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Toxins, Volume 11, Issue 9 (September 2019)

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Cover Story (view full-size image) Animal venoms, especially from spiders, are among the most promising sources of novel drug leads. [...] Read more.
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Open AccessArticle
Alkaloid Lindoldhamine Inhibits Acid-Sensing Ion Channel 1a and Reveals Anti-Inflammatory Properties
Toxins 2019, 11(9), 542; https://doi.org/10.3390/toxins11090542 (registering DOI) - 18 Sep 2019
Abstract
Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation [...] Read more.
Acid-sensing ion channels (ASICs), which are present in almost all types of neurons, play an important role in physiological and pathological processes. The ASIC1a subtype is the most sensitive channel to the medium’s acidification, and it plays an important role in the excitation of neurons in the central nervous system. Ligands of the ASIC1a channel are of great interest, both fundamentally and pharmaceutically. Using a two-electrode voltage-clamp electrophysiological approach, we characterized lindoldhamine (a bisbenzylisoquinoline alkaloid extracted from the leaves of Laurus nobilis L.) as a novel inhibitor of the ASIC1a channel. Lindoldhamine significantly inhibited the ASIC1a channel’s response to physiologically-relevant stimuli of pH 6.5–6.85 with IC50 range 150–9 μM, but produced only partial inhibition of that response to more acidic stimuli. In mice, the intravenous administration of lindoldhamine at a dose of 1 mg/kg significantly reversed complete Freund’s adjuvant-induced thermal hyperalgesia and inflammation; however, this administration did not affect the pain response to an intraperitoneal injection of acetic acid (which correlated well with the function of ASIC1a in the peripheral nervous system). Thus, we describe lindoldhamine as a novel antagonist of the ASIC1a channel that could provide new approaches to drug design and structural studies regarding the determinants of ASIC1a activation. Full article
(This article belongs to the Special Issue Biological Activities of Alkaloids: From Toxicology to Pharmacology)
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Open AccessArticle
Assessment of Dried Blood Spots for Multi-Mycotoxin Biomarker Analysis in Pigs and Broiler Chickens
Toxins 2019, 11(9), 541; https://doi.org/10.3390/toxins11090541 (registering DOI) - 18 Sep 2019
Abstract
Dried blood spots (DBSs), a micro-sampling technique whereby a drop of blood is collected on filter paper has multiple advantages over conventional blood sampling regarding the sampling itself, as well as transportation and storage. This is the first paper describing the development and [...] Read more.
Dried blood spots (DBSs), a micro-sampling technique whereby a drop of blood is collected on filter paper has multiple advantages over conventional blood sampling regarding the sampling itself, as well as transportation and storage. This is the first paper describing the development and validation of a method for the determination of 23 mycotoxins and phase I metabolites in DBSs from pigs and broiler chickens using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The targeted mycotoxins belong to groups for which the occurrence in feed is regulated by the European Union, namely, aflatoxins, ochratoxin A and several Fusarium mycotoxins, and to two groups of unregulated mycotoxins, namely Alternaria mycotoxins and Fusarium mycotoxins (enniatins and beauvericin). The impact of blood haematocrit, DBS sampling volume and size of the analysed DBS disk on the validation results was assessed. No effects of variation in size of the analysed disk, haematocrit and spotted blood volume were observed for most mycotoxins, except for the aflatoxins and β-zearalanol (BZAL) at the lowest haematocrit (26%) level and for the enniatins (ENNs) at the lowest volume (40 µL). The developed method was transferred to an LC-high resolution mass spectrometry instrument to determine phase II metabolites. Then, the DBS technique was applied in a proof-of-concept toxicokinetic study including a comparison with LC-MS/MS data from plasma obtained with conventional venous blood sampling. A strong correlation (r > 0.947) was observed between plasma and DBS concentrations. Finally, DBSs were also applied in a pilot exposure assessment study to test their applicability under field conditions. Full article
(This article belongs to the Special Issue Mycotoxin Biomarkers of Exposure)
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Open AccessArticle
Astaxanthin Protects OTA-Induced Lung Injury in Mice through the Nrf2/NF-κB Pathway
Toxins 2019, 11(9), 540; https://doi.org/10.3390/toxins11090540 - 17 Sep 2019
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Abstract
The aim of this research was to evaluate the potential protective mechanism of astaxanthin (ASTA) against oxidative damage and inflammation caused by ochratoxin (OTA) in mouse lung. We divided mice into a control group (CG), an OTA group (PG), an astaxanthin group (AG), [...] Read more.
The aim of this research was to evaluate the potential protective mechanism of astaxanthin (ASTA) against oxidative damage and inflammation caused by ochratoxin (OTA) in mouse lung. We divided mice into a control group (CG), an OTA group (PG), an astaxanthin group (AG), and an OTA+ASTA group (JG). Oxidative indices (malondialdehyde (MDA), total superoxide dismutase (T-SOD), and reduced glutathione (GSH)) and inflammatory markers (interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α)) were assayed in the lung, and the lung-weight-to-body-weight ratio was calculated. Apoptosis was detected in pathological sections by the TdT-mediated dUTP nick-end labeling (TUNEL) assay. Oxidative damage and inflammation were detected in the lung of mice after exposure to OTA. Besides, Nrf2- and NF-κB-pathway-associated proteins were detected by Western blot. In contrast with OTA, ASTA significantly raised the expression of Nrf2, HO-1, and MnSOD, while the expression of other proteins (Keap1, TLR4, and NF-κB) was significantly decreased. These results indicate that ASTA exerted protective effects against OTA-induced oxidative damage and inflammation in the lung by regulating the Nrf2 and NF-κB pathways. Full article
(This article belongs to the Special Issue Mycotoxins, Immunity, and Inflammation)
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Open AccessArticle
Identification of a Novel Saxitoxin Analogue, 12β-Deoxygonyautoxin 3, in the Cyanobacterium, Anabaena circinalis (TA04)
Toxins 2019, 11(9), 539; https://doi.org/10.3390/toxins11090539 - 16 Sep 2019
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Abstract
Saxitoxin (STX) and its analogues, the potent voltage-gated sodium channel blockers, are biosynthesized by freshwater cyanobacteria and marine dinoflagellates. We previously identified several biosynthetic intermediates in the extract of the cyanobacterium, Anabaena circinalis (TA04), that are primarily produced during the early and middle [...] Read more.
