zhao, Biao Huang and Bingnan Han
Toxins 2023, 15(8), 501; https://doi.org/10.3390/toxins15080501 - 14 Aug 2023
Cited by 1 | Viewed by 1232
Abstract
Okadaic acid (OA), a marine biotoxin produced by microalgae, poses a significant threat to mariculture, seafood safety, and human health. The establishment of a novel, highly sensitive detection method for OA would have significant practical and scientific implications. Therefore, the purpose of this [...] Read more.
Okadaic acid (OA), a marine biotoxin produced by microalgae, poses a significant threat to mariculture, seafood safety, and human health. The establishment of a novel, highly sensitive detection method for OA would have significant practical and scientific implications. Therefore, the purpose of this study was to develop an innovative approach for OA detection. A competitive amplified luminescent proximity homogeneous assay (AlphaLISA) was developed using the principle of specific antigen–antibody binding based on the energy transfer between chemiluminescent microspheres. The method was non-washable, sensitive, and rapid, which could detect 2 × 10−2–200 ng/mL of OA within 15 min, and the detection limit was 4.55 × 10−3 ng/mL. The average intra- and inter-assay coefficients of variation were 2.54% and 6.26%, respectively. Detection of the actual sample results exhibited a good correlation with high-performance liquid chromatography. In conclusion, a simple, rapid, sensitive, and accurate AlphaLISA method was established for detecting OA and is expected to significantly contribute to marine biotoxin research. Full article
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16 pages, 2621 KiB  
Article
A Metalloproteinase Cocktail from the Venom of Protobothrops flavoviridis Cleaves Amyloid Beta Peptides at the α-Cleavage Site
by Eugene Futai, Hajime Kawasaki, Shinichi Sato, Khadija Daoudi, Masafumi Hidaka, Taisuke Tomita and Tomohisa Ogawa
Toxins 2023, 15(8), 500; https://doi.org/10.3390/toxins15080500 - 12 Aug 2023
Viewed by 2567
Abstract
A disintegrin and metalloproteinase (ADAM) family proteins are a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell surface protein ectodomains, including amyloid precursor protein (APP). Human ADAM 9, 10, and 17 proteolyze APPs and produce non-amyloid-genic p3 [...] Read more.
A disintegrin and metalloproteinase (ADAM) family proteins are a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell surface protein ectodomains, including amyloid precursor protein (APP). Human ADAM 9, 10, and 17 proteolyze APPs and produce non-amyloid-genic p3 peptides, instead of neurotoxic amyloid-β peptides (Aβs; Aβ40 and Aβ42), which form fibrils and accumulate in the brain of patients with Alzheimer’s disease (AD). The ADAM family is closely related to snake venom metalloproteinases (SVMPs), which are derived from ancestral ADAMs but act as soluble proteinases. To test the therapeutic potential of SVMPs, we purified SVMPs from Protobothrops flavoviridis venom using metal ion affinity and pooled into a cocktail. Thus, 9 out of 11 SVMPs in the P. flavoviridis genome were identified in the cocktail. SVMPs inhibited Aβ secretion when added to human cell culture medium without affecting APP proteolysis. SVMPs degraded synthetic Aβ40 and Aβ42 peptides at the same cleavage site (α-site of APP) as ADAM9, 10, and 17. SVMPs did not degrade Aβ fibrils but interfered with their formation, assessed using thioflavin-T. Thus, SVMPs have therapeutic potential for AD as an Aβ-degrading protease, and the finding adds to the discovery of bioactive peptides from venoms as novel therapeutics. Full article
(This article belongs to the Special Issue Potential Therapeutic Applications of Animal Venoms and Toxins)
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20 pages, 1699 KiB  
Review
Gut Microbiota Interventions to Retain Residual Kidney Function
by Denise Mafra, Julie A. Kemp, Natalia A. Borges, Michelle Wong and Peter Stenvinkel
Toxins 2023, 15(8), 499; https://doi.org/10.3390/toxins15080499 - 11 Aug 2023
Cited by 3 | Viewed by 2478
Abstract
Residual kidney function for patients with chronic kidney disease (CKD) is associated with better quality of life and outcome; thus, strategies should be implemented to preserve kidney function. Among the multiple causes that promote kidney damage, gut dysbiosis due to increased uremic toxin [...] Read more.
