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Toxins, Volume 8, Issue 7 (July 2016)

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Open AccessArticle Tempo and Mode of the Evolution of Venom and Poison in Tetrapods
Toxins 2016, 8(7), 193; doi:10.3390/toxins8070193
Received: 27 April 2016 / Revised: 7 June 2016 / Accepted: 14 June 2016 / Published: 23 June 2016
Cited by 5 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Toxic weaponry in the form of venom and poison has evolved in most groups of animals, including all four major lineages of tetrapods. Moreover, the evolution of such traits has been linked to several key aspects of the biology of toxic animals including
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Toxic weaponry in the form of venom and poison has evolved in most groups of animals, including all four major lineages of tetrapods. Moreover, the evolution of such traits has been linked to several key aspects of the biology of toxic animals including life-history and diversification. Despite this, attempts to investigate the macroevolutionary patterns underlying such weaponry are lacking. In this study we analyse patterns of venom and poison evolution across reptiles, amphibians, mammals, and birds using a suite of phylogenetic comparative methods. We find that each major lineage has a characteristic pattern of trait evolution, but mammals and reptiles evolve under a surprisingly similar regime, whilst that of amphibians appears to be particularly distinct and highly contrasting compared to other groups. Our results also suggest that the mechanism of toxin acquisition may be an important distinction in such evolutionary patterns; the evolution of biosynthesis is far less dynamic than that of sequestration of toxins from the diet. Finally, contrary to the situation in amphibians, other tetrapod groups show an association between the evolution of toxic weaponry and higher diversification rates. Taken together, our study provides the first broad-scale analysis of macroevolutionary patterns of venom and poison throughout tetrapods. Full article
(This article belongs to the collection Evolution of Venom Systems)
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Open AccessArticle Comparative Immunogenicity of the Tetanus Toxoid and Recombinant Tetanus Vaccines in Mice, Rats, and Cynomolgus Monkeys
Toxins 2016, 8(7), 194; doi:10.3390/toxins8070194
Received: 11 March 2016 / Revised: 12 June 2016 / Accepted: 13 June 2016 / Published: 25 June 2016
Cited by 1 | PDF Full-text (1750 KB) | HTML Full-text | XML Full-text
Abstract
Tetanus is caused by the tetanus neurotoxin (TeNT) and is one of the most dreaded diseases especially in the developing countries. The current vaccine against tetanus is based on an inactivated tetanus toxin, which is effective but has many drawbacks. In our previous
[...] Read more.
Tetanus is caused by the tetanus neurotoxin (TeNT) and is one of the most dreaded diseases especially in the developing countries. The current vaccine against tetanus is based on an inactivated tetanus toxin, which is effective but has many drawbacks. In our previous study, we developed a recombinant tetanus vaccine based on protein TeNT-Hc, with clear advantages over the toxoid vaccine in terms of production, characterization, and homogeneity. In this study, the titers, growth extinction, and persistence of specific antibodies induced by the two types of vaccine in mice, rats, and cynomolgus monkeys were compared. The booster vaccination efficacy of the two types of vaccines at different time points and protection mechanism in animals were also compared. The recombinant tetanus vaccine induced persistent and better antibody titers and strengthened the immunity compared with the commercially available toxoid vaccine in animals. Our results provide a theoretical basis for the development of a safe and effective recombinant tetanus vaccine to enhance the immunity of adolescents and adults as a substitute for the current toxoid vaccine. Full article
(This article belongs to the Section Bacterial Toxins)
Open AccessArticle Characterization of the Deep-Sea Streptomyces sp. SCSIO 02999 Derived VapC/VapB Toxin-Antitoxin System in Escherichia coli
Toxins 2016, 8(7), 195; doi:10.3390/toxins8070195
Received: 23 May 2016 / Revised: 13 June 2016 / Accepted: 20 June 2016 / Published: 1 July 2016
Cited by 1 | PDF Full-text (3279 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Toxin-antitoxin (TA) systems are small genetic elements that are ubiquitous in prokaryotes. Most studies on TA systems have focused on commensal and pathogenic bacteria; yet very few studies have focused on TAs in marine bacteria, especially those isolated from a deep sea environment.
[...] Read more.
Toxin-antitoxin (TA) systems are small genetic elements that are ubiquitous in prokaryotes. Most studies on TA systems have focused on commensal and pathogenic bacteria; yet very few studies have focused on TAs in marine bacteria, especially those isolated from a deep sea environment. Here, we characterized a type II VapC/VapB TA system from the deep-sea derived Streptomyces sp. SCSIO 02999. The VapC (virulence-associated protein) protein belongs to the PIN (PilT N-terminal) superfamily. Overproduction of VapC strongly inhibited cell growth and resulted in a bleb-containing morphology in E. coli. The toxicity of VapC was neutralized through direct protein–protein interaction by a small protein antitoxin VapB encoded by a neighboring gene. Antitoxin VapB alone or the VapB/VapC complex negatively regulated the vapBC promoter activity. We further revealed that three conserved Asp residues in the PIN domain were essential for the toxic effect of VapC. Additionally, the VapC/VapB TA system stabilized plasmid in E. coli. Furthermore, VapC cross-activated transcription of several TA operons via a partially Lon-dependent mechanism in E. coli, and the activated toxins accumulated more preferentially than their antitoxin partners. Collectively, we identified and characterized a new deep sea TA system in the deep sea Streptomyces sp. and demonstrated that the VapC toxin in this system can cross-activate TA operons in E. coli. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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Open AccessArticle Liquid Chromatography with a Fluorimetric Detection Method for Analysis of Paralytic Shellfish Toxins and Tetrodotoxin Based on a Porous Graphitic Carbon Column
Toxins 2016, 8(7), 196; doi:10.3390/toxins8070196
Received: 16 May 2016 / Revised: 21 June 2016 / Accepted: 23 June 2016 / Published: 28 June 2016
Cited by 2 | PDF Full-text (1948 KB) | HTML Full-text | XML Full-text
Abstract
Paralytic shellfish toxins (PST) traditionally have been analyzed by liquid chromatography with either pre- or post-column derivatization and always with a silica-based stationary phase. This technique resulted in different methods that need more than one run to analyze the toxins. Furthermore, tetrodotoxin (TTX)
[...] Read more.
Paralytic shellfish toxins (PST) traditionally have been analyzed by liquid chromatography with either pre- or post-column derivatization and always with a silica-based stationary phase. This technique resulted in different methods that need more than one run to analyze the toxins. Furthermore, tetrodotoxin (TTX) was recently found in bivalves of northward locations in Europe due to climate change, so it is important to analyze it along with PST because their signs of toxicity are similar in the bioassay. The methods described here detail a new approach to eliminate different runs, by using a new porous graphitic carbon stationary phase. Firstly we describe the separation of 13 PST that belong to different groups, taking into account the side-chains of substituents, in one single run of less than 30 min with good reproducibility. The method was assayed in four shellfish matrices: mussel (Mytillus galloprovincialis), clam (Pecten maximus), scallop (Ruditapes decussatus) and oyster (Ostrea edulis). The results for all of the parameters studied are provided, and the detection limits for the majority of toxins were improved with regard to previous liquid chromatography methods: the lowest values were those for decarbamoyl-gonyautoxin 2 (dcGTX2) and gonyautoxin 2 (GTX2) in mussel (0.0001 mg saxitoxin (STX)·diHCl kg−1 for each toxin), decarbamoyl-saxitoxin (dcSTX) in clam (0.0003 mg STX·diHCl kg−1), N-sulfocarbamoyl-gonyautoxins 2 and 3 (C1 and C2) in scallop (0.0001 mg STX·diHCl kg−1 for each toxin) and dcSTX (0.0003 mg STX·diHCl kg−1 ) in oyster; gonyautoxin 2 (GTX2) showed the highest limit of detection in oyster (0.0366 mg STX·diHCl kg−1). Secondly, we propose a modification of the method for the simultaneous analysis of PST and TTX, with some minor changes in the solvent gradient, although the detection limit for TTX does not allow its use nowadays for regulatory purposes. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
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Open AccessArticle Biofilm-Forming Methicillin-Resistant Staphylococcus aureus Survive in Kupffer Cells and Exhibit High Virulence in Mice
Toxins 2016, 8(7), 198; doi:10.3390/toxins8070198
Received: 28 March 2016 / Revised: 15 June 2016 / Accepted: 24 June 2016 / Published: 30 June 2016
Cited by 2 | PDF Full-text (9212 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Although Staphylococcus aureus is part of the normal body flora, heavy usage of antibiotics has resulted in the emergence of methicillin-resistant strains (MRSA). MRSA can form biofilms and cause indwelling foreign body infections, bacteremia, soft tissue infections, endocarditis, and osteomyelitis. Using an in
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Although Staphylococcus aureus is part of the normal body flora, heavy usage of antibiotics has resulted in the emergence of methicillin-resistant strains (MRSA). MRSA can form biofilms and cause indwelling foreign body infections, bacteremia, soft tissue infections, endocarditis, and osteomyelitis. Using an in vitro assay, we screened 173 clinical blood isolates of MRSA and selected 20 high-biofilm formers (H-BF) and low-biofilm formers (L-BF). These were intravenously administered to mice and the general condition of mice, the distribution of bacteria, and biofilm in the liver, lung, spleen, and kidney were investigated. MRSA count was the highest in the liver, especially within Kupffer cells, which were positive for acid polysaccharides that are associated with intracellular biofilm. After 24 h, the general condition of the mice worsened significantly in the H-BF group. In the liver, bacterial deposition and aggregation and the biofilm-forming spot number were all significantly greater for H-BF group than for L-BF. CFU analysis revealed that bacteria in the H-BF group survived for long periods in the liver. These results indicate that the biofilm-forming ability of MRSA is a crucial factor for intracellular persistence, which could lead to chronic infections. Full article
(This article belongs to the collection Staphylococcus aureus Toxins)
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Open AccessArticle The Stress Response Regulator AflSkn7 Influences Morphological Development, Stress Response, and Pathogenicity in the Fungus Aspergillus flavus
Toxins 2016, 8(7), 202; doi:10.3390/toxins8070202
Received: 12 March 2016 / Revised: 22 June 2016 / Accepted: 23 June 2016 / Published: 5 July 2016
Cited by 5 | PDF Full-text (7138 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
This study focused on AflSkn7, which is a stress response regulator in the aflatoxin-producing Aspergillus flavus. The ΔAflSkn7 mutants exhibited partially defective conidial formation and a complete inability to generate sclerotia, indicating AflSkn7 affects A. flavus asexual and sexual development. The
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This study focused on AflSkn7, which is a stress response regulator in the aflatoxin-producing Aspergillus flavus. The ΔAflSkn7 mutants exhibited partially defective conidial formation and a complete inability to generate sclerotia, indicating AflSkn7 affects A. flavus asexual and sexual development. The mutants tolerated osmotic stress but were partially susceptible to the effects of cell wall stress. Additionally, the ΔAflSkn7 mutants were especially sensitive to oxidative stress. These observations confirmed that AflSkn7 influences oxidative stress responses rather than osmotic stress responses. Additionally, AflSkn7 was observed to increase aflatoxin biosynthesis and seed infection rates. These results indicate AflSkn7 affects A. flavus morphological development, stress response, aflatoxin production, and pathogenicity. The results of this study may facilitate the development of new methods to manage A. flavus infections. Full article
(This article belongs to the collection Aflatoxins)
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Open AccessArticle Activation and Desensitization of Peripheral Muscle and Neuronal Nicotinic Acetylcholine Receptors by Selected, Naturally-Occurring Pyridine Alkaloids
Toxins 2016, 8(7), 204; doi:10.3390/toxins8070204
Received: 29 January 2016 / Revised: 24 June 2016 / Accepted: 24 June 2016 / Published: 4 July 2016
Cited by 1 | PDF Full-text (2222 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Teratogenic alkaloids can cause developmental defects due to the inhibition of fetal movement that results from desensitization of fetal muscle-type nicotinic acetylcholine receptors (nAChRs). We investigated the ability of two known teratogens, the piperidinyl-pyridine anabasine and its 1,2-dehydropiperidinyl analog anabaseine, to activate and
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Teratogenic alkaloids can cause developmental defects due to the inhibition of fetal movement that results from desensitization of fetal muscle-type nicotinic acetylcholine receptors (nAChRs). We investigated the ability of two known teratogens, the piperidinyl-pyridine anabasine and its 1,2-dehydropiperidinyl analog anabaseine, to activate and desensitize peripheral nAChRs expressed in TE-671 and SH-SY5Y cells. Activation-concentration response curves for each alkaloid were obtained in the same multi-well plate. To measure rapid desensitization, cells were first exposed to five potentially-desensitizing concentrations of each alkaloid in log10 molar increments from 10 nM to 100 µM and then to a fixed concentration of acetylcholine (ACh), which alone produces near-maximal activation. The fifty percent desensitization concentration (DC50) was calculated from the alkaloid concentration-ACh response curve. Agonist fast desensitization potency was predicted by the agonist potency measured in the initial response. Anabaseine was a more potent desensitizer than anabasine. Relative to anabaseine, nicotine was more potent to autonomic nAChRs, but less potent to the fetal neuromuscular nAChRs. Our experiments have demonstrated that anabaseine is more effective at desensitizing fetal muscle-type nAChRs than anabasine or nicotine and, thus, it is predicted to be more teratogenic. Full article
(This article belongs to the collection Toxicity of Natural Alkaloids)
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Open AccessArticle Cloning a Chymotrypsin-Like 1 (CTRL-1) Protease cDNA from the Jellyfish Nemopilema nomurai
Toxins 2016, 8(7), 205; doi:10.3390/toxins8070205
Received: 16 March 2016 / Revised: 30 May 2016 / Accepted: 28 June 2016 / Published: 5 July 2016
Cited by 2 | PDF Full-text (2943 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
An enzyme in a nematocyst extract of the Nemopilema nomurai jellyfish, caught off the coast of the Republic of Korea, catalyzed the cleavage of chymotrypsin substrate in an amidolytic kinetic assay, and this activity was inhibited by the serine protease inhibitor, phenylmethanesulfonyl fluoride.
[...] Read more.
An enzyme in a nematocyst extract of the Nemopilema nomurai jellyfish, caught off the coast of the Republic of Korea, catalyzed the cleavage of chymotrypsin substrate in an amidolytic kinetic assay, and this activity was inhibited by the serine protease inhibitor, phenylmethanesulfonyl fluoride. We isolated the full-length cDNA sequence of this enzyme, which contains 850 nucleotides, with an open reading frame of 801 encoding 266 amino acids. A blast analysis of the deduced amino acid sequence showed 41% identity with human chymotrypsin-like (CTRL) and the CTRL-1 precursor. Therefore, we designated this enzyme N. nomurai CTRL-1. The primary structure of N. nomurai CTRL-1 includes a leader peptide and a highly conserved catalytic triad of His69, Asp117, and Ser216. The disulfide bonds of chymotrypsin and the substrate-binding sites are highly conserved compared with the CTRLs of other species, including mammalian species. Nemopilema nomurai CTRL-1 is evolutionarily more closely related to Actinopterygii than to Scyphozoan (Aurelia aurita) or Hydrozoan (Hydra vulgaris). The N. nomurai CTRL1 was amplified from the genomic DNA with PCR using specific primers designed based on the full-length cDNA, and then sequenced. The N. nomurai CTRL1 gene contains 2434 nucleotides and four distinct exons. The 5′ donor splice (GT) and 3′ acceptor splice sequences (AG) are wholly conserved. This is the first report of the CTRL1 gene and cDNA structures in the jellyfish N. nomurai. Full article
(This article belongs to the Section Animal Venoms)
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Open AccessArticