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Toxins, Volume 8, Issue 4 (April 2016) – 34 articles

Cover Story (view full-size image): Clostridium sordellii lethal toxin (TcsL) is a powerful virulence factor responsible for severe toxic shock in man and animals. TcsL glucosylates small GTPases lead to cell death. The catalytic domain of TcsL (TcsL-cat) was found to preferentially bind to phosphatidylserine (PS)-containing membranes and to increase the glucosylation of Rac and Ras anchored to lipid membrane. The PS binding site is localized on the tip of the four-helix bundle which is rich in positively charged amino acids. Functional PS-binding site is required for TcsL-cat binding to the plasma membrane and subsequent cytotoxicity. View this article.
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1196 KiB  
Review
A Disintegrin and Metalloprotease (ADAM): Historical Overview of Their Functions
by Nives Giebeler and Paola Zigrino
Toxins 2016, 8(4), 122; https://doi.org/10.3390/toxins8040122 - 23 Apr 2016
Cited by 116 | Viewed by 10722
Abstract
Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and [...] Read more.
Since the discovery of the first disintegrin protein from snake venom and the following identification of a mammalian membrane-anchored metalloprotease-disintegrin implicated in fertilization, almost three decades of studies have identified additional members of these families and several biochemical mechanisms regulating their expression and activity in the cell. Most importantly, new in vivo functions have been recognized for these proteins including cell partitioning during development, modulation of inflammatory reactions, and development of cancers. In this review, we will overview the a disintegrin and metalloprotease (ADAM) family of proteases highlighting some of the major research achievements in the analysis of ADAMs’ function that have underscored the importance of these proteins in physiological and pathological processes over the years. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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243 KiB  
Review
Botulinum Toxin A and Lower Urinary Tract Dysfunction: Pathophysiology and Mechanisms of Action
by Jia-Fong Jhang and Hann-Chorng Kuo
Toxins 2016, 8(4), 120; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040120 - 21 Apr 2016
Cited by 32 | Viewed by 4383
Abstract
The use of onabotulinumtoxinA (BoNT-A) for the treatment of lower urinary tract diseases (LUTD) has increased markedly in recent years. The indications for BoNT-A treatment of LUTD now include neurogenic or idiopathic detrusor overactivity, interstitial cystitis/bladder pain syndrome and voiding dysfunction. The mechanisms [...] Read more.
The use of onabotulinumtoxinA (BoNT-A) for the treatment of lower urinary tract diseases (LUTD) has increased markedly in recent years. The indications for BoNT-A treatment of LUTD now include neurogenic or idiopathic detrusor overactivity, interstitial cystitis/bladder pain syndrome and voiding dysfunction. The mechanisms of BoNT-A action on LUTDs affect many different aspects. Traditionally, the effects of BoNT-A were believed to be attributable to inhibition of acetylcholine release from the presynaptic efferent nerves at the neuromuscular junctions in the detrusor or urethral sphincter. BoNT-A injection in the bladder also regulated sensory nerve function by blocking neurotransmitter release and reducing receptor expression in the urothelium. In addition, recent studies revealed an anti-inflammatory effect for BoNT-A. Substance P and nerve growth factor in the urine and bladder tissue decreased after BoNT-A injection. Mast cell activation in the bladder also decreased. BoNT-A-induced improvement of urothelium function plays an important mitigating role in bladder dysfunction. Vascular endothelial growth factor expression in urothelium decreased after BoNT-A injection, as did apoptosis. Studies also revealed increased apoptosis in the prostate after BoNT-A injection. Although BoNT-A injection has been widely used to treat different LUTDs refractory to conventional treatment, currently, onabotulinumtoxinA has been proven effective only on urinary incontinence due to IDO and NDO in several large-scale clinical trials. The effects of onabotulinumtoxinA on other LUTDs such as interstitial cystitis, benign prostatic hyperplasia, dysfunctional voiding or detrusor sphincter dyssynergia have not been well demonstrated. Full article
(This article belongs to the Section Bacterial Toxins)
913 KiB  
Article
Application of LC-MS/MS MRM to Determine Staphylococcal Enterotoxins (SEB and SEA) in Milk
by Mirjana Andjelkovic, Varvara Tsilia, Andreja Rajkovic, Koen De Cremer and Joris Van Loco
Toxins 2016, 8(4), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040118 - 20 Apr 2016
Cited by 35 | Viewed by 7399
Abstract
Staphylococcus aureus is one of the important aetiological agents of food intoxications in Europe and can cause gastro-enteritis through the production of various staphylococcal enterotoxins (SEs) in foods. Due to their stability and ease of production and dissemination, some SEs have also been [...] Read more.
Staphylococcus aureus is one of the important aetiological agents of food intoxications in Europe and can cause gastro-enteritis through the production of various staphylococcal enterotoxins (SEs) in foods. Due to their stability and ease of production and dissemination, some SEs have also been studied as potential agents for bioterrorism. Therefore, specific and accurate analytical tools are required to detect and quantify SEs. Online solid-phase extraction liquid chromatography electrospray ionization tandem mass spectrometry (online SPE-LC-ESI-MS/MS) based on multiple reaction monitoring (MRM) was used to detect and quantify two types of SE (A and B) spiked in milk and buffer solution. SE extraction and concentration was performed according to the European Screening Method developed by the European Reference Laboratory for Coagulase Positive Staphylococci. Trypsin digests were screened for the presence of SEs using selected proteotypic heavy-labeled peptides as internal standards. SEA and SEB were successfully detected in milk samples using LC-MS/MS in MRM mode. The selected SE peptides were proteotypic for each toxin, allowing the discrimination of SEA and SEB in a single run. The detection limit of SEA and SEB was approximately 8 and 4 ng/g, respectively. Full article
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3723 KiB  
Review
From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins
by Aida Verdes, Prachi Anand, Juliette Gorson, Stephen Jannetti, Patrick Kelly, Abba Leffler, Danny Simpson, Girish Ramrattan and Mandë Holford
Toxins 2016, 8(4), 117; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040117 - 19 Apr 2016
Cited by 38 | Viewed by 11019
Abstract
Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this [...] Read more.
Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa. Full article
(This article belongs to the Special Issue Venomics, Venom Proteomics and Venom Transcriptomics)
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Article
The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases
by Fang Ye, Youtian Hu, Weiwei Yu, Zili Xie, Jun Hu, Zhijian Cao, Wenxin Li and Yingliang Wu
Toxins 2016, 8(4), 115; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040115 - 19 Apr 2016
Cited by 18 | Viewed by 4974
Abstract
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural [...] Read more.