Residual kidney function for patients with chronic kidney disease (CKD) is associated with better quality of life and outcome; thus, strategies should be implemented to preserve kidney function. Among the multiple causes that promote kidney damage, gut dysbiosis due to increased uremic toxin production and endotoxemia need attention. Several strategies have been proposed to modulate the gut microbiota in these patients, and diet has gained increasing attention in recent years since it is the primary driver of gut dysbiosis. In addition, medications and faecal transplantation may be valid strategies. Modifying gut microbiota composition may mitigate chronic kidney damage and preserve residual kidney function. Although various studies have shown the influential role of diet in modulating gut microbiota composition, the effects of this modulation on residual kidney function remain limited. This review discusses the role of gut microbiota metabolism on residual kidney function and vice versa and how we could preserve the residual kidney function by modulating the gut microbiota balance. Full article
(This article belongs to the Special Issue Kidney Replacement Therapy by Hemodialysis: 21st Century Challenges)
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20 pages, 2638 KiB  
Article
Unveiling the Protein Components of the Secretory-Venom Gland and Venom of the Scorpion Centruroides possanii (Buthidae) through Omic Technologies
by Patricia Elizabeth García-Villalvazo, Juana María Jiménez-Vargas, Gisela Jareth Lino-López, Erika Patricia Meneses, Manuel de Jesús Bermúdez-Guzmán, Carlos Eduardo Barajas-Saucedo, Iván Delgado Enciso, Lourival Domingos Possani and Laura Leticia Valdez-Velazquez
Toxins 2023, 15(8), 498; https://doi.org/10.3390/toxins15080498 - 9 Aug 2023
Cited by 2 | Viewed by 1777
Abstract
Centruroides possanii is a recently discovered species of “striped scorpion” found in Mexico. Certain species of Centruroides are known to be toxic to mammals, leading to numerous cases of human intoxications in the country. Venom components are thought to possess therapeutic potential and/or [...] Read more.
Centruroides possanii is a recently discovered species of “striped scorpion” found in Mexico. Certain species of Centruroides are known to be toxic to mammals, leading to numerous cases of human intoxications in the country. Venom components are thought to possess therapeutic potential and/or biotechnological applications. Hence, obtaining and analyzing the secretory gland transcriptome and venom proteome of C. possanii is relevant, and that is what is described in this communication. Since this is a newly described species, first, its LD50 to mice was determined and estimated to be 659 ng/g mouse weight. Using RNA extracted from this species and preparing their corresponding cDNA fragments, a transcriptome analysis was obtained on a Genome Analyzer (Illumina) using the 76-base pair-end sequencing protocol. Via high-throughput sequencing, 19,158,736 reads were obtained and ensembled in 835,204 sequences. Of them, 28,399 transcripts were annotated with Pfam. A total of 244 complete transcripts were identified in the transcriptome of C. possanii. Of these, 109 sequences showed identity to toxins that act on ion channels, 47 enzymes, 17 protease inhibitors (PINs), 11 defense peptides (HDPs), and 60 in other components. In addition, a sample of the soluble venom obtained from this scorpion was analyzed using an Orbitrap Velos apparatus, which allowed for identification by liquid chromatography followed by mass spectrometry (LC-MS/MS) of 70 peptides and proteins: 23 toxins, 27 enzymes, 6 PINs, 3 HDPs, and 11 other components. Until now, this work has the highest number of scorpion venom components identified through omics technologies. The main novel findings described here were analyzed in comparison with the known data from the literature, and this process permitted some new insights in this field. Full article
(This article belongs to the Special Issue Animal Venoms: Proteomics, Biochemical Activities and Application)
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11 pages, 2673 KiB  
Article
The Impact of Storage Temperature and Time on Ergot Alkaloid Concentrations
by Jensen E. Cherewyk, Taylor J. Grusie-Ogilvie, Sarah E. Parker, Barry R. Blakley and Ahmad N. Al-Dissi
Toxins 2023, 15(8), 497; https://doi.org/10.3390/toxins15080497 - 5 Aug 2023
Cited by 1 | Viewed by 1186
Abstract
Ergot sclerotia produce toxic secondary metabolites, ergot alkaloids, that infect cereal crops and grasses. Ergot alkaloids have two isomeric configurations: the C-8-R-isomer (R-epimer), and the C-8-S-isomer (S-epimer). Ergot contaminated matrices, such as cereal grains or [...] Read more.
Ergot sclerotia produce toxic secondary metabolites, ergot alkaloids, that infect cereal crops and grasses. Ergot alkaloids have two isomeric configurations: the C-8-R-isomer (R-epimer), and the C-8-S-isomer (S-epimer). Ergot contaminated matrices, such as cereal grains or grasses, may be stored for extended periods at various temperatures before being analyzed, utilized, or consumed. This study assessed the concentration of six common ergot alkaloids in both configurations found in naturally contaminated wheat over time (one, two, and four months) at different temperatures (room temperature, +4 °C, and −20 °C) using ultra-high-performance liquid chromatography–tandem mass spectrometry. The data indicate that the total ergot concentration within a natural contaminated sample varies over time at room temperature, +4 °C, and −20 °C. The total ergot concentration increased until month two, and decreased at month four, independent of temperature (p < 0.05). The total R-epimer concentration appeared to be less stable over time than the total S-epimer concentration. The changes in the total R and total S-epimer concentrations may have been caused by changes in the ergocristine and ergocristinine concentrations, respectively. Time and temperature should be considered when storing potentially contaminated matrices in a laboratory or practical agriculture situations. Quantification of ergot contaminated matrices should occur prior to their use to ensure the most reliable estimates of the concentration of ergot. Full article
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15 pages, 3730 KiB  
Article
Selenomethionine Antagonized microRNAs Involved in Apoptosis of Rat Articular Cartilage Induced by T-2 Toxin
by Fangfang Yu, Kangting Luo, Miao Wang, Jincai Luo, Lei Sun, Shuiyuan Yu, Juan Zuo and Yanjie Wang
Toxins 2023, 15(8), 496; https://doi.org/10.3390/toxins15080496 - 4 Aug 2023
Cited by 3 | Viewed by 1178
Abstract
T-2 toxin and selenium deficiency are considered important etiologies of Kashin–Beck disease (KBD), although the exact mechanism is still unclear. To identify differentially expressed microRNAs (DE-miRNAs) in the articular cartilage of rats exposed to T-2 toxin and selenomethionine (SeMet) supplementation, thirty-six 4-week-old Sprague [...] Read more.