Saxitoxin (STX) and its analogues, the potent voltage-gated sodium channel blockers, are biosynthesized by freshwater cyanobacteria and marine dinoflagellates. We previously identified several biosynthetic intermediates in the extract of the cyanobacterium, Anabaena circinalis (TA04), that are primarily produced during the early and middle stages in the biosynthetic pathway to produce STX. These findings allowed us to propose a putative biosynthetic pathway responsible for STX production based on the structures of these intermediates. In the present study, we identified 12β-deoxygonyautoxin 3 (12β-deoxyGTX3), a novel STX analogue produced by A. circinalis (TA04), by comparing the retention time and MS/MS fragmentation pattern with those of synthetic standards using LC–MS. The presence of this compound in A. circinalis (TA04) is consistent with stereoselective enzymatic oxidations at C11 and C12, and 11-O-sulfation, during the late stage of STX biosynthesis, as proposed in previous studies. Full article
(This article belongs to the Special Issue Marine Toxins Detection)
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Open AccessArticle
The Cadherin Cry1Ac Binding-Region is Necessary for the Cooperative Effect with ABCC2 Transporter Enhancing Insecticidal Activity of Bacillus thuringiensis Cry1Ac Toxin
Toxins 2019, 11(9), 538; https://doi.org/10.3390/toxins11090538 - 14 Sep 2019
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Abstract
Bacillus thuringiensis Cry1Ac toxin binds to midgut proteins, as cadherin (CAD) and ABCC2 transporter, to form pores leading to larval death. In cell lines, co-expression of CAD and ABCC2 enhance Cry1Ac toxicity significantly, but the mechanism remains elusive. Here, we show that the [...] Read more.
Bacillus thuringiensis Cry1Ac toxin binds to midgut proteins, as cadherin (CAD) and ABCC2 transporter, to form pores leading to larval death. In cell lines, co-expression of CAD and ABCC2 enhance Cry1Ac toxicity significantly, but the mechanism remains elusive. Here, we show that the expression of Helicoverpa armigera CAD (HaCAD-GFP) in Hi5 cells induces susceptibility to Cry1Ac and enhanced Cry1Ac toxicity when co-expressed with H. armigera ABCC2 (HaABCC2-GFP), since Cry1Ac toxicity increased 735-fold compared to Hi5 cells expressing HaCAD-GFP alone or 28-fold compared to HaABCC2-GFP alone. In contrast, the expression of the Spodoptera litura CAD (SlCAD-GFP) in Hi5 cells did not induce susceptibility to Cry1Ac nor it potentiated Cry1Ac toxicity with HaABCC2-GFP. To identify the CAD regions involved in the enhancement of Cry1Ac toxicity with ABCC2, the different CAD domains were replaced between SlCAD-GFP and HaCad-GFP proteins, and cytotoxicity assays were performed in Hi5 cells in the absence or presence of HaABCC2-GFP. The HaCAD toxin-binding region (TB), specifically the CAD repeat-11, was necessary to enhance Cry1Ac toxicity with ABCC2. We propose that CAD TB is involved in recruiting Cry1Ac to localize it in a good position for its interaction with the ABCC2, resulting in efficient toxin membrane insertion enhancing Cry1Ac toxicity. Full article
(This article belongs to the Special Issue Insecticidal Toxins from Bacillus thuringiensis)
Open AccessArticle
Twenty-Eight Fungal Secondary Metabolites Detected in Pig Feed Samples: Their Occurrence, Relevance and Cytotoxic Effects In Vitro
Toxins 2019, 11(9), 537; https://doi.org/10.3390/toxins11090537 - 14 Sep 2019
Viewed by 174
Abstract
Feed samples are frequently contaminated by a wide range of chemically diverse natural products, which can be determined using highly sensitive analytical techniques. Next to already well-investigated mycotoxins, unknown or unregulated fungal secondary metabolites have also been found, some of which at significant [...] Read more.
Feed samples are frequently contaminated by a wide range of chemically diverse natural products, which can be determined using highly sensitive analytical techniques. Next to already well-investigated mycotoxins, unknown or unregulated fungal secondary metabolites have also been found, some of which at significant concentrations. In our study, 1141 pig feed samples were analyzed for more than 800 secondary fungal metabolites using the same LC-MS/MS method and ranked according to their prevalence. Effects on the viability of the 28 most relevant were tested on an intestinal porcine epithelial cell line (IPEC-J2). The most frequently occurring compounds were determined as being cyclo-(L-Pro-L-Tyr), moniliformin, and enniatin B, followed by enniatin B1, aurofusarin, culmorin, and enniatin A1. The main mycotoxins, deoxynivalenol and zearalenone, were found only at ranks 8 and 10. Regarding cytotoxicity, apicidin, gliotoxin, bikaverin, and beauvericin led to lower IC50 values, between 0.52 and 2.43 µM, compared to deoxynivalenol (IC50 = 2.55 µM). Significant cytotoxic effects were also seen for the group of enniatins, which occurred in up to 82.2% of the feed samples. Our study gives an overall insight into the amount of fungal secondary metabolites found in pig feed samples compared to their cytotoxic effects in vitro. Full article
(This article belongs to the Special Issue Toxicological Effects of Mycotoxin on Target Cells)
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Open AccessArticle
The Effect of Blue Light on the Production of Citrinin in Monascus purpureus M9 by Regulating the mraox Gene through lncRNA AOANCR
Toxins 2019, 11(9), 536; https://doi.org/10.3390/toxins11090536 - 13 Sep 2019
Viewed by 207
Abstract
Blue light, as an important environmental factor, can regulate the production of various secondary metabolites of Monascus purpureus M9, including mycotoxin-citrinin, pigments, and monacolin K. The analysis of citrinin in Monascus M9 exposed to blue light for 0 min./d, 15 min./d, and 60 [...] Read more.