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K+ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the “evolutionary” Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel–specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Article
Identification and Characterization of the HicAB Toxin-Antitoxin System in the Opportunistic Pathogen Pseudomonas aeruginosa
by Gang Li, Mengyu Shen, Shuguang Lu, Shuai Le, Yinling Tan, Jing Wang, Xia Zhao, Wei Shen, Keke Guo, Yuhui Yang, Hongbin Zhu, Xiancai Rao, Fuquan Hu and Ming Li
Toxins 2016, 8(4), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040113 - 19 Apr 2016
Cited by 38 | Viewed by 7386
Abstract
Toxin-antitoxin (TA) systems are small genetic modules that are widely distributed in the genomes of bacteria and archaea and have been proposed to fulfill numerous functions. Here, we describe the identification and characterization of a type II TA system, comprising the hicAB locus [...] Read more.
Toxin-antitoxin (TA) systems are small genetic modules that are widely distributed in the genomes of bacteria and archaea and have been proposed to fulfill numerous functions. Here, we describe the identification and characterization of a type II TA system, comprising the hicAB locus in the human opportunistic pathogen Pseudomonas aeruginosa. The hicAB locus consists of genes hicA and hicB encoding a toxin and its cognate antitoxin, respectively. BLAST analysis revealed that hicAB is prevalent in approximately 36% of P. aeruginosa strains and locates in the same genomic region. RT-PCR demonstrated that hicAB forms a bicistronic operon that is cotranscribed under normal growth conditions. Overproduction of HicA inhibited the growth of Escherichia coli, and this effect could be counteracted by co-expression of HicB. The Escherichia coli kill/rescue assay showed that the effect of HicA is bacteriostatic, rather than bactericidal. Deletion of hicAB had no effect on the biofilm formation and virulence of P. aeruginosa in a mice infection model. Collectively, this study presents the first characterization of the HicAB system in the opportunistic pathogen P. aeruginosa. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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1237 KiB  
Review
Peptide Toxins in Solitary Wasp Venoms
by Katsuhiro Konno, Kohei Kazuma and Ken-ichi Nihei
Toxins 2016, 8(4), 114; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040114 - 18 Apr 2016
Cited by 42 | Viewed by 7160
Abstract
Solitary wasps paralyze insects or spiders with stinging venom and feed the paralyzed preys to their larva. Accordingly, the venoms should contain a variety of constituents acting on nervous systems. However, only a few solitary wasp venoms have been chemically studied despite thousands [...] Read more.
Solitary wasps paralyze insects or spiders with stinging venom and feed the paralyzed preys to their larva. Accordingly, the venoms should contain a variety of constituents acting on nervous systems. However, only a few solitary wasp venoms have been chemically studied despite thousands of species inhabiting the planet. We have surveyed bioactive substances in solitary wasp venoms found in Japan and discovered a variety of novel bioactive peptides. Pompilidotoxins (PMTXs), in the venoms of the pompilid wasps Anoplius samariensis and Batozonellus maculifrons, are small peptides consisting of 13 amino acids without a disulfide bond. PMTXs slowed Na+ channel inactivation, in particular against neuronal type Na+ channels, and were rather selective to the Nav1.6 channel. Mastoparan-like cytolytic and antimicrobial peptides are the major components of eumenine wasp venoms. They are rich in hydrophobic and basic amino acids, adopting a α-helical secondary structure, and showing mast cell degranulating, antimicrobial and hemolytic activities. The venom of the spider wasp Cyphononyx fulvognathus contained four bradykinin-related peptides. They are hyperalgesic and, dependent on the structure, differently associated with B1 or B2 receptors. Further survey led to the isolation of leucomyosuppressin-like FMRFamide peptides from the venoms of the digger wasps Sphex argentatus and Isodontia harmandi. These results of peptide toxins in solitary wasp venoms from our studies are summarized. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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1222 KiB  
Article
The Response of Selected Triticum spp. Genotypes with Different Ploidy Levels to Head Blight Caused by Fusarium culmorum (W.G.Smith) Sacc.
by Marian Wiwart, Elżbieta Suchowilska, Wolfang Kandler, Michael Sulyok, Urszula Wachowska and Rudolf Krska
Toxins 2016, 8(4), 112; https://doi.org/10.3390/toxins8040112 - 15 Apr 2016
Cited by 12 | Viewed by 4681
Abstract
Several cultivars and pure lines of Triticum monococcum, T. dicoccon, T. polonicum, T. spelta and T. aestivum were inoculated with Fusarium culmorum, the causal agent of Fusarium head blight in wheat. During the three-year study, the infection decreased the [...] Read more.
Several cultivars and pure lines of Triticum monococcum, T. dicoccon, T. polonicum, T. spelta and T. aestivum were inoculated with Fusarium culmorum, the causal agent of Fusarium head blight in wheat. During the three-year study, the infection decreased the values of the analyzed yield components: spike weight (by 5.6% to 15.8%), number of kernels per spike (by 2.8% to 11.8%) and one kernel weight (by 8.4% to 10.7%). T. spelta was characterized by the weakest average response to infection. The grain from inoculated spikes contained significantly higher concentrations of deoxynivalenol (DON) and its 3-β-d-glucoside (D3G) than control grain. The D3G/DON ratio ranged from 11.4% to 21.4% in control grain and from 8.1% to 11.6% in inoculated grain. The lowest levels of mycotoxins were found in spelt, and the highest in T. polonicum lines and Kamut. PCA revealed that the grain of T. polonicum was characterized by an entirely different mycotoxin profile. The weakest response to F. culmorum infections was noted in T. spelta, and the strongest response in T. polonicum breeding lines and Kamut. Full article
(This article belongs to the Collection Fusarium Toxins – Relevance for Human and Animal Health)
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1311 KiB  
Review
Ochratoxin A: Molecular Interactions, Mechanisms of Toxicity and Prevention at the Molecular Level
by Tamás Kőszegi and Miklós Poór
Toxins 2016, 8(4), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040111 - 15 Apr 2016
Cited by 203 | Viewed by 19080
Abstract
Ochratoxin A (OTA) is a widely-spread mycotoxin all over the world causing major health risks. The focus of the present review is on the molecular and cellular interactions of OTA. In order to get better insight into the mechanism of its toxicity and [...] Read more.