T-2 toxin and selenium deficiency are considered important etiologies of Kashin–Beck disease (KBD), although the exact mechanism is still unclear. To identify differentially expressed microRNAs (DE-miRNAs) in the articular cartilage of rats exposed to T-2 toxin and selenomethionine (SeMet) supplementation, thirty-six 4-week-old Sprague Dawley rats were divided into a control group (gavaged with 4% anhydrous ethanol), a T-2 group (gavaged with 100 ng/g·bw/day T-2 toxin), and a T-2 + SeMet group (gavaged with 100 ng/g·bw/day T-2 toxin and 0.5 mg/kg·bw/day SeMet), respectively. Toluidine blue staining was performed to detect the pathological changes of articular cartilage. Three rats per group were randomly selected for high-throughput sequencing of articular cartilage. Target genes of DE-miRNAs were predicted using miRanda and RNAhybrid databases, and the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway were enriched. The network map of miRNA-target genes was constructed using Cytoscape software. The expression profiles of miRNAs associated with KBD were obtained from the Gene Expression Omnibus database. Additionally, the DE-miRNAs were selected for real-time quantitative PCR (RT-qPCR) verification. Toluidine blue staining demonstrated that T-2 toxin damaged articular cartilage and SeMet effectively alleviated articular cartilage lesions. A total of 50 DE-miRNAs (28 upregulated and 22 downregulated) in the T-2 group vs. the control group, 18 DE-miRNAs (6 upregulated and 12 downregulated) in the T-2 + SeMet group vs. the control group, and 25 DE-miRNAs (5 upregulated and 20 downregulated) in the T-2 + SeMet group vs. the T-2 group were identified. Enrichment analysis showed the target genes of DE-miRNAs were associated with apoptosis, and in the MAPK and TGF-β signaling pathways in the T-2 group vs. the control group. However, the pathway of apoptosis was not significant in the T-2 + SeMet group vs. the control group. These results indicated that T-2 toxin induced apoptosis, whereas SeMet supplementation antagonized apoptosis. Apoptosis and autophagy occurred simultaneously in the T-2 + SeMet group vs. T-2 group, and autophagy may inhibit apoptosis to protect cartilage. Compared with the GSE186593 dataset, the evidence of miR-133a-3p involved in apoptosis was more abundant. The results of RT-qPCR validation were consistent with RNA sequencing results. Our findings suggested that apoptosis was involved in articular cartilage lesions induced by T-2 toxin, whereas SeMet supplementation antagonized apoptosis, and that miR-133a-3p most probably played a central role in the apoptosis process. Full article
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12 pages, 1012 KiB  
Article
Alternaria Mycotoxins Analysis and Exposure Investigation in Ruminant Feeds
by Xin Mao, Wanzhao Chen, Huimin Wu, Ying Shao, Ya’ning Zhu, Qingyong Guo, Yanshen Li and Lining Xia
Toxins 2023, 15(8), 495; https://doi.org/10.3390/toxins15080495 - 4 Aug 2023
Cited by 1 | Viewed by 1198
Abstract
Alternaria mycotoxins are a class of important, agriculture-related hazardous materials, and their contamination in ruminant feeds and products might bring severe toxic effects to animals and even human beings. To control these hazardous compounds, a reliable and sensitive LC-MS/MS (liquid chromatography–tandem mass spectrometry) [...] Read more.
Alternaria mycotoxins are a class of important, agriculture-related hazardous materials, and their contamination in ruminant feeds and products might bring severe toxic effects to animals and even human beings. To control these hazardous compounds, a reliable and sensitive LC-MS/MS (liquid chromatography–tandem mass spectrometry) method was established for simultaneous determination of six target Alternaria mycotoxins in ruminant feeds, including ALT (Altenuene), AME (Alternariol Monomethyl Ether), AOH (Alternariol), ATX-Ι (Altertoxins I), TeA (Tenuazonic Acid), and TEN (Tentoxin). This developed analytical method was used for the determination of the presence of these substances in cattle and sheep feeds in Xinjiang Province, China. The results revealed that Alternaria mycotoxins are ubiquitously detected in feed samples. Especially, AME, AOH, TeA, and TEN are the most frequently found mycotoxins with a positive rate over 40% and a concentration range of 4~551 µg/kg. The proposed method could be applied for exposure investigation of Alternaria mycotoxins in ruminant feeds and for the reduction in the health risk to animals and even consumers. Full article
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11 pages, 1569 KiB  
Article
Purification and Activity of the Second Recombinant Enzyme for Biodegrading Linearized Microcystins by Sphingopyxis sp. USTB-05
by Junhui Teng, Meijie Song, Qianqian Xu, Qianwen Zou, Haiyang Zhang, Chunhua Yin, Xiaolu Liu, Yang Liu and Hai Yan
Toxins 2023, 15(8), 494; https://doi.org/10.3390/toxins15080494 - 4 Aug 2023
Cited by 2 | Viewed by 1238
Abstract
Hepatotoxic microcystins (MCs) are produced and released by the harmful bloom-forming cyanobacteria, which severely threaten drinking water safety and human health due to their high toxicity, widespread distribution, and structural stability. The linearized microcystinase (MlrB) further hydrolyses the poisonous linearized MCs produced by [...] Read more.