Blue light, as an important environmental factor, can regulate the production of various secondary metabolites of Monascus purpureus M9, including mycotoxin-citrinin, pigments, and monacolin K. The analysis of citrinin in Monascus M9 exposed to blue light for 0 min./d, 15 min./d, and 60 min./d showed that 15 min./d of blue light illumination could significantly increase citrinin production, while 60 min./d of blue light illumination decreased citrinin production. Analysis of long non-coding RNA (LncRNA) was performed on the transcripts of Monascus M9 under three culture conditions, and this analysis identified an lncRNA named AOANCR that can negatively regulate the mraox gene. Fermentation studies suggested that alternate respiratory pathways could be among the pathways that are involved in the regulation of the synthesis of citrinin by environmental factors. Aminophylline and citric acid were added to the culture medium to simulate the process of generating cyclic adenosine monophosphate (cAMP) in cells under illumination conditions. The results of the fermentation showed that aminophylline and citric acid could increase the expression of the mraox gene, decrease the expression of lncRNA AOANCR, and reduce the yield of citrinin. This result also indicates a reverse regulation relationship between lncRNA AOANCR and the mraox gene. A blue light signal might regulate the mraox gene at least partially through lncRNA AOANCR, thereby regulating citrinin production. Citrinin has severe nephrotoxicity in mammals, and it is important to control the residual amout of citrinin in red yeast products during fermentation. LncRNA AOANCR and mraox can potentially be used as new targets for the control of citrinin production. Full article
Open AccessArticle
Molecular Characterization of Equine Staphylococcus aureus Isolates Exhibiting Reduced Oxacillin Susceptibility
Toxins 2019, 11(9), 535; https://doi.org/10.3390/toxins11090535 - 13 Sep 2019
Viewed by 196
Abstract
The detection of borderline oxacillin-resistant Staphylococcus aureus (BORSA) represents a challenge to both, veterinary and human laboratories. Between 2015 and 2017, 19 equine S. aureus with elevated minimal inhibitory concentrations for oxacillin were detected in routine diagnostics. The aim of this study was [...] Read more.
The detection of borderline oxacillin-resistant Staphylococcus aureus (BORSA) represents a challenge to both, veterinary and human laboratories. Between 2015 and 2017, 19 equine S. aureus with elevated minimal inhibitory concentrations for oxacillin were detected in routine diagnostics. The aim of this study was to characterize these isolates to identify factors possibly associated with the BORSA phenotype. All S. aureus were subjected to antimicrobial susceptibility testing and whole genome sequencing (WGS). A quantifiable β-lactamase activity assay was performed for a representative subset of 13 isolates. The WGS data analysis of the 19 BORSA isolates identified two different genomic lineages, sequence type (ST) 1 and ST1660. The core genome multilocus sequence typing (cgMLST) revealed a close relatedness of all isolates belonging to either ST1 or ST1660. The WGS analysis identified the resistance genes aadD, dfrG, tet(L), and/or blaZ and aacA-aphD. Phenotypic resistance to penicillins, aminoglycosides, tetracyclines, fluoroquinolones and sulfamethoxazole/trimethoprim was observed in the respective isolates. For the penicillin-binding proteins 1–4, amino acid substitutions were predicted using WGS data. Since neither transglycosylase nor transpeptidase domains were affected, these alterations might not explain the BORSA phenotype. Moreover, β-lactamase activity was found to be associated with an inducible blaZ gene. The lineage-specific differences regarding the expression profiles were noted. Full article
Open AccessArticle
Impact of the Lipopolysaccharide Chemotype of Salmonella Enterica Serovar Typhimurium on Virulence in Gnotobiotic Piglets
Toxins 2019, 11(9), 534; https://doi.org/10.3390/toxins11090534 - 13 Sep 2019
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Abstract
Salmonella Typhimurium is an enteric pathogen that causes acute and chronic infections in humans and animals. One-week-old germ-free piglets were orally colonized/infected with the Salmonella Typhimurium LT2 strain or its isogenic rough ΔrfaL, ΔrfaG or ΔrfaC mutants with exactly [...] Read more.
Salmonella Typhimurium is an enteric pathogen that causes acute and chronic infections in humans and animals. One-week-old germ-free piglets were orally colonized/infected with the Salmonella Typhimurium LT2 strain or its isogenic rough ΔrfaL, ΔrfaG or ΔrfaC mutants with exactly defined lipopolysaccharide (LPS) defects. After 24 h, the piglets were euthanized and the colonization of the small intestine, translocations into the mesenteric lymph nodes, liver, spleen, lungs, and bacteremia, along with changes in the ileum histology, and transcription levels of the tight junction proteins claudin-1, claudin-2, and occludin were all assessed. Additionally, transcription levels of IL-8, TNF-α, and IL-10 in the terminal ileum, and their local and systemic protein levels were evaluated. Wild-type Salmonella Typhimurium showed the highest translocation, histopathological changes, upregulation of claudins and downregulation of occludin, transcription of the cytokines, intestinal IL-8 and TNF-α levels, and systemic TNF-α and IL-10 levels. Depending on the extent of the incompleteness of the LPS, the levels of the respective elements decreased, or no changes were observed at all in the piglets colonized/infected with Δrfa mutants. Intestinal IL-10 and systemic IL-8 levels were not detected in any piglet groups. This study provided foundational data on the gnotobiotic piglet response to colonization/infection with the exactly defined rough Salmonella Typhimurium LT2 isogenic mutants. Full article
(This article belongs to the Section Bacterial Toxins)
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Open AccessReview
Rationally Designed Synthetic Haptens to Generate Anti-Ciguatoxin Monoclonal Antibodies, and Development of a Practical Sandwich ELISA to Detect Ciguatoxins
Toxins 2019, 11(9), 533; https://doi.org/10.3390/toxins11090533 - 13 Sep 2019
Viewed by 206
Abstract
“Ciguatera” fish poisoning (CFP) is one of the well-known food poisoning caused by the ingestion of fish that have accumulated trace amounts of ciguatoxins (CTXs). CFP affects more than 50,000 individuals annually. The difficulty in preventing CFP comes from the lack of reliable [...] Read more.
“Ciguatera” fish poisoning (CFP) is one of the well-known food poisoning caused by the ingestion of fish that have accumulated trace amounts of ciguatoxins (CTXs). CFP affects more than 50,000 individuals annually. The difficulty in preventing CFP comes from the lack of reliable methods for analysis of CTXs in contaminated fish, together with the normal appearance, taste, and smell of CTX-contaminated fish. Thus, a sensitive, accurate, routine, and portable analytical method to detect CTXs is urgently required. Monoclonal antibodies (mAbs) specific against either wing of major CTX congeners (CTX1B, 54-deoxyCTX1B, CTX3C, and 51-hydroxyCTX3C) were generated by immunizing mice with rationally designed synthetic haptens-KLH conjugates instead of the CTXs. Haptenic groups with a surface area greater than 400 Å2 are required to produce mAbs that can strongly bind to CTXs. Furthermore, a highly sensitive fluorescence-based sandwich enzyme-linked immunosorbent assay (ELISA) was developed. This protocol can detect and quantify four major CTX congeners (CTX1B, 54-deoxyCTX1B, CTX3C, and 51-hydroxyCTX3C) with a limit of detection (LOD) of less than 1 pg/mL. The LOD determined for this sandwich ELISA is sufficient to detect CTX1B-contaminated fish at the FDA guidance level of 0.01 ppb. Full article
(This article belongs to the Special Issue Marine Toxins Detection)
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Open AccessArticle
Aflatoxin B1 Conversion by Black Soldier Fly (Hermetia illucens) Larval Enzyme Extracts
Toxins 2019, 11(9), 532; https://doi.org/10.3390/toxins11090532 - 12 Sep 2019
Viewed by 254
Abstract
The larvae of the black soldier fly (Hermetia illucens L., BSFL) have received increased industrial interest as a novel protein source for food and feed. Previous research has found that insects, including BSFL, are capable of metabolically converting aflatoxin B1 (AFB [...] Read more.