Ochratoxin A (OTA) is a widely-spread mycotoxin all over the world causing major health risks. The focus of the present review is on the molecular and cellular interactions of OTA. In order to get better insight into the mechanism of its toxicity and on the several attempts made for prevention or attenuation of its toxic action, a detailed description is given on chemistry and toxicokinetics of this mycotoxin. The mode of action of OTA is not clearly understood yet, and seems to be very complex. Inhibition of protein synthesis and energy production, induction of oxidative stress, DNA adduct formation, as well as apoptosis/necrosis and cell cycle arrest are possibly involved in its toxic action. Since OTA binds very strongly to human and animal albumin, a major emphasis is done regarding OTA-albumin interaction. Displacement of OTA from albumin by drugs and by natural flavonoids are discussed in detail, hypothesizing their potentially beneficial effect in order to prevent or attenuate the OTA-induced toxic consequences. Full article
(This article belongs to the Collection Ochratoxins-Collection)
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1529 KiB  
Article
Detection of Enterotoxigenic Potential and Determination of Clonal Profile in Staphylococcus aureus and Coagulase-Negative Staphylococci Isolated from Bovine Subclinical Mastitis in Different Brazilian States
by Priscila Luiza Mello, Danilo Flávio Moraes Riboli, Luiza Pinheiro, Lisiane De Almeida Martins, Maria Aparecida Vasconcelos Paiva Brito and Maria De Lourdes Ribeiro de Souza da Cunha
Toxins 2016, 8(4), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040104 - 15 Apr 2016
Cited by 34 | Viewed by 6047
Abstract
Epidemiological studies have identified Staphylococcus aureus as the most common agent involved in food poisoning. However, current research highlights the importance of toxigenic coagulase-negative staphylococci (CoNS) isolated from food. The aim of this study was to characterize Staphylococcus spp. isolated from cows with [...] Read more.
Epidemiological studies have identified Staphylococcus aureus as the most common agent involved in food poisoning. However, current research highlights the importance of toxigenic coagulase-negative staphylococci (CoNS) isolated from food. The aim of this study was to characterize Staphylococcus spp. isolated from cows with bovine subclinical mastitis regarding the presence of genes responsible for the production of staphylococcal enterotoxins and of the tst-1 gene encoding toxic shock syndrome toxin 1, and to determine the clonal profile of the isolates carrying any of the genes studied. A total of 181 strains isolated in different Brazilian states, including the South, Southeast, and Northeast regions, were analyzed. The sea gene was the most frequent, which was detected in 18.2% of the isolates, followed by seb in 7.7%, sec in 14.9%, sed in 0.5%, see in 8.2%, seg in 1.6%, seh in 25.4%, sei in 6.6%, and ser in 1.6%. The sej, ses, set, and tst-1 genes were not detected in any of the isolates. The typing of the isolates by pulsed-field gel electrophoresis revealed important S. aureus and S. epidermidis clusters in different areas and the presence of enterotoxin genes in lineages isolated from animals that belong to herds located geographically close to each other. Full article
(This article belongs to the Collection Staphylococcus aureus Toxins)
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2291 KiB  
Article
The Kunitz-Type Protein ShPI-1 Inhibits Serine Proteases and Voltage-Gated Potassium Channels
by Rossana García-Fernández, Steve Peigneur, Tirso Pons, Carlos Alvarez, Lidice González, María A. Chávez and Jan Tytgat
Toxins 2016, 8(4), 110; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040110 - 13 Apr 2016
Cited by 33 | Viewed by 6532
Abstract
The bovine pancreatic trypsin inhibitor (BPTI)-Kunitz-type protein ShPI-1 (UniProt: P31713) is the major protease inhibitor from the sea anemone Stichodactyla helianthus. This molecule is used in biotechnology and has biomedical potential related to its anti-parasitic effect. A pseudo wild-type variant, rShPI-1A, [...] Read more.
The bovine pancreatic trypsin inhibitor (BPTI)-Kunitz-type protein ShPI-1 (UniProt: P31713) is the major protease inhibitor from the sea anemone Stichodactyla helianthus. This molecule is used in biotechnology and has biomedical potential related to its anti-parasitic effect. A pseudo wild-type variant, rShPI-1A, with additional residues at the N- and C-terminal, has a similar three-dimensional structure and comparable trypsin inhibition strength. Further insights into the structure-function relationship of rShPI-1A are required in order to obtain a better understanding of the mechanism of action of this sea anemone peptide. Using enzyme kinetics, we now investigated its activity against other serine proteases. Considering previous reports of bifunctional Kunitz-type proteins from anemones, we also studied the effect of rShPI-1A on voltage-gated potassium (Kv) channels. rShPI-1A binds Kv1.1, Kv1.2, and Kv1.6 channels with IC50 values in the nM range. Hence, ShPI-1 is the first member of the sea anemone type 2 potassium channel toxins family with tight-binding potency against several proteases and different Kv1 channels. In depth sequence analysis and structural comparison of ShPI-1 with similar protease inhibitors and Kv channel toxins showed apparent non-sequence conservation for known key residues. However, we detected two subtle patterns of coordinated amino acid substitutions flanking the conserved cysteine residues at the N- and C-terminal ends. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Article
Metal Ion Activation of Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B
by Harald Genth, Ilona Schelle and Ingo Just
Toxins 2016, 8(4), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040109 - 13 Apr 2016
Cited by 6 | Viewed by 5213
Abstract
Lethal Toxin from Clostridium sordellii (TcsL) and Toxin B from Clostridium difficile (TcdB) belong to the family of the “Large clostridial glycosylating toxins.” These toxins mono-O-glucosylate low molecular weight GTPases of the Rho and Ras families by exploiting UDP-glucose as a hexose donor. [...] Read more.
Lethal Toxin from Clostridium sordellii (TcsL) and Toxin B from Clostridium difficile (TcdB) belong to the family of the “Large clostridial glycosylating toxins.” These toxins mono-O-glucosylate low molecular weight GTPases of the Rho and Ras families by exploiting UDP-glucose as a hexose donor. TcsL is casually involved in the toxic shock syndrome and the gas gangrene. TcdB—together with Toxin A (TcdA)—is causative for the pseudomembranous colitis (PMC). Here, we present evidence for the in vitro metal ion activation of the glucosyltransferase and the UDP-glucose hydrolysis activity of TcsL and TcdB. The following rating is found for activation by divalent metal ions: Mn2+ > Co2+ > Mg2+ >> Ca2+, Cu2+, Zn2+. TcsL and TcdB thus require divalent metal ions providing an octahedral coordination sphere. The EC50 values for TcsL were estimated at about 28 µM for Mn2+ and 180 µM for Mg2+. TcsL and TcdB further require co-stimulation by monovalent K+ (not by Na+). Finally, prebound divalent metal ions were dispensible for the cytopathic effects of TcsL and TcdB, leading to the conclusion that TcsL and TcdB recruit intracellular metal ions for activation of the glucosyltransferase activity. With regard to the intracellular metal ion concentrations, TcsL and TcdB are most likely activated by K+ and Mg2+ (rather than Mn2+) in mammalian target cells. Full article
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Article
Review Over a 3-Year Period of European Union Proficiency Tests for Detection of Staphylococcal Enterotoxins in Food Matrices
by Yacine Nia, Isabelle Mutel, Adrien Assere, Bertrand Lombard, Frederic Auvray and Jacques-Antoine Hennekinne
Toxins 2016, 8(4), 107; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040107 - 13 Apr 2016
Cited by 19 | Viewed by 5752
Abstract
Staphylococcal food poisoning outbreaks are a major cause of foodborne illnesses in Europe and their notifications have been mandatory since 2005. Even though the European regulation on microbiological criteria for food defines a criterion on staphylococcal enterotoxin (SE) only in cheese and dairy [...] Read more.