Hepatotoxic microcystins (MCs) are produced and released by the harmful bloom-forming cyanobacteria, which severely threaten drinking water safety and human health due to their high toxicity, widespread distribution, and structural stability. The linearized microcystinase (MlrB) further hydrolyses the poisonous linearized MCs produced by the microcystinase-catalysed MCs to form tetrapeptides. Here, the purification and activity of MlrB were investigated. The results showed that the linearized products generated by 12.5 mg/L MC-LR and MC-RR were removed by purified recombinant MlrB at a protein concentration of 1 mg/L within 30 min. The high catalytic activity of MlrB can be obtained via heterologous expression and affinity purification, which lays the foundation for further studies on the properties and mechanism of MCs biodegradation enzymes. Full article
(This article belongs to the Special Issue Cyanobacterial Toxins: Toxins Production and Risk Assessment)
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13 pages, 2172 KiB  
Article
Evaluation of the Bioaccessible Fraction of T-2 Toxin from Cereals and Its Effect on the Viability of Caco-2 Cells Exposed to Tyrosol
by Carmen Martínez-Alonso, Mercedes Taroncher, Yelko Rodríguez-Carrasco and María-José Ruiz
Toxins 2023, 15(8), 493; https://doi.org/10.3390/toxins15080493 - 4 Aug 2023
Cited by 2 | Viewed by 1000
Abstract
The bioaccessibility of mycotoxins is an important factor that has to be considered when assessing the risk they pose to human health. Bioactive compounds like phenolics could play a protective role against the toxic effects of contaminants. In this work, the bioaccessible fraction [...] Read more.
The bioaccessibility of mycotoxins is an important factor that has to be considered when assessing the risk they pose to human health. Bioactive compounds like phenolics could play a protective role against the toxic effects of contaminants. In this work, the bioaccessible fraction of the T-2 toxin (T-2) contained in breakfast cereals and its effect on the viability of Caco-2 cells were investigated. Furthermore, the effect of tyrosol (a polyphenol abundant in EVOO) on T-2-induced cytotoxicity was evaluated in the same cell line. After standardized in vitro gastrointestinal digestion, the T-2 toxin was released from T-2-spiked breakfast cereals and further quantified by UHPLC-MS/MS. The bioaccessible fraction of T-2 was 51 ± 4%. The cell viability study was performed by pre-treating the cells for 24 h with tyrosol (25, 50 and 100 µM) and subsequently adding T-2 at 15 nM or by treating the cells with a combination of tyrosol and T-2. In the simultaneous treatment, 25 µM tyrosol prevented the toxic effects produced by the exposure to T-2 at 15 nM; however, cytotoxic effects were observed for the other combinations tested. The pre-treatment of Caco-2 cells with tyrosol did not attenuate the cytotoxic effects caused by exposure to T-2. These results suggest that tyrosol at low concentrations (25 µM) could exert a cytoprotective effect on Caco-2 cells against 15 nM T-2 when administered simultaneously with T-2. However, more studies are required to corroborate this hypothesis. Full article
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16 pages, 2179 KiB  
Article
Biotransformation of Deoxynivalenol by a Dual-Member Bacterial Consortium Isolated from Tenebrio molitor Larval Feces
by Yang Wang, Donglei Zhao, Wei Zhang, Songxue Wang, Kai Huang and Baoyuan Guo
Toxins 2023, 15(8), 492; https://doi.org/10.3390/toxins15080492 - 4 Aug 2023
Viewed by 1205
Abstract
In this study, a dual-member bacterial consortium with the ability to oxidize deoxynivalenol (DON) to 3-keto-DON, designated SD, was first screened from the feces of Tenebrio molitor larvae. This consortium consisted of Pseudomonas sp. SD17-1 and Devosia sp. SD17-2, as determined by 16S [...] Read more.