The larvae of the black soldier fly (Hermetia illucens L., BSFL) have received increased industrial interest as a novel protein source for food and feed. Previous research has found that insects, including BSFL, are capable of metabolically converting aflatoxin B1 (AFB1), but recovery of total AFB1 is less than 20% when accounting for its conversion to most known metabolites. The aim of this study was to examine the conversion of AFB1 by S9 extracts of BSFL reared on substrates with or without AFB1. Liver S9 of Aroclor-induced rats was used as a reference. To investigate whether cytochrome P450 enzymes are involved in the conversion of AFB1, the inhibitor piperonyl butoxide (PBO) was tested in a number of treatments. The results showed that approximately 60% of AFB1 was converted to aflatoxicol and aflatoxin P1. The remaining 40% of AFB1 was not converted. Cytochrome P450s were indeed responsible for metabolic conversion of AFB1 into AFP1, and a cytoplasmic reductase was most likely responsible for conversion of AFB1 into aflatoxicol. Full article
(This article belongs to the Special Issue Mycotoxins in Feed and Food Chain: Present Status and Future Concerns)
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Open AccessArticle
Evaluation of High-Resolution Mass Spectrometry for the Quantitative Analysis of Mycotoxins in Complex Feed Matrices
Toxins 2019, 11(9), 531; https://doi.org/10.3390/toxins11090531 - 12 Sep 2019
Viewed by 241
Abstract
The selective and sensitive analysis of mycotoxins in highly complex feed matrices is a great challenge. In this study, the suitability of OrbitrapTM-based high-resolution mass spectrometry (HRMS) for routine mycotoxin analysis in complex feeds was demonstrated by the successful validation of [...] Read more.
The selective and sensitive analysis of mycotoxins in highly complex feed matrices is a great challenge. In this study, the suitability of OrbitrapTM-based high-resolution mass spectrometry (HRMS) for routine mycotoxin analysis in complex feeds was demonstrated by the successful validation of a full MS/data-dependent MS/MS acquisition method for the quantitative determination of eight Fusarium mycotoxins in forage maize and maize silage according to the Commission Decision 2002/657/EC. The required resolving power for accurate mass assignments (<5 ppm) was determined as 35,000 full width at half maximum (FWHM) and 70,000 FWHM for forage maize and maize silage, respectively. The recovery (RA), intra-day precision (RSDr), and inter-day precision (RSDR) of measurements were in the range of 94 to 108%, 2 to 16%, and 2 to 12%, whereas the decision limit (CCα) and the detection capability (CCβ) varied from 11 to 88 µg/kg and 20 to 141 µg/kg, respectively. A set of naturally contaminated forage maize and maize silage samples collected in northern Germany in 2017 was analyzed to confirm the applicability of the HRMS method to real samples. At least four Fusarium mycotoxins were quantified in each sample, highlighting the frequent co-occurrence of mycotoxins in feed. Full article
(This article belongs to the Special Issue Advanced Methods for Mycotoxins Detection)
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Open AccessReview
The Diversity of Cyanobacterial Toxins on Structural Characterization, Distribution and Identification: A Systematic Review
Toxins 2019, 11(9), 530; https://doi.org/10.3390/toxins11090530 - 12 Sep 2019
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Abstract
The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of water pollution caused by cyanotoxins, which poses a serious threat to human health. However, the structural characterization, distribution and identification techniques of cyanotoxins have not been comprehensively reviewed in [...] Read more.
The widespread distribution of cyanobacteria in the aquatic environment is increasing the risk of water pollution caused by cyanotoxins, which poses a serious threat to human health. However, the structural characterization, distribution and identification techniques of cyanotoxins have not been comprehensively reviewed in previous studies. This paper aims to elaborate the existing information systematically on the diversity of cyanotoxins to identify valuable research avenues. According to the chemical structure, cyanotoxins are mainly classified into cyclic peptides, alkaloids, lipopeptides, nonprotein amino acids and lipoglycans. In terms of global distribution, the amount of cyanotoxins are unbalanced in different areas. The diversity of cyanotoxins is more obviously found in many developed countries than that in undeveloped countries. Moreover, the threat of cyanotoxins has promoted the development of identification and detection technology. Many emerging methods have been developed to detect cyanotoxins in the environment. This communication provides a comprehensive review of the diversity of cyanotoxins, and the detection and identification technology was discussed. This detailed information will be a valuable resource for identifying the various types of cyanotoxins which threaten the environment of different areas. The ability to accurately identify specific cyanotoxins is an obvious and essential aspect of cyanobacterial research. Full article
Open AccessReview
New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease
Toxins 2019, 11(9), 529; https://doi.org/10.3390/toxins11090529 - 12 Sep 2019
Viewed by 163
Abstract
Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells [...] Read more.
Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney disease (CKD), and cardiovascular calcification (CVC) is one of the strongest predictors of CVD in this population. Cardiovascular calcification results from complex cellular interactions involving the endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial cells and resident fibroblasts), and monocyte-derived macrophages. Indeed, the production of pro-inflammatory cytokines and oxidative stress by monocyte-derived macrophages is responsible for the osteogenic transformation and mineralization of vascular/valvular cells. However, monocytes/macrophages show the ability to modify their phenotype, and consequently their functions, when facing environmental modifications. This plasticity complicates efforts to understand the pathogenesis of CVC—particularly in a CKD setting, where both uraemic toxins and CKD treatment may affect monocyte/macrophage functions and thereby influence CVC. Here, we review (i) the mechanisms by which each monocyte/macrophage subset either promotes or prevents CVC, and (ii) how both uraemic toxins and CKD therapies might affect these monocyte/macrophage functions. Full article
(This article belongs to the Special Issue The Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD))
Open AccessReview
Antibodies and Vaccines Against Botulinum Toxins: Available Measures and Novel Approaches
Toxins 2019, 11(9), 528; https://doi.org/10.3390/toxins11090528 - 12 Sep 2019
Viewed by 166
Abstract
Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a [...] Read more.