Staphylococcal food poisoning outbreaks are a major cause of foodborne illnesses in Europe and their notifications have been mandatory since 2005. Even though the European regulation on microbiological criteria for food defines a criterion on staphylococcal enterotoxin (SE) only in cheese and dairy products, European Food Safety Authority (EFSA) data reported that various types of food matrices are involved in staphylococcal food poisoning outbreaks. The European Screening Method (ESM) of European Union Reference Laboratory for Coagulase Positive Staphylococci (EURL CPS) was validated in 2011 for SE detection in food matrices and is currently the official method used for screening purposes in Europe. In this context, EURLCPS is annually organizing Inter-Laboratory Proficiency Testing Trials (ILPT) to evaluate the competency of the European countries’ National Reference Laboratories (NRLs) to analyse SE content in food matrices. A total of 31 NRLs representing 93% of European countries participated in these ILPTs. Eight food matrices were used for ILPT over the period 2013–2015, including cheese, freeze-dried cheese, tuna, mackerel, roasted chicken, ready-to-eat food, milk, and pastry. Food samples were spiked with four SE types (i.e., SEA, SEC, SED, and SEE) at various concentrations. Homogeneity and stability studies showed that ILPT samples were both homogeneous and stable. The analysis of results obtained by participants for a total of 155 blank and 620 contaminated samples allowed for evaluation of trueness (>98%) and specificity (100%) of ESM. Further to the validation study of ESM carried out in 2011, these three ILPTs allowed for the assessment of the proficiency of the NRL network and the performance of ESM on a large variety of food matrices and samples. The ILPT design presented here will be helpful for the organization of ILPT on SE detection by NRLs or other expert laboratories. Full article
(This article belongs to the Collection Rapid Detection of Bacterial Toxins)
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Article
Morphologic, Phylogenetic and Chemical Characterization of a Brackish Colonial Picocyanobacterium (Coelosphaeriaceae) with Bioactive Properties
by Kerstin Häggqvist, Anna Toruńska-Sitarz, Agata Błaszczyk, Hanna Mazur-Marzec and Jussi Meriluoto
Toxins 2016, 8(4), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040108 - 12 Apr 2016
Cited by 8 | Viewed by 5688
Abstract
Despite their cosmopolitan distribution, knowledge on cyanobacteria in the family Coelosphaeriaceae is limited. In this study, a single species culture of a coelosphaeran cyanobacterium isolated from a brackish rock pool in the Baltic Sea was established. The strain was characterized by morphological features, [...] Read more.
Despite their cosmopolitan distribution, knowledge on cyanobacteria in the family Coelosphaeriaceae is limited. In this study, a single species culture of a coelosphaeran cyanobacterium isolated from a brackish rock pool in the Baltic Sea was established. The strain was characterized by morphological features, partial 16S rRNA sequence and nonribosomal oligopeptide profile. The bioactivity of fractionated extracts against several serine proteases, as well as protein-serine/threonine phosphatases was studied. Phylogenetic analyses of the strain suggested a close relationship with Snowella litoralis, but its morphology resembled Woronichinia compacta. The controversial morphologic and phylogenetic results demonstrated remaining uncertainties regarding species division in this cyanobacteria family. Chemical analyses of the strain indicated production of nonribosomal oligopeptides. In fractionated extracts, masses and ion fragmentation spectra of seven possible anabaenopeptins were identified. Additionally, fragmentation spectra of cyanopeptolin-like peptides were collected in several of the fractions. The nonribosomal oligopeptide profile adds another potential identification criterion in future inter- and intraspecies comparisons of coelosphaeran cyanobacteria. The fractionated extracts showed significant activity against carboxypeptidase A and trypsin. Inhibition of these important metabolic enzymes might have impacts at the ecosystem level in aquatic habitats with high cyanobacteria densities. Full article
(This article belongs to the Special Issue Bioactivity and Toxicity in Marine Cyanobacteria)
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Article
δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats
by Bruna Luiza Emerich, Renata C. M. Ferreira, Marta N. Cordeiro, Márcia Helena Borges, Adriano M. C. Pimenta, Suely G. Figueiredo, Igor Dimitri G. Duarte and Maria Elena De Lima
Toxins 2016, 8(4), 106; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040106 - 12 Apr 2016
Cited by 30 | Viewed by 7684
Abstract
PnTx4(6-1), henceforth renamed δ-Ctenitoxin-Pn1a (δ-CNTX-Pn1a), a peptide from Phoneutria nigriventer spider venom, initially described as an insect toxin, binds to site 3 of sodium channels in nerve cord synaptosomes and slows down sodium current inactivation in isolated axons in cockroaches (Periplaneta americana [...] Read more.
PnTx4(6-1), henceforth renamed δ-Ctenitoxin-Pn1a (δ-CNTX-Pn1a), a peptide from Phoneutria nigriventer spider venom, initially described as an insect toxin, binds to site 3 of sodium channels in nerve cord synaptosomes and slows down sodium current inactivation in isolated axons in cockroaches (Periplaneta americana). δ-CNTX-Pn1a does not cause any apparent toxicity to mice, when intracerebroventricularly injected (30 μg). In this study, we evaluated the antinociceptive effect of δ-CNTX-Pn1a in three animal pain models and investigated its mechanism of action in acute pain. In the inflammatory pain model, induced by carrageenan, δ-CNTX-Pn1a restored the nociceptive threshold of rats, when intraplantarly injected, 2 h and 30 min after carrageenan administration. Concerning the neuropathic pain model, δ-CNTX-Pn1a, when intrathecally administered, reversed the hyperalgesia evoked by sciatic nerve constriction. In the acute pain model, induced by prostaglandin E2, intrathecal administration of δ-CNTX-Pn1a caused a dose-dependent antinociceptive effect. Using antagonists of the receptors, we showed that the antinociceptive effect of δ-CNTX-Pn1a involves both the cannabinoid system, through CB1 receptors, and the opioid system, through μ and δ receptors. Our data show, for the first time, that δ-Ctenitoxin-Pn1a is able to induce antinociception in inflammatory, neuropathic and acute pain models. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Article
Quantitative Proteomic Analysis of Venoms from Russian Vipers of Pelias Group: Phospholipases A2 are the Main Venom Components
by Sergey I. Kovalchuk, Rustam H. Ziganshin, Vladislav G. Starkov, Victor I. Tsetlin and Yuri N. Utkin
Toxins 2016, 8(4), 105; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040105 - 12 Apr 2016
Cited by 28 | Viewed by 5602
Abstract
Venoms of most Russian viper species are poorly characterized. Here, by quantitative chromato-mass-spectrometry, we analyzed protein and peptide compositions of venoms from four Vipera species (V. kaznakovi, V. renardi, V. orlovi and V. nikolskii) inhabiting different regions of Russia. [...] Read more.