In this study, a dual-member bacterial consortium with the ability to oxidize deoxynivalenol (DON) to 3-keto-DON, designated SD, was first screened from the feces of Tenebrio molitor larvae. This consortium consisted of Pseudomonas sp. SD17-1 and Devosia sp. SD17-2, as determined by 16S rRNA-based phylogenetic analysis. A temperature of 30 °C, a pH of 8.0–9.0, and an initial inoculum concentration ratio of Devosia to Pseudomonas of 0.1 were optimal single-factor parameters for the DON oxidation activity of the bacterial consortium SD. Genome-based bioinformatics analysis revealed the presence of an intact PQQ biosynthesis operon (pqqFABCDEG) and four putative pyrroloquinoline quinone (PQQ)-dependent alcohol dehydrogenase (ADH) genes in the genomes of Pseudomonas strain SD17-1 and Devosia strain SD17-2, respectively. Biochemical analyses further confirmed the PQQ-producing phenotype of Pseudomonas and the DON-oxidizing enzymatic activities of two of four PQQ-dependent ADHs in Devosia. The addition of PQQ-containing a cell-free fermentation supernatant from Pseudomonas activated DON-oxidizing activity of Devosia. In summary, as members of the bacterial consortium SD, Pseudomonas and Devosia play indispensable and complementary roles in SD’s oxidation of DON. Specifically, Pseudomonas is responsible for producing the necessary PQQ cofactor, whereas Devosia expresses the PQQ-dependent DON dehydrogenase, together facilitating the oxidation of DON. Full article
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17 pages, 783 KiB  
Article
In Vivo Genotoxicity and Toxicity Assessment of Sterigmatocystin Individually and in Mixture with Aflatoxin B1
by Maria Alonso-Jauregui, Adela López de Cerain, Amaya Azqueta, Adriana Rodriguez-Garraus, Ana Gloria Gil, Elena González-Peñas and Ariane Vettorazzi
Toxins 2023, 15(8), 491; https://doi.org/10.3390/toxins15080491 - 3 Aug 2023
Cited by 4 | Viewed by 1174
Abstract
Mycotoxins are natural food and feed contaminants produced by several molds. The primary mode of exposure in humans and animals is through mixtures. Aflatoxin B1 (AFB1) and sterigmatocystin (STER) are structurally related mycotoxins that share the same biosynthetic route. Few in vivo genotoxicity [...] Read more.
Mycotoxins are natural food and feed contaminants produced by several molds. The primary mode of exposure in humans and animals is through mixtures. Aflatoxin B1 (AFB1) and sterigmatocystin (STER) are structurally related mycotoxins that share the same biosynthetic route. Few in vivo genotoxicity assays have been performed with STER. In the present genotoxicity study, Wistar rats were dosed orally with STER (20 mg/kg b.w.), AFB1 (0.25 mg/kg b.w.) or a mixture of both in an integrated micronucleus (bone marrow) and comet study (liver and kidney). STER was dosed at the highest feasible dose in corn oil. No increase in the percentage of micronuclei in bone marrow was observed at any condition. Slight DNA damage was detected in the livers of animals treated with AFB1 or the mixture (DNA strand breaks and Fpg (Formamidopyrimidine DNA glycosylase)-sensitive sites, respectively). Plasma, liver, and kidney samples were analyzed with LC-MS/MS demonstrating exposure to both mycotoxins. General toxicity parameters (organs absolute weight, biochemistry, and histopathology) were not altered either individually or in the mixture. The overall absence of individual genotoxicity did not allow us to set any type of interaction in the mixture. However, a possible toxicokinetic interaction was observed. Full article
(This article belongs to the Special Issue Genotoxic and Carcinogenic Potential of Emerging Mycotoxins)
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18 pages, 15978 KiB  
Article
In Silico–Ex Vitro Iteration Strategy for Affinity Maturation of Anti-Ricin Peptides and the SPR Biosensing Application
by Zhifang Yang, Chuang Wang, Jia Liu, Lan Xiao, Lei Guo and Jianwei Xie
Toxins 2023, 15(8), 490; https://doi.org/10.3390/toxins15080490 - 3 Aug 2023
Viewed by 1343
Abstract
The highly toxic plant toxin ricin is one of the most known threatening toxins. Accurate and sensitive biosensing methods for the first emergency response and intoxication treatment, are always pursued in the biodefense field. Screening affinity molecules is the fundamental mainstream approach for [...] Read more.