Botulinum neurotoxin (BoNT) is produced by the anaerobic, Gram-positive bacterium Clostridium botulinum. As one of the most poisonous toxins known and a potential bioterrosism agent, BoNT is characterized by a complex mode of action comprising: internalization, translocation and proteolytic cleavage of a substrate, which inhibits synaptic exocytotic transmitter release at neuro-muscular nerve endings leading to peripheral neuroparalysis of the skeletal and autonomic nervous systems. There are seven major serologically distinct toxinotypes (A–G) of BoNT which act on different substrates. Human botulism is generally caused by BoNT/A, B and E. Due to its extreme lethality and potential use as biological weapon, botulism remains a global public health concern. Vaccination against BoNT, although an effective strategy, remains undesirable due to the growing expectation around therapeutic use of BoNTs in various pathological conditions. This review focuses on the current approaches for botulism control by immunotherapy, highlighting the future challenges while the molecular underpinnings among subtypes variants and BoNT sequences found in non-clostridial species remain to be elucidated. Full article
(This article belongs to the Special Issue Characterization and Quantitative Analysis of Botulinum Neurotoxin)
Open AccessArticle
Naja atra Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca2+/PP2A/AMPK Axis
Toxins 2019, 11(9), 527; https://doi.org/10.3390/toxins11090527 - 12 Sep 2019
Viewed by 153
Abstract
Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and [...] Read more.
Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated Naja atra (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca2+-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca2+ or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca2+/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction. Full article
(This article belongs to the Section Animal Venoms)
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Open AccessArticle
Structures of Reaction Products and Degradation Pathways of Aflatoxin B1 by Ultrasound Treatment
Toxins 2019, 11(9), 526; https://doi.org/10.3390/toxins11090526 - 12 Sep 2019
Viewed by 161
Abstract
Ultrasound is an emerging decontamination technology with potential use in the global food processing industry. In the present study, we explored power ultrasound for processing aqueous aflatoxin B1 (AFB1). AFB1 was degraded by 85.1% after 80 min of ultrasound [...] Read more.
Ultrasound is an emerging decontamination technology with potential use in the global food processing industry. In the present study, we explored power ultrasound for processing aqueous aflatoxin B1 (AFB1). AFB1 was degraded by 85.1% after 80 min of ultrasound exposure. The reaction products of AFB1 were identified and their molecular formulae elucidated by ultra-high-performance liquid chromatography Q-Orbitrap mass spectrometry. Eight main reaction products were found, and their structures were clarified by parental ion fragmentation. Two degradation pathways were proposed according to the degradation product structures: One involved the addition of H• and OH• radicals, whereas the other involved H2O2 epoxidation and H•, OH•, and H2O2 oxidation of AFB1. Ultrasound treatment significantly reduced AFB1 bioactivity and toxicity by disrupting the C8=C9 double bond in the furan ring and modifying the lactone ring and methoxy group. Full article
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Open AccessReview
Vaccine Production to Protect Animals Against Pathogenic Clostridia
Toxins 2019, 11(9), 525; https://doi.org/10.3390/toxins11090525 - 11 Sep 2019
Viewed by 248
Abstract
Clostridium is a broad genus of anaerobic, spore-forming, rod-shaped, Gram-positive bacteria that can be found in different environments all around the world. The genus includes human and animal pathogens that produce potent exotoxins that cause rapid and potentially fatal diseases responsible for countless [...] Read more.
Clostridium is a broad genus of anaerobic, spore-forming, rod-shaped, Gram-positive bacteria that can be found in different environments all around the world. The genus includes human and animal pathogens that produce potent exotoxins that cause rapid and potentially fatal diseases responsible for countless human casualties and billion-dollar annual loss to the agricultural sector. Diseases include botulism, tetanus, enterotoxemia, gas gangrene, necrotic enteritis, pseudomembranous colitis, blackleg, and black disease, which are caused by pathogenic Clostridium. Due to their ability to sporulate, they cannot be eradicated from the environment. As such, immunization with toxoid or bacterin-toxoid vaccines is the only protective method against infection. Toxins recovered from Clostridium cultures are inactivated to form toxoids, which are then formulated into multivalent vaccines. This review discusses the toxins, diseases, and toxoid production processes of the most common pathogenic Clostridium species, including Clostridium botulinum, Clostridium tetani, Clostridium perfringens, Clostridium chauvoei, Clostridium septicum, Clostridium novyi and Clostridium hemolyticum. Full article
(This article belongs to the Special Issue Characterization and Quantitative Analysis of Botulinum Neurotoxin)
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Open AccessArticle
Lebetin 2, a Snake Venom-Derived B-Type Natriuretic Peptide, Provides Immediate and Prolonged Protection against Myocardial Ischemia-Reperfusion Injury via Modulation of Post-Ischemic Inflammatory Response
Toxins 2019, 11(9), 524; https://doi.org/10.3390/toxins11090524 - 10 Sep 2019
Viewed by 312
Abstract
Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, [...] Read more.
Myocardial infarction (MI) followed by left ventricular (LV) remodeling is the most frequent cause of heart failure. Lebetin 2 (L2), a snake venom-derived natriuretic peptide, exerts cardioprotection during acute myocardial ischemia-reperfusion (IR) ex vivo. However, its effects on delayed consequences of IR injury, including post-MI inflammation and fibrosis have not been defined. Here, we determined whether a single L2 injection exerts cardioprotection in IR murine models in vivo, and whether inflammatory response to ischemic injury plays a role in L2-induced effects. We quantified infarct size (IS), fibrosis, inflammation, and both endothelial cell and cardiomyocyte densities in injured myocardium and compared these values with those induced by B-type natriuretic peptide (BNP). Both L2 and BNP reduced IS, fibrosis, and inflammatory response after IR, as evidenced by decreased leukocyte and proinflammatory M1 macrophage infiltrations in the infarcted area compared to untreated animals. However, only L2 increased anti-inflammatory M2-like macrophages. L2 also induced a higher density of endothelial cells and cardiomyocytes. Our data show that L2 has strong, acute, prolonged cardioprotective effects in post-MI that are mediated, at least in part, by the modulation of the post-ischemic inflammatory response and especially, by the enhancement of M2-like macrophages, thus reducing IR-induced necrotic and fibrotic effects. Full article
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Open AccessArticle
Detoxification of the Fumonisin Mycotoxins in Maize: An Enzymatic Approach
Toxins 2019, 11(9), 523; https://doi.org/10.3390/toxins11090523 - 10 Sep 2019
Viewed by 253
Abstract
Enzymatic detoxification has become a promising approach for control of mycotoxins postharvest in grains through modification of chemical structures determining their toxicity. In the present study fumonisin esterase FumD (EC 3.1.1.87) (FUMzyme®; BIOMIN, Tulln, Austria), hydrolysing fumonisin (FB) mycotoxins by [...] Read more.