Venoms of most Russian viper species are poorly characterized. Here, by quantitative chromato-mass-spectrometry, we analyzed protein and peptide compositions of venoms from four Vipera species (V. kaznakovi, V. renardi, V. orlovi and V. nikolskii) inhabiting different regions of Russia. In all these species, the main components were phospholipases A2, their content ranging from 24% in V. orlovi to 65% in V. nikolskii. Altogether, enzyme content in venom of V. nikolskii reached ~85%. Among the non-enzymatic proteins, the most abundant were disintegrins (14%) in the V. renardi venom, C-type lectin like (12.5%) in V. kaznakovi, cysteine-rich venom proteins (12%) in V. orlovi and venom endothelial growth factors (8%) in V. nikolskii. In total, 210 proteins and 512 endogenous peptides were identified in the four viper venoms. They represented 14 snake venom protein families, most of which were found in the venoms of Vipera snakes previously. However, phospholipase B and nucleotide degrading enzymes were reported here for the first time. Compositions of V. kaznakovi and V. orlovi venoms were described for the first time and showed the greatest similarity among the four venoms studied, which probably reflected close relationship between these species within the “kaznakovi” complex. Full article
(This article belongs to the Special Issue Venomics, Venom Proteomics and Venom Transcriptomics)
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Article
Comparison of Enzyme-Linked Immunosorbent Assay, Surface Plasmon Resonance and Biolayer Interferometry for Screening of Deoxynivalenol in Wheat and Wheat Dust
by Melanie Sanders, Daniel McPartlin, Kara Moran, Yirong Guo, Mia Eeckhout, Richard O’Kennedy, Sarah De Saeger and Chris Maragos
Toxins 2016, 8(4), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040103 - 11 Apr 2016
Cited by 21 | Viewed by 5642
Abstract
A sample preparation method was developed for the screening of deoxynivalenol (DON) in wheat and wheat dust. Extraction was carried out with water and was successful due to the polar character of DON. For detection, an enzyme-linked immunosorbent assay (ELISA) was compared to [...] Read more.
A sample preparation method was developed for the screening of deoxynivalenol (DON) in wheat and wheat dust. Extraction was carried out with water and was successful due to the polar character of DON. For detection, an enzyme-linked immunosorbent assay (ELISA) was compared to the sensor-based techniques of surface plasmon resonance (SPR) and biolayer interferometry (BLI) in terms of sensitivity, affinity and matrix effect. The matrix effects from wheat and wheat dust using SPR were too high to further use this screenings method. The preferred ELISA and BLI methods were validated according to the criteria established in Commission Regulation 519/2014/EC and Commission Decision 2002/657/EC. A small survey was executed on 16 wheat lots and their corresponding dust samples using the validated ELISA method. A linear correlation (r = 0.889) was found for the DON concentration in dust versus the DON concentration in wheat (LOD wheat: 233 μg/kg, LOD wheat dust: 458 μg/kg). Full article
(This article belongs to the Collection Biorecognition Assays for Mycotoxins)
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Article
Tentacle Transcriptome and Venom Proteome of the Pacific Sea Nettle, Chrysaora fuscescens (Cnidaria: Scyphozoa)
by Dalia Ponce, Diane L. Brinkman, Jeremy Potriquet and Jason Mulvenna
Toxins 2016, 8(4), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040102 - 05 Apr 2016
Cited by 70 | Viewed by 12240
Abstract
Jellyfish venoms are rich sources of toxins designed to capture prey or deter predators, but they can also elicit harmful effects in humans. In this study, an integrated transcriptomic and proteomic approach was used to identify putative toxins and their potential role in [...] Read more.
Jellyfish venoms are rich sources of toxins designed to capture prey or deter predators, but they can also elicit harmful effects in humans. In this study, an integrated transcriptomic and proteomic approach was used to identify putative toxins and their potential role in the venom of the scyphozoan jellyfish Chrysaora fuscescens. A de novo tentacle transcriptome, containing more than 23,000 contigs, was constructed and used in proteomic analysis of C. fuscescens venom to identify potential toxins. From a total of 163 proteins identified in the venom proteome, 27 were classified as putative toxins and grouped into six protein families: proteinases, venom allergens, C-type lectins, pore-forming toxins, glycoside hydrolases and enzyme inhibitors. Other putative toxins identified in the transcriptome, but not the proteome, included additional proteinases as well as lipases and deoxyribonucleases. Sequence analysis also revealed the presence of ShKT domains in two putative venom proteins from the proteome and an additional 15 from the transcriptome, suggesting potential ion channel blockade or modulatory activities. Comparison of these potential toxins to those from other cnidarians provided insight into their possible roles in C. fuscescens venom and an overview of the diversity of potential toxin families in cnidarian venoms. Full article
(This article belongs to the Special Issue Venomics, Venom Proteomics and Venom Transcriptomics)
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Article
Structural Characterization of Humanized Nanobodies with Neutralizing Activity against the Bordetella pertussis CyaA-Hemolysin: Implications for a Potential Epitope of Toxin-Protective Antigen
by Aijaz Ahmad Malik, Chompounoot Imtong, Nitat Sookrung, Gerd Katzenmeier, Wanpen Chaicumpa and Chanan Angsuthanasombat
Toxins 2016, 8(4), 99; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040099 - 01 Apr 2016
Cited by 13 | Viewed by 5532
Abstract
Previously, the 126-kDa CyaA-hemolysin (CyaA-Hly) fragment cloned from Bordetella pertussis—the causative agent of whooping cough—and functionally expressed in Escherichia coli was revealed as a key determinant for CyaA-mediated hemolysis against target erythrocytes. Here, phagemid-transfected E. coli clones producing nanobodies capable of binding [...] Read more.
Previously, the 126-kDa CyaA-hemolysin (CyaA-Hly) fragment cloned from Bordetella pertussis—the causative agent of whooping cough—and functionally expressed in Escherichia coli was revealed as a key determinant for CyaA-mediated hemolysis against target erythrocytes. Here, phagemid-transfected E. coli clones producing nanobodies capable of binding to CyaA-Hly were selected from a humanized-camel VH/VHH phage-display library. Subsequently verified for binding activities by indirect ELISA and Western blotting, four CyaA-Hly-specific nanobodies were obtained and designated according to the presence/absence of VHH-hallmark amino acids as VHH2, VH5, VH18 and VHH37. In vitro neutralization assay revealed that all four ~17-kDa His-tagged VH/VHH nanobodies, in particular VHH37, which were over-expressed as inclusions and successfully unfolded-refolded, were able to effectively inhibit CyaA-Hly-mediated hemolysis. Phage-mimotope searching revealed that only peptides with sequence homologous to Linker 1 connecting Blocks I and II within the CyaA-RTX subdomain were able to bind to these four CyaA-Hly-specific nanobodies. Structural analysis of VHH37 via homology modeling and intermolecular docking confirmed that this humanized nanobody directly interacts with CyaA-RTX/Linker 1 through multiple hydrogen and ionic bonds. Altogether, our present data demonstrate that CyaA-RTX/Linker 1 could serve as a potential epitope of CyaA-protective antigen that may be useful for development of peptide-based pertussis vaccines. Additionally, such toxin-specific nanobodies have a potential for test-driven development of a ready-to-use therapeutic in passive immunization for mitigation of disease severity. Full article
(This article belongs to the Section Bacterial Toxins)
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Review
Heated Debates: Hot-Water Immersion or Ice Packs as First Aid for Cnidarian Envenomations?
by Christie L. Wilcox and Angel A. Yanagihara
Toxins 2016, 8(4), 97; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040097 - 01 Apr 2016
Cited by 27 | Viewed by 19412
Abstract
Cnidarian envenomations are an important public health problem, responsible for more deaths than shark attacks annually. For this reason, optimization of first-aid care is essential. According to the published literature, cnidarian venoms and toxins are heat labile at temperatures safe for human application, [...] Read more.
Cnidarian envenomations are an important public health problem, responsible for more deaths than shark attacks annually. For this reason, optimization of first-aid care is essential. According to the published literature, cnidarian venoms and toxins are heat labile at temperatures safe for human application, which supports the use of hot-water immersion of the sting area(s). However, ice packs are often recommended and used by emergency personnel. After conducting a systematic review of the evidence for the use of heat or ice in the treatment of cnidarian envenomations, we conclude that the majority of studies to date support the use of hot-water immersion for pain relief and improved health outcomes. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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Article
EGA Protects Mammalian Cells from Clostridium difficile CDT, Clostridium perfringens Iota Toxin and Clostridium botulinum C2 Toxin
by Leonie Schnell, Ann-Katrin Mittler, Mirko Sadi, Michel R. Popoff, Carsten Schwan, Klaus Aktories, Andrea Mattarei, Domenico Azarnia Tehran, Cesare Montecucco and Holger Barth
Toxins 2016, 8(4), 101; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040101 - 01 Apr 2016
Cited by 7 | Viewed by 6952
Abstract
The pathogenic bacteria Clostridium difficile, Clostridium perfringens and Clostridium botulinum produce the binary actin ADP-ribosylating toxins CDT, iota and C2, respectively. These toxins are composed of a transport component (B) and a separate enzyme component (A). When both components assemble on the [...] Read more.
The pathogenic bacteria Clostridium difficile, Clostridium perfringens and Clostridium botulinum produce the binary actin ADP-ribosylating toxins CDT, iota and C2, respectively. These toxins are composed of a transport component (B) and a separate enzyme component (A). When both components assemble on the surface of mammalian target cells, the B components mediate the entry of the A components via endosomes into the cytosol. Here, the A components ADP-ribosylate G-actin, resulting in depolymerization of F-actin, cell-rounding and eventually death. In the present study, we demonstrate that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA), a compound that protects cells from multiple toxins and viruses, also protects different mammalian epithelial cells from all three binary actin ADP-ribosylating toxins. In contrast, EGA did not inhibit the intoxication of cells with Clostridium difficile toxins A and B, indicating a possible different entry route for this toxin. EGA does not affect either the binding of the C2 toxin to the cells surface or the enzyme activity of the A components of CDT, iota and C2, suggesting that this compound interferes with cellular uptake of the toxins. Moreover, for C2 toxin, we demonstrated that EGA inhibits the pH-dependent transport of the A component across cell membranes. EGA is not cytotoxic, and therefore, we propose it as a lead compound for the development of novel pharmacological inhibitors against clostridial binary actin ADP-ribosylating toxins. Full article
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Article
Detection and Quantification of ADP-Ribosylated RhoA/B by Monoclonal Antibody
by Astrid Rohrbeck, Viola Fühner, Anke Schröder, Sandra Hagemann, Xuan-Khang Vu, Sarah Berndt, Michael Hust, Andreas Pich and Ingo Just
Toxins 2016, 8(4), 100; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040100 - 01 Apr 2016
Cited by 9 | Viewed by 6154
Abstract
Clostridium botulinum exoenzyme C3 is the prototype of C3-like ADP-ribosyltransferases that modify the GTPases RhoA, B, and C. C3 catalyzes the transfer of an ADP-ribose moiety from the co-substrate nicotinamide adenine dinucleotide (NAD) to asparagine-41 of Rho-GTPases. Although C3 does not possess cell-binding/-translocation [...] Read more.
Clostridium botulinum exoenzyme C3 is the prototype of C3-like ADP-ribosyltransferases that modify the GTPases RhoA, B, and C. C3 catalyzes the transfer of an ADP-ribose moiety from the co-substrate nicotinamide adenine dinucleotide (NAD) to asparagine-41 of Rho-GTPases. Although C3 does not possess cell-binding/-translocation domains, C3 is able to efficiently enter intact cells, including neuronal and macrophage-like cells. Conventionally, the detection of C3 uptake into cells is carried out via the gel-shift assay of modified RhoA. Since this gel-shift assay does not always provide clear, evaluable results an additional method to confirm the ADP-ribosylation of RhoA is necessary. Therefore, a new monoclonal antibody has been generated that specifically detects ADP-ribosylated RhoA/B, but not RhoC, in Western blot and immunohistochemical assay. The scFv antibody fragment was selected by phage display using the human naive antibody gene libraries HAL9/10. Subsequently, the antibody was produced as scFv-Fc and was found to be as sensitive as a commercially available RhoA antibody providing reproducible and specific results. We demonstrate that this specific antibody can be successfully applied for the analysis of ADP-ribosylated RhoA/B in C3-treated Chinese hamster ovary (CHO) and HT22 cells. Moreover, ADP-ribosylation of RhoA was detected within 10 min in C3-treated CHO wild-type cells, indicative of C3 cell entry. Full article
(This article belongs to the Section Bacterial Toxins)
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Article
Mechanisms that Determine the Differential Stability of Stx+ and Stx Lysogens
by Michael P. Colon, Dolonchapa Chakraborty, Yonatan Pevzner and Gerald B. Koudelka
Toxins 2016, 8(4), 96; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040096 - 31 Mar 2016
Cited by 14 | Viewed by 6420
Abstract
Phages 933W, BAA2326, 434, and λ are evolutionarily-related temperate lambdoid phages that infect Escherichia coli. Although these are highly-similar phages, BAA2326 and 933W naturally encode Shiga toxin 2 (Stx+), but phage 434 and λ do not (Stx). Previous [...] Read more.