The highly toxic plant toxin ricin is one of the most known threatening toxins. Accurate and sensitive biosensing methods for the first emergency response and intoxication treatment, are always pursued in the biodefense field. Screening affinity molecules is the fundamental mainstream approach for developing biosensing methods. Compared with common affinity molecules such as antibodies and oligonucleotide aptamers, peptides have great potential as biosensing modules with more accessible chemical synthesis capability and better batch-to-batch stability than antibodies, more abundant interaction sites, and robust sensing performance towards complex environments. However, anti-ricin peptides are so scant to be screened and discovered, and an advanced screening strategy is the utmost to tackle this issue. Here, we present a new in silico-in vitro iteration-assisted affinity maturation strategy of anti-ricin peptides. We first obtained affinity peptides targeting ricin through phage display with five panning rounds of “coating-elution-amplification-enrichment” procedures. The binding affinity and kinetic parameters characterized by surface plasmon resonance (SPR) showed that we had obtained four peptides owning dissociation constants (KD) around 2~35 μM, in which peptide PD-2-R5 has the lower KD of 4.7 μM and higher stable posture to interact with ricin. We then constructed a new strategy for affinity maturity, composing two rounds of in silico-in vitro iterations. Firstly, towards the single-site alanine scanning mutation peptide library, the molecular docking predictions match the SPR evaluation results well, laying a solid foundation for designing a full saturation mutated peptide library. Secondly, plenty of in silico saturation mutation prediction results guided the discovery of peptides PD2-R5-T3 and PD-2-R5-T4 with higher affinity from only a limited number of SPR evaluation experiments. Both evolved peptides had increased affinity by about 5~20 times, i.e., KD of 230 nM and 900 nM. A primary cellular toxicity assay indicated that both peptides could protect cells against ricin damage. We further established an SPR assay based on PD-2-R5-T3 and PD-2-R5-T4 elongated with an antifouling peptide linkage and achieved good linearity with a sensitivity of 1 nM and 0.5 nM, respectively. We hope this new affinity-mature strategy will find its favorable position in relevant peptide evolution, biosensing, and medical countermeasures for biotoxins to protect society’s security and human life better. Full article
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16 pages, 990 KiB  
Review
Chemistry and Functions of Imported Fire Ant Venom
by Jian Chen
Toxins 2023, 15(8), 489; https://doi.org/10.3390/toxins15080489 - 3 Aug 2023
Cited by 1 | Viewed by 1734
Abstract
In the United States, imported fire ants are often referred to as red imported fire ants, Solenopsis invicta Buren, black imported fire ants, S. richteri Forel, and their hybrid (S. invicta × S. richteri). Due to their aggressive stings and toxic [...] Read more.
In the United States, imported fire ants are often referred to as red imported fire ants, Solenopsis invicta Buren, black imported fire ants, S. richteri Forel, and their hybrid (S. invicta × S. richteri). Due to their aggressive stings and toxic venom, imported fire ants pose a significant threat to public health, agriculture, and ecosystem health. However, venom plays a vital role in the survival of fire ants by serving various crucial functions in defense, foraging, and colony health maintenance. Numerous reviews and book chapters have been published on fire ant venom. Due to its medical importance and the expanding global distribution of these ants, fire ant venom research remains an active and highly productive area, leading to the discovery of new components and functions. This review summarizes the recent advances in our understanding of fire ant venom chemistry and its functions within fire ant colonies. Full article
(This article belongs to the Special Issue Ant Venom)
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14 pages, 3909 KiB  
Article
Isolation and Characterization of the Zearalenone-Degrading Strain, Bacillus spizizenii B73, Inspired by Esterase Activity
by Xue Liu, Na Wu, Mingyu Zhang, Feng Xue and Qing Xu
Toxins 2023, 15(8), 488; https://doi.org/10.3390/toxins15080488 - 2 Aug 2023
Cited by 2 | Viewed by 1429
Abstract
Zearalenone (ZEN) is a widespread mycotoxin found in grain and feed, presenting a serious threat to animal and human health. This study investigated the ability of the novel strain B73, isolated from petroleum-contaminated soil, to detoxify ZEN. B73 was identified as Bacillus spizizenii [...] Read more.
Zearalenone (ZEN) is a widespread mycotoxin found in grain and feed, presenting a serious threat to animal and human health. This study investigated the ability of the novel strain B73, isolated from petroleum-contaminated soil, to detoxify ZEN. B73 was identified as Bacillus spizizenii through physiological and biochemical tests, and further confirmed based on the 16S rRNA gene sequence and the complete genome sequence. B. spizizenii B73 was capable of degrading up to 99.3% of ZEN at a concentration of 10 μg/mL in a minimal medium (pH = 7.0) within 8 h at 37 °C via HPLC-UV. In addition, B. spizizenii B73 was used to treat ZEN-contaminated wheat bran, dried distillers grains (DDGS), and corn meal, whereby the respective degradation rates reached 96.32%, 98.73%, and 80.31% after 36 h of treatment. HPLC-Q-Exactive-MS/MS analysis revealed one of the degradation products to have the formula C17H24O4. B. spizizenii B73 is a novel strain isolated from petroleum-contaminated soil, and the extracellular enzymes secreted by this strain show a remarkable ability to degrade ZEN. Full article
(This article belongs to the Special Issue Strategies to Prevent Mycotoxin Contamination of Food and Feed)
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9 pages, 1445 KiB  
Article
Comparative Analysis of Alpha-1 Orthosteric-Site Binding by a Clade of Central American Pit Vipers (Genera Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium)
by Lee Jones, Callum Waite, Edgar Neri-Castro and Bryan G. Fry
Toxins 2023, 15(8), 487; https://doi.org/10.3390/toxins15080487 - 2 Aug 2023
Cited by 1 | Viewed by 1144
Abstract
The distribution and relative potency of post-synaptic neurotoxic activity within Crotalinae venoms has been the subject of less investigation in comparison with Elapidae snake venoms. No previous studies have investigated post-synaptic neurotoxic activity within the Atropoides, Metlapilcoatlus, Cerrophidion, and Porthidium [...] Read more.