Enzymatic detoxification has become a promising approach for control of mycotoxins postharvest in grains through modification of chemical structures determining their toxicity. In the present study fumonisin esterase FumD (EC 3.1.1.87) (FUMzyme®; BIOMIN, Tulln, Austria), hydrolysing fumonisin (FB) mycotoxins by de-esterification, was utilised to develop an enzymatic reduction method in a maize kernel enzyme incubation mixture. Efficacy of the FumD FB reduction method in “low” and “high” FB contaminated home-grown maize was compared by monitoring FB1 hydrolysis to the hydrolysed FB1 (HFB1) product utilising a validated LC-MS/MS analytical method. The method was further evaluated in terms of enzyme activity and treatment duration by assessing enzyme kinetic parameters and the relative distribution of HFB1 between maize kernels and the residual aqueous environment. FumD treatments resulted in significant reduction (≥80%) in “low” (≥1000 U/L, p < 0.05) and “high” (100 U/L, p < 0.05; ≥1000 U/L, p < 0.0001) FB contaminated maize after 1 h respectively, with an approximate 1:1 µmol conversion ratio of FB1 into the formation of HFB1. Enzyme kinetic parameters indicated that, depending on the activity of FumD utilised, a significantly (p < 0.05) higher FB1 conversion rate was noticed in “high” FB contaminated maize. The FumD FB reduction method in maize could find application in commercial maize-based practices as well as in communities utilising home-grown maize as a main dietary staple and known to be exposed above the tolerable daily intake levels. Full article
(This article belongs to the Special Issue Novel Approaches to Minimising Mycotoxin Contamination)
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Open AccessReview
Modifying Phosphate Toxicity in Chronic Kidney Disease
Toxins 2019, 11(9), 522; https://doi.org/10.3390/toxins11090522 - 09 Sep 2019
Viewed by 250
Abstract
Phosphate toxicity is a well-established phenomenon, especially in chronic kidney disease (CKD), where hyperphosphatemia is a frequent occurrence when CKD is advanced. Many therapeutic efforts are targeted at phosphate, and comprise dietary intervention, modifying dialysis schemes, treating uncontrolled hyperparathyroidism and importantly, phosphate binder [...] Read more.
Phosphate toxicity is a well-established phenomenon, especially in chronic kidney disease (CKD), where hyperphosphatemia is a frequent occurrence when CKD is advanced. Many therapeutic efforts are targeted at phosphate, and comprise dietary intervention, modifying dialysis schemes, treating uncontrolled hyperparathyroidism and importantly, phosphate binder therapy. Despite all these interventions, hyperphosphatemia persists in many, and its pathological influence is ongoing. In nephrological care, a somewhat neglected aspect of treatment—when attempts fail to lower exposure to a toxin like phosphate—is to explore the possibility of “anti-dotes”. Indeed, quite a long list of factors modify, or are mediators of phosphate toxicity. Addressing these, especially when phosphate itself cannot be sufficiently controlled, may provide additional protection. In this narrative overview, several factors are discussed that may qualify as either such a modifier or mediator, that can be influenced by other means than simply lowering phosphate exposure. A wider scope when targeting phosphate-induced comorbidity in CKD, in particular cardiovascular disease, may alleviate the burden of disease that is the consequence of this potentially toxic mineral in CKD. Full article
(This article belongs to the Special Issue The Chronic Kidney Disease - Mineral Bone Disorder (CKD-MBD))
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Open AccessArticle
First Report of Microcystis Strains Producing MC-FR and -WR Toxins in Japan
Toxins 2019, 11(9), 521; https://doi.org/10.3390/toxins11090521 - 09 Sep 2019
Viewed by 269
Abstract
Microcystins (MCs) are a group of cyclic heptapeptide hepatotoxins produced by Microcystis and several other genera of cyanobacteria. Many structural variants have been characterized using various methods such as liquid chromatography–mass spectrometry (LC-MS) analysis, enzyme-linked immunosorbent assay (ELISA) and protein phosphatase 2A (PP2A) [...] Read more.
Microcystins (MCs) are a group of cyclic heptapeptide hepatotoxins produced by Microcystis and several other genera of cyanobacteria. Many structural variants have been characterized using various methods such as liquid chromatography–mass spectrometry (LC-MS) analysis, enzyme-linked immunosorbent assay (ELISA) and protein phosphatase 2A (PP2A) inhibition assay. The representative MC, MC-LR, and related cyanobacterial toxins strongly inhibit PP2A activity and can therefore be assayed by measuring the extent of PP2A inhibition. However, these methods require reference toxin standards for the quantification and identification of known MCs. To obtain various MC-producing cyanobacterial strains, we surveyed and collected MC-producing cyanobacteria from environmental sources of water in Okinawa, Japan. Using a dual assay (LC-MS analysis and PP2A inhibition assay), we identified and isolated Microcystis strains producing five MC variants (MC-LR, -RR, -LA, -FR and -WR). Approximately 4 mg of MC-WR and -FR toxins were purified from the laboratory culture of the Microcystis isolate NIES-4344. Pure MC-WR and -FR variants were prepared for future use as toxin standards in LC-MS analysis. Phylogenetic analysis based on ftsZ revealed that the NIES-4344 strain belongs to the identified groups in Microcystis aeruginosa. This is the first report of Microcystis strains producing mainly MC-WR and -FR toxins in Japan. Full article
(This article belongs to the Special Issue Marine Toxins Detection)
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Open AccessArticle
The Histone Deacetylases HosA and HdaA Affect the Phenotype and Transcriptomic and Metabolic Profiles of Aspergillus niger
Toxins 2019, 11(9), 520; https://doi.org/10.3390/toxins11090520 - 07 Sep 2019
Viewed by 325
Abstract
Histone acetylation is an important modification for the regulation of chromatin accessibility and is controlled by two kinds of histone-modifying enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). In filamentous fungi, there is increasing evidence that HATs and HDACs are critical factors related [...] Read more.