Phages 933W, BAA2326, 434, and λ are evolutionarily-related temperate lambdoid phages that infect Escherichia coli. Although these are highly-similar phages, BAA2326 and 933W naturally encode Shiga toxin 2 (Stx+), but phage 434 and λ do not (Stx). Previous reports suggest that the 933W Stx+ prophage forms less stable lysogens in E. coli than does the Stx prophages λ, P22, and 434. The higher spontaneous induction frequency of the Stx+ prophage may be correlated with both virulence and dispersion of the Stx2-encoding phage. Here, we examined the hypothesis that lysogen instability is a common feature of Stx+ prophages. We found in both the absence and presence of prophage inducers (DNA damaging agents, salts), the Stx+ prophages induce at higher frequencies than do Stx prophages. The observed instability of Stx+ prophages does not appear to be the result of any differences in phage development properties between Stx+ and Stx phages. Our results indicate that differential stability of Stx+ and Stx prophages results from both RecA-dependent and RecA-independent effects on the intracellular concentration of the respective cI repressors. Full article
(This article belongs to the Collection Shiga Toxins)
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Article
ADAM10 Cell Surface Expression but Not Activity Is Critical for Staphylococcus aureus α-Hemolysin-Mediated Activation of the NLRP3 Inflammasome in Human Monocytes
by Ejiofor A.D. Ezekwe, Chengyu Weng and Joseph A. Duncan
Toxins 2016, 8(4), 95; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040095 - 30 Mar 2016
Cited by 24 | Viewed by 7835
Abstract
The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin [...] Read more.
The Staphylococcus aureus toxin, α-hemolysin, is an important and well-studied virulence factor in staphylococcal infection. It is a soluble monomeric protein that, once secreted by the bacterium, forms a heptameric pore in the membrane of a broad range of host cell types. Hemolysin was recently discovered to bind and activate a disintegrin and metalloprotease 10 (ADAM10). In epithelial and endothelial cells, ADAM10 activation is required for the toxin’s activity against these cells. In host monocytic cells, α-hemolysin activates the nucleotide-binding domain and leucine-rich repeat containing gene family, pyrin domain containing 3 (NLRP3) inflammasome leading to production of pro-inflammatory cytokines and cell death. We now show that ADAM10 is critical for α-hemolysin-mediated activation of the NLRP3 inflammasome in human monocytes as siRNA knockdown or chemical blockade of ADAM10-α-hemolysin interaction leads to diminished inflammasome activation and cell death by reducing the available ADAM10 on the cell surface. Unlike epithelial cell and endothelial cell damage, which requires α-hemolysin induced ADAM10 activation, ADAM10 protease activity was not required for NLRP3 inflammasome activation. This work confirms the importance of ADAM10 in immune activation by α-hemolysin, but indicates that host cell signal induction by the toxin is different between host cell types. Full article
(This article belongs to the Collection Staphylococcus aureus Toxins)
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Review
Natural Co-Occurrence of Mycotoxins in Foods and Feeds and Their in vitro Combined Toxicological Effects
by Marie-Caroline Smith, Stéphanie Madec, Emmanuel Coton and Nolwenn Hymery
Toxins 2016, 8(4), 94; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040094 - 26 Mar 2016
Cited by 386 | Viewed by 16547
Abstract
Some foods and feeds are often contaminated by numerous mycotoxins, but most studies have focused on the occurrence and toxicology of a single mycotoxin. Regulations throughout the world do not consider the combined effects of mycotoxins. However, several surveys have reported the natural [...] Read more.
Some foods and feeds are often contaminated by numerous mycotoxins, but most studies have focused on the occurrence and toxicology of a single mycotoxin. Regulations throughout the world do not consider the combined effects of mycotoxins. However, several surveys have reported the natural co-occurrence of mycotoxins from all over the world. Most of the published data has concerned the major mycotoxins aflatoxins (AFs), ochratoxin A (OTA), zearalenone (ZEA), fumonisins (FUM) and trichothecenes (TCTs), especially deoxynivalenol (DON). Concerning cereals and derived cereal product samples, among the 127 mycotoxin combinations described in the literature, AFs+FUM, DON+ZEA, AFs+OTA, and FUM+ZEA are the most observed. However, only a few studies specified the number of co-occurring mycotoxins with the percentage of the co-contaminated samples, as well as the main combinations found. Studies of mycotoxin combination toxicity showed antagonist, additive or synergic effects depending on the tested species, cell model or mixture, and were not necessarily time- or dose-dependent. This review summarizes the findings on mycotoxins and their co-occurrence in various foods and feeds from all over the world as well as in vitro experimental data on their combined toxicity. Full article
(This article belongs to the Collection Fusarium Toxins – Relevance for Human and Animal Health)
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Review
Hemorrhage Caused by Snake Venom Metalloproteinases: A Journey of Discovery and Understanding
by José María Gutiérrez, Teresa Escalante, Alexandra Rucavado and Cristina Herrera
Toxins 2016, 8(4), 93; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040093 - 26 Mar 2016
Cited by 135 | Viewed by 11019
Abstract
The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main [...] Read more.
The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases)
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Article
Neutralization of the Principal Toxins from the Venoms of Thai Naja kaouthia and Malaysian Hydrophis schistosus: Insights into Toxin-Specific Neutralization by Two Different Antivenoms
by Kae Yi Tan, Choo Hock Tan, Shin Yee Fung and Nget Hong Tan
Toxins 2016, 8(4), 86; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040086 - 26 Mar 2016
Cited by 56 | Viewed by 5803
Abstract
Antivenom neutralization against cobra venoms is generally low in potency, presumably due to poor toxin-specific immunoreactivity. This study aimed to investigate the effectiveness of two elapid antivenoms to neutralize the principal toxins purified from the venoms of the Thai monocled cobra (Naja [...] Read more.