The distribution and relative potency of post-synaptic neurotoxic activity within Crotalinae venoms has been the subject of less investigation in comparison with Elapidae snake venoms. No previous studies have investigated post-synaptic neurotoxic activity within the Atropoides, Metlapilcoatlus, Cerrophidion, and Porthidium clade. Given the specificity of neurotoxins to relevant prey types, we aimed to uncover any activity present within this clade of snakes that may have been overlooked due to lower potency upon humans and thus not appearing as a clinical feature. Using biolayer interferometry, we assessed the relative binding of crude venoms to amphibian, lizard, bird, rodent and human α-1 nAChR orthosteric sites. We report potent alpha-1 orthosteric site binding in venoms from Atropoides picadoi, Metlapilcoatlus occiduus, M. olmec, M. mexicanus, M. nummifer. Lower levels of binding, but still notable, were evident for Cerrophidion godmani, C. tzotzilorum and C. wilsoni venoms. No activity was observed for Porthidium venoms, which is consistent with significant alpha-1 orthosteric site neurotoxicity being a trait that was amplified in the last common ancestor of Atropoides/Cerrophidion/Metlapilcoatlus subsequent to the split by Porthidium. We also observed potent taxon-selective activity, with strong selection for non-mammalian targets (amphibian, lizard, and bird). As these are poorly studied snakes, much of what is known about them is from clinical reports. The lack of affinity towards mammalian targets may explain the knowledge gap in neurotoxic activity within these species, since symptoms would not appear in bite reports. This study reports novel venom activity, which was previously unreported, indicating toxins that bind to post-synaptic receptors may be more widespread in pit vipers than previously considered. While these effects appear to not be clinically significant due to lineage-specific effects, they are of significant evolutionary novelty and of biodiscovery interest. This work sets the stage for future research directions, such as the use of in vitro and in vivo models to determine whether the alpha-1 orthosteric site binding observed within this study confers neurotoxic venom activity. Full article
(This article belongs to the Special Issue Snakebite and Clinical Toxinology)
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21 pages, 4973 KiB  
Article
Mycolactone A vs. B: Multiscale Simulations Reveal the Roles of Localization and Association in Isomer-Specific Toxicity
by John D. M. Nguyen, Gabriel C. A. da Hora and Jessica M. J. Swanson
Toxins 2023, 15(8), 486; https://doi.org/10.3390/toxins15080486 - 2 Aug 2023
Viewed by 1452
Abstract
Mycolactone is an exotoxin produced by Mycobacterium ulcerans that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing several secretory and transmembrane proteins, resulting in cytotoxic and [...] Read more.
Mycolactone is an exotoxin produced by Mycobacterium ulcerans that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing several secretory and transmembrane proteins, resulting in cytotoxic and immunomodulatory effects. Interestingly, only one of the two dominant isoforms of mycolactone is cytotoxic. Here, we investigate the origin of this specificity by performing extensive molecular dynamics (MD) simulations with enhanced free energy sampling to query the association trends of the two isoforms with both the Sec61 translocon, using two distinct cryo-electron microscopy (cryo-EM) models as references, and the ER membrane, which serves as a toxin reservoir prior to association. Our results suggest that mycolactone B (the cytotoxic isoform) has a stronger association with the ER membrane than mycolactone A due to more favorable interactions with membrane lipids and water molecules. This could increase the reservoir of toxin proximal to the Sec61 translocon. In one model of Sec61 inhibited by mycolactone, we find that isomer B interacts more closely with residues thought to play a key role in signal peptide recognition and, thus, are essential for subsequent protein translocation. In the other model, we find that isomer B interacts more closely with the lumenal and lateral gates of the translocon, the dynamics of which are essential for protein translocation. These interactions induce a more closed conformation, which has been suggested to block signal peptide insertion and subsequent protein translocation. Collectively, these findings suggest that isomer B’s unique cytotoxicity is a consequence of both increased localization to the ER membrane and channel-locking association with the Sec61 translocon, facets that could be targeted in the development of Buruli Ulcer diagnostics and Sec61-targeted therapeutics. Full article
(This article belongs to the Section Bacterial Toxins)
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16 pages, 4158 KiB  
Article
First Confirmed Case of Canine Mortality Due to Dihydroanatoxin-a in Central Texas, USA
by Anthea Fredrickson, Aaron Richter, Katherine A. Perri and Schonna R. Manning
Toxins 2023, 15(8), 485; https://doi.org/10.3390/toxins15080485 - 1 Aug 2023
Cited by 2 | Viewed by 1197
Abstract
The frequency of dogs becoming ill or dying from accidental exposure to cyanotoxins, produced by cyanobacteria, is increasing throughout the United States. In January and February of 2021, two dogs died and five dogs became ill after swimming in Lake Travis, central Texas, [...] Read more.
The frequency of dogs becoming ill or dying from accidental exposure to cyanotoxins, produced by cyanobacteria, is increasing throughout the United States. In January and February of 2021, two dogs died and five dogs became ill after swimming in Lake Travis, central Texas, USA; one deceased dog (C1) was subjected to pathological testing. Algal materials, sediment samples, zebra mussel viscera, periphyton from shells, as well as fluids and tissues from the digestive tract of C1 were investigated for the following cyanotoxins: anatoxin-a, homoanatoxin-a, dihydroanatoxin-a (dhATX), cylindrospermopsin, saxitoxin, and microcystins. Necropsy results of C1 indicated neurotoxicosis with significant levels of dhATX in the duodenum tissues (10.51 ng/g dry weight (DW)), jejunum tissue (6.076 ng/g DW), and stomach contents (974.88 ng/g DW). Algae collected near the site of C1’s death contained levels of dhATX, ranging from 13 to 33 µg/g. By comparison, dhATX was detected at much lower concentrations in sediment samples (310.23 ng/g DW) and the periphyton on zebra mussel shells (38.45 ng/g DW). While dhATX was suspected in the deaths of canines from an event in Texas in 2019, this is the first report linking dhATX neurotoxicosis through pathological findings in Texas and potentially in the United States. Full article
(This article belongs to the Special Issue Unveiling the Toxic Effects of Harmful Algal Blooms)
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12 pages, 1606 KiB  
Article
Fusarium Species and Mycotoxins Associated with Sorghum Grains in Uruguay
by Ana Belén Corallo, Agustina del Palacio, María Oliver, Susana Tiscornia, Macarena Simoens, Jaqueline Cea, Inés de Aurrecoechea, Inés Martínez, Alicia Sanchez, Silvina Stewart and Dinorah Pan
Toxins 2023, 15(8), 484; https://doi.org/10.3390/toxins15080484 - 31 Jul 2023
Cited by 2 | Viewed by 1170
Abstract
Grain mold and stalk rot are among the fungal diseases that cause significant losses in sorghum worldwide and are caused by different Fusarium spp. The presence of Fusarium species in sorghum grains causes yield losses and mycotoxin contamination, which represents a risk to [...] Read more.
Grain mold and stalk rot are among the fungal diseases that cause significant losses in sorghum worldwide and are caused by different Fusarium spp. The presence of Fusarium species in sorghum grains causes yield losses and mycotoxin contamination, which represents a risk to consumers. In this study, Fusarium graminearum species complex (FGSC) had a high incidence, followed by Fusarium fujikuroi species complex (FFSC) and F. incarnatum-equiseti species complex. Within FFSC, F. proliferatum, F. andiyazi, F. fujikuroi, F. thapsinum, F. verticillioides and F. subglutinans were identified, and this was the first report of F. fujikuroi in sorghum. The most frequent toxins found in sorghum samples were deoxynivalenol (DON) and zearalenone (ZEN). The presence of fumonisins and nivalenol (NIV) was detected at low levels. This study adds new knowledge about the occurrence of Fusarium species and mycotoxins in sorghum grains. Furthermore, this is the first report in Uruguay on fungicide sensitivity for Fusarium isolates from sorghum, which constitutes an important starting point for defining management practices to minimize fungal infection and mycotoxin contamination. Full article
(This article belongs to the Section Mycotoxins)
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21 pages, 4151 KiB  
Article
Beyond Angiogenesis: The Multitasking Approach of the First PEGylated Vascular Endothelial Growth Factor (CdtVEGF) from Brazilian Rattlesnake Venom
by Isabela Ferreira, Isadora Oliveira, Karla Bordon, Mouzarllem Reis, Gisele Wiezel, Caroline Sanchez, Luísa Santos, Norival Santos-Filho, Manuela Pucca, Lusânia Antunes, Daiana Lopes and Eliane Arantes
Toxins 2023, 15(8), 483; https://doi.org/10.3390/toxins15080483 - 31 Jul 2023
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Abstract
A pioneering study regarding the isolation, biochemical evaluation, functional assays and first PEGylation report of a novel vascular endothelial growth factor from Crotalus durissus terrificus venom (CdtVEGF and PEG-CdtVEGF). CdtVEGF was isolated from crude venom using two different [...] Read more.
A pioneering study regarding the isolation, biochemical evaluation, functional assays and first PEGylation report of a novel vascular endothelial growth factor from Crotalus durissus terrificus venom (CdtVEGF and PEG-CdtVEGF). CdtVEGF was isolated from crude venom using two different chromatographic steps, representing 2% of soluble venom proteins. Its primary sequence was determined using mass spectrometry analysis, and the molecule demonstrated no affinity to heparin. The Brazilian crotalid antivenom recognized CdtVEGF. Both native and PEGylated CdtVEGF were able to induce new vessel formation and migration, and to increase the metabolic activity of human umbilical endothelial vascular cells (HUVEC), resulting in better wound closure (~50% within 12 h) using the native form. CdtVEGF induced leukocyte recruitment to the peritoneal cavity in mice, with a predominance of neutrophil influx followed by lymphocytes, demonstrating the ability to activate the immune system. The molecule also induced a dose-dependent increase in vascular permeability, and PEG-CdtVEGF showed less in vivo inflammatory activity than CdtVEGF. By unraveling the intricate properties of minor components of snake venom like svVEGF, this study illuminates the indispensable significance of exploring these molecular tools to unveil physiological and pathological processes, elucidates the mechanisms of snakebite envenomings, and could possibly be used to design a therapeutic drug. Full article
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