Histone acetylation is an important modification for the regulation of chromatin accessibility and is controlled by two kinds of histone-modifying enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). In filamentous fungi, there is increasing evidence that HATs and HDACs are critical factors related to mycelial growth, stress response, pathogenicity and production of secondary metabolites (SMs). In this study, seven A. niger histone deacetylase-deficient strains were constructed to investigate their effects on the strain growth phenotype as well as the transcriptomic and metabolic profiles of secondary metabolic pathways. Phenotypic analysis showed that deletion of hosA in A. niger FGSC A1279 leads to a significant reduction in growth, pigment production, sporulation and stress resistance, and deletion of hdaA leads to an increase in pigment production in liquid CD medium. According to the metabolomic analysis, the production of the well-known secondary metabolite fumonisin was reduced in both the hosA and hdaA mutants, and the production of kojic acid was reduced in the hdaA mutant and slightly increased in the hosA mutant. Results suggested that the histone deacetylases HosA and HdaA play a role in development and SM biosynthesis in A. niger FGSC A1279. Histone deacetylases offer new strategies for regulation of SM synthesis. Full article
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Open AccessArticle
Development of an UPLC-MS/MS Method for the Analysis of Mycotoxins in Rumen Fluid with and without Maize Silage Emphasizes the Importance of Using Matrix-Matched Calibration
Toxins 2019, 11(9), 519; https://doi.org/10.3390/toxins11090519 - 07 Sep 2019
Viewed by 367
Abstract
Ruminants are less susceptible to the effects of mycotoxins than monogastric animals as their rumen microbiota are claimed to degrade and/or deactivate at least some of these toxic compounds. However, the mycotoxin degradation is not well-known yet. For this, a sensitive, specific, and [...] Read more.
Ruminants are less susceptible to the effects of mycotoxins than monogastric animals as their rumen microbiota are claimed to degrade and/or deactivate at least some of these toxic compounds. However, the mycotoxin degradation is not well-known yet. For this, a sensitive, specific, and accurate analytical method is needed to determine mycotoxins in the rumen fluid. This study aims to develop and thoroughly validate an ultra-performance liquid chromatography tandem mass spectrometry method for the quantitative determination in the rumen fluid of some of the most relevant mycotoxins found in maize silage in Western Europe: deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEN), mycophenolic acid (MPA), roquefortine C (ROQ-C) and enniatin B (ENN B), as well as their metabolites deepoxy-deoxynivalenol (DOM-1), α-zearalenol (α-ZEL), β-zearalenol (β-ZEL), zearalanone (ZAN), α-zearalanol (α-ZAL) and β-zearalanol (β-ZAL). As feed is often present in the rumen fluid samples, the potential interaction of feed particles with the mycotoxin extraction and analysis was investigated. Extraction recovery and matrix effects were determined in the rumen fluid with and without maize silage. Differences in those parameters between rumen fluid alone and rumen fluid with maize silage highlight the importance of using matrix-matched calibration curves for the quantification of mycotoxins in rumen fluid samples. A cross-validation of the method with rumen fluid and maize silage demonstrates that this analytical method can be applied in research on rumen fluid samples to investigate the degradation of the reported mycotoxins by rumen microbiota if matrix-matched calibration is performed. Full article
(This article belongs to the Special Issue Application of LC-MS/MS in the Mycotoxins Studies)
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Open AccessCommunication
Heterologous Expression and Characterization of A Novel Ochratoxin A Degrading Enzyme, N-acyl-L-amino Acid Amidohydrolase, from Alcaligenes faecalis
Toxins 2019, 11(9), 518; https://doi.org/10.3390/toxins11090518 - 06 Sep 2019
Viewed by 312
Abstract
Ochratoxin A (OTA) is a well-known, natural contaminant in foods and feeds because of its toxic effects, such as nephrotoxicity in various animals. Recent studies have revealed that Alcaligenes faecalis could generate enzymes to efficiently degrade OTA to ochratoxin α (OTα) in vitro. [...] Read more.
Ochratoxin A (OTA) is a well-known, natural contaminant in foods and feeds because of its toxic effects, such as nephrotoxicity in various animals. Recent studies have revealed that Alcaligenes faecalis could generate enzymes to efficiently degrade OTA to ochratoxin α (OTα) in vitro. In an effort to obtain the OTA degrading mechanism, we purified and identified a novel degrading enzyme, N-acyl-L-amino acid amidohydrolase (AfOTase), from A. faecalis DSM 16503 via mass spectrometry. The same gene of the enzyme was also encountered in other A. faecalis strains. AfOTase belongs to peptidase family M20 and contains metal ions at the active site. In this study, recombination AfOTase was expressed and characterized in Escherichia coli. The molecular mass of recombinant rAfOTase was approximately 47.0 kDa, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme exhibited a wide temperature range (30–70 °C) and pH adaptation (4.5–9.0) and the optimal temperature and pH were 50 °C and 6.5, respectively. Full article
(This article belongs to the Section Mycotoxins)
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Open AccessArticle
Serrulin: A Glycine-Rich Bioactive Peptide from the Hemolymph of the Yellow Tityus serrulatus Scorpion
Toxins 2019, 11(9), 517; https://doi.org/10.3390/toxins11090517 - 06 Sep 2019
Viewed by 397
Abstract
Antimicrobial peptides (AMPs) are small molecules, which have a potential use as antibiotic or pharmacological tools. In chelicerate organisms, such as scorpions, these molecules constitute an alternative defense system against microorganisms. The aim of this work was to identify AMPs in the hemolymph [...] Read more.
Antimicrobial peptides (AMPs) are small molecules, which have a potential use as antibiotic or pharmacological tools. In chelicerate organisms, such as scorpions, these molecules constitute an alternative defense system against microorganisms. The aim of this work was to identify AMPs in the hemolymph of the Tityus serrulatus scorpion. Fractions of plasma and hemocytes were subjected to high-performance liquid chromatography (HPLC) and then analyzed to determine their activity in inhibiting microbial growth. One of the fractions from the hemocytes presents antimicrobial activity against microorganisms, such as Gram-negative and Gram-positive bacteria, fungi, and yeast. These fractions were analyzed by mass spectrometry, and a fragment of 3564 Da. was identified. The peptide was called serrulin, because it is derived from the species T. serrulatus. A comparison of the amino acid sequence of serrulin with databases shows that it has a similarity to the glycine-rich peptides described in Cupienius salai and Acanthoscurria gomesiana (spiders). Furthermore, serrulin has no hemolytic activity against human erythrocytes. While the presence of AMPs in T. serrulatus venom has been described in other works, this is the first work to characterize the presence of these molecules in the hemolymph (hemocytes) of this species and show its potential use as an alternative to conventional antibiotics against different species of microorganisms. Full article
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Open AccessReview
Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls
Toxins 2019, 11(9), 516; https://doi.org/10.3390/toxins11090516 - 04 Sep 2019
Viewed by 349
Abstract
Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. [...] Read more.
Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. One promising alternative for the discovery of novel potent analgesics is to take inspiration from Mother Nature; in this context, the detailed investigation of the intriguing analgesia implemented in Buruli ulcer, an infectious disease caused by the bacterium Mycobacterium ulcerans and characterized by painless ulcerative lesions, seems particularly promising. More precisely, in this disease, the painless skin ulcers are caused by mycolactone, a polyketide lactone exotoxin. In fact, mycolactone exerts a wide range of effects on the host, besides being responsible for analgesia, as it has been shown notably to modulate the immune response or to provoke apoptosis. Several cellular mechanisms and different targets have been proposed to account for the analgesic effect of the toxin, such as nerve degeneration, the inhibition of inflammatory mediators and the activation of angiotensin II receptor 2. In this review, we discuss the current knowledge in the field, highlighting possible controversies. We first discuss the different pain-mimicking experimental models that were used to study the effect of mycolactone. We then detail the different variants of mycolactone that were used in such models. Overall, based on the results and the discussions, we conclude that the development of mycolactone-derived molecules can represent very promising perspectives for new analgesic drugs, which could be effective for specific pain indications. Full article
(This article belongs to the Special Issue Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer)
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Open AccessReview
Updates on the Effect of Mycotoxins on Male Reproductive Efficiency in Mammals
Toxins 2019, 11(9), 515; https://doi.org/10.3390/toxins11090515 - 03 Sep 2019
Viewed by 364
Abstract
Mycotoxins are ubiquitous and unavoidable harmful fungal products with the ability to cause disease in both animals and humans, and are found in almost all types of foods, with a greater prevalence in hot humid environments. These mycotoxins vary greatly in structure and [...] Read more.
Mycotoxins are ubiquitous and unavoidable harmful fungal products with the ability to cause disease in both animals and humans, and are found in almost all types of foods, with a greater prevalence in hot humid environments. These mycotoxins vary greatly in structure and biochemical effects; therefore, by better understanding the toxicological and pathological aspects of mycotoxins, we can be better equipped to fight the diseases, as well as the biological and economic devastations, they induce. Multiple studies point to the association between a recent increase in male infertility and the increased occurrence of these mycotoxins in the environment. Furthermore, understanding how mycotoxins may induce an accumulation of epimutations during parental lifetimes can shed light on their implications with respect to fertility and reproductive efficiency. By acknowledging the diversity of mycotoxin molecular function and mode of action, this review aims to address the current limited knowledge on the effects of these chemicals on spermatogenesis and the various endocrine and epigenetics patterns associated with their disruptions. Full article
(This article belongs to the Special Issue Dietary Mycotoxin Exposure: Emerging Risks to Human Health)
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Open AccessArticle
Comparative Structure–Activity Analysis of the Antimicrobial Activity, Cytotoxicity, and Mechanism of Action of the Fungal Cyclohexadepsipeptides Enniatins and Beauvericin
Toxins 2019, 11(9), 514; https://doi.org/10.3390/toxins11090514 - 03 Sep 2019
Viewed by 370
Abstract
Filamentous fungi, although producing noxious molecules such as mycotoxins, have been used to produce numerous drugs active against human diseases such as paclitaxel, statins, and penicillin, saving millions of human lives. Cyclodepsipeptides are fungal molecules with potentially adverse and positive effects. Although these [...] Read more.
Filamentous fungi, although producing noxious molecules such as mycotoxins, have been used to produce numerous drugs active against human diseases such as paclitaxel, statins, and penicillin, saving millions of human lives. Cyclodepsipeptides are fungal molecules with potentially adverse and positive effects. Although these peptides are not novel, comparative studies of their antimicrobial activity, toxicity, and mechanism of action are still to be identified. In this study, the fungal cyclohexadepsipeptides enniatin (ENN) and beauvericin (BEA) were assessed to determine their antimicrobial activity and cytotoxicity against human cells. Results showed that these peptides were active against Gram-positive bacteria, Mycobacterium, and fungi, but not against Gram-negative bacteria. ENN and BEA had a limited hemolytic effect, yet were found to be toxic at low doses to nucleated human cells. Both peptides also interacted with bacterial lipids, causing low to no membrane permeabilization, but induced membrane depolarization and inhibition of macromolecules synthesis. The structure–activity analysis showed that the chemical nature of the side chains present on ENN and BEA (either iso-propyl, sec-butyl, or phenylmethyl) impacts their interaction with lipids, antimicrobial action, and toxicity. Full article
(This article belongs to the Section Mycotoxins)
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Open AccessArticle
Molecular Determinants of Brevetoxin Binding to Voltage-Gated Sodium Channels
Toxins 2019, 11(9), 513; https://doi.org/10.3390/toxins11090513 - 03 Sep 2019
Viewed by 378
Abstract
Brevetoxins are produced by dinoflagellates such as Karenia brevis in warm-water red tides and cause neurotoxic shellfish poisoning. They bind to voltage-gated sodium channels at neurotoxin receptor 5, making the channels more active by shifting the voltage-dependence of activation to more negative potentials [...] Read more.
Brevetoxins are produced by dinoflagellates such as Karenia brevis in warm-water red tides and cause neurotoxic shellfish poisoning. They bind to voltage-gated sodium channels at neurotoxin receptor 5, making the channels more active by shifting the voltage-dependence of activation to more negative potentials and by slowing the inactivation process. Previous work using photoaffinity labeling identified binding to the IS6 and IVS5 transmembrane segments of the channel α subunit. We used alanine-scanning mutagenesis to identify molecular determinants for brevetoxin binding in these regions as well as adjacent regions IVS5-SS1 and IVS6. Most of the mutant channels containing single alanine substitutions expressed functional protein in tsA-201 cells and bound to the radioligand [42-3H]-PbTx3. Binding affinity for the great majority of mutant channels was indistinguishable from wild type. However, transmembrane segments IS6, IVS5 and IVS6 each contained 2 to 4 amino acid positions where alanine substitution resulted in a 2–3-fold reduction in brevetoxin affinity, and additional mutations caused a similar increase in brevetoxin affinity. These findings are consistent with a model in which brevetoxin binds to a protein cleft comprising transmembrane segments IS6, IVS5 and IVS6 and makes multiple distributed interactions with these α helices. Determination of brevetoxin affinity for Nav1.2, Nav1.4 and Nav1.5 channels showed that Nav1.5 channels had a characteristic 5-fold reduction in affinity for brevetoxin relative to the other channel isoforms, suggesting the interaction with sodium channels is specific despite the distributed binding determinants. Full article
(This article belongs to the Special Issue Marine Toxins Detection)
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