Antivenom neutralization against cobra venoms is generally low in potency, presumably due to poor toxin-specific immunoreactivity. This study aimed to investigate the effectiveness of two elapid antivenoms to neutralize the principal toxins purified from the venoms of the Thai monocled cobra (Naja kaouthia, Nk-T) and the Malaysian beaked sea snake (Hydrophis schistosus, Hs-M). In mice, N. kaouthia Monovalent Antivenom (NKMAV) neutralization against Nk-T long neurotoxin (LNTX) and cytotoxin was moderate (potency of 2.89–6.44 mg toxin/g antivenom protein) but poor against the short neurotoxin (SNTX) (1.33 mg/g). Its cross-neutralization against Hs-M LNTX of Hs-M is compatible (0.18 mg/g) but much weaker against Hs-M SNTX (0.22 mg/g). Using CSL (Seqirus Limited) Sea Snake Antivenom (SSAV), we observed consistently weak neutralization of antivenom against SNTX of both species, suggesting that this is the limiting factor on the potency of antivenom neutralization against venoms containing SNTX. Nevertheless, SSAV outperformed NKMAV in neutralizing SNTXs of both species (0.61–2.49 mg/g). The superior efficacy of SSAV against SNTX is probably partly attributable to the high abundance of SNTX in sea snake venom used as immunogen in SSAV production. The findings indicate that improving the potency of cobra antivenom may be possible with a proper immunogen formulation that seeks to overcome the limitation on SNTX immunoreactivity. Full article
(This article belongs to the Section Animal Venoms)
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Article
Biodistribution and Lymphatic Tracking of the Main Neurotoxin of Micrurus fulvius Venom by Molecular Imaging
by Irene Vergara, Erick Y. Castillo, Mario E. Romero-Piña, Itzel Torres-Viquez, Dayanira Paniagua, Leslie V. Boyer, Alejandro Alagón and Luis Alberto Medina
Toxins 2016, 8(4), 85; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040085 - 26 Mar 2016
Cited by 8 | Viewed by 6411
Abstract
The venom of the Eastern coral snake Micrurus fulvius can cause respiratory paralysis in the bitten patient, which is attributable to β-neurotoxins (β-NTx). The aim of this work was to study the biodistribution and lymphatic tracking by molecular imaging of the main β-NTx [...] Read more.
The venom of the Eastern coral snake Micrurus fulvius can cause respiratory paralysis in the bitten patient, which is attributable to β-neurotoxins (β-NTx). The aim of this work was to study the biodistribution and lymphatic tracking by molecular imaging of the main β-NTx of M. fulvius venom. β-NTx was bioconjugated with the chelator diethylenetriaminepenta-acetic acid (DTPA) and radiolabeled with the radionuclide Gallium-67. Radiolabeling efficiency was 60%–78%; radiochemical purity ≥92%; and stability at 48 h ≥ 85%. The median lethal dose (LD50) and PLA2 activity of bioconjugated β-NTx decreased 3 and 2.5 times, respectively, in comparison with native β-NTx. The immune recognition by polyclonal antibodies decreased 10 times. Biodistribution of β-NTx-DTPA-67Ga in rats showed increased uptake in popliteal, lumbar nodes and kidneys that was not observed with 67Ga-free. Accumulation in organs at 24 h was less than 1%, except for kidneys, where the average was 3.7%. The inoculation site works as a depot, since 10% of the initial dose of β-NTx-DTPA-67Ga remains there for up to 48 h. This work clearly demonstrates the lymphatic system participation in the biodistribution of β-NTx-DTPA-67Ga. Our approach could be applied to analyze the role of the lymphatic system in snakebite for a better understanding of envenoming. Full article
(This article belongs to the Section Animal Venoms)
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Article
Rapid Detection of Escherichia coli O157 and Shiga Toxins by Lateral Flow Immunoassays
by Jinliang Wang, Robab Katani, Lingling Li, Narasimha Hegde, Elisabeth L. Roberts, Vivek Kapur and Chitrita DebRoy
Toxins 2016, 8(4), 92; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040092 - 25 Mar 2016
Cited by 30 | Viewed by 8765
Abstract
Shiga toxin-producing Escherichia coli O157:H7 (STEC) cause food-borne illness that may be fatal. STEC strains enumerate two types of potent Shiga toxins (Stx1 and Stx2) that are responsible for causing diseases. It is important to detect the E. coli O157 and Shiga toxins [...] Read more.
Shiga toxin-producing Escherichia coli O157:H7 (STEC) cause food-borne illness that may be fatal. STEC strains enumerate two types of potent Shiga toxins (Stx1 and Stx2) that are responsible for causing diseases. It is important to detect the E. coli O157 and Shiga toxins in food to prevent outbreak of diseases. We describe the development of two multi-analyte antibody-based lateral flow immunoassays (LFIA); one for the detection of Stx1 and Stx2 and one for the detection of E. coli O157 that may be used simultaneously to detect pathogenic E. coli O157:H7. The LFIA strips were developed by conjugating nano colloidal gold particles with monoclonal antibodies against Stx1 and Stx2 and anti-lipid A antibodies to capture Shiga toxins and O157 antigen, respectively. Our results indicate that the LFIA for Stx is highly specific and detected Stx1 and Stx2 within three hours of induction of STEC with ciprofloxacin at 37 °C. The limit of detection for E. coli O157 LFIA was found to be 105 CFU/mL in ground beef spiked with the pathogen. The LFIAs are rapid, accurate and easy to use and do not require sophisticated equipment or trained personnel. Following the assay, colored bands on the membrane develop for end-point detection. The LFIAs may be used for screening STEC in food and the environment. Full article
(This article belongs to the Collection Rapid Detection of Bacterial Toxins)
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237 KiB  
Review
Intravesical OnabotulinumtoxinA Injection for Overactive Bladder Patients with Frailty, Medical Comorbidities or Prior Lower Urinary Tract Surgery
by Chun-Hou Liao, Chung-Cheng Wang and Yuan-Hong Jiang
Toxins 2016, 8(4), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins8040091 - 25 Mar 2016
Cited by 15 | Viewed by 4779
Abstract
Overactive bladder (OAB) symptoms increase with age and involve several comorbidities. OnabotulinumtoxinA (BoNT-A) intravesical injection is a treatment choice for patients who are intolerant of or refractory to antimuscarinics. However, the increased risk of urinary tract infection and elevated post-void residual (PVR) volume [...] Read more.
Overactive bladder (OAB) symptoms increase with age and involve several comorbidities. OnabotulinumtoxinA (BoNT-A) intravesical injection is a treatment choice for patients who are intolerant of or refractory to antimuscarinics. However, the increased risk of urinary tract infection and elevated post-void residual (PVR) volume post-treatment require resolution. Male sex, baseline PVR > 100 mL, and comorbidities are independent risk factors of adverse events (AEs) such as acute urinary retention (AUR). Intravesical BoNT-A injection is safe and effective for OAB patients with frailty, medical comorbidities such as Parkinson’s disease (PD), chronic cerebrovascular accidents (CVA), dementia, or diabetes, or a history of prior lower urinary tract surgery (prostate or transvaginal sling surgery). Post-treatment, 60% of frail elderly patients had a PVR volume > 150 mL and 11% had AUR. Although intravesical BoNT-A injection is safe for PD patients, CVA patients had higher strain voiding rates. Diabetic patients were at increased risk of large PVR urine volume and general weakness post-treatment. Treatment results were similar between patients with and without a history of prostate or transvaginal sling surgery. Possible AEs and bladder management strategies should be conveyed to patients before treatment. Careful patient selection is important, and therapeutic safety and efficacy should be carefully balanced. Full article
(This article belongs to the Special Issue Botulinum Toxin A on Lower Urinary Tract Dysfunction)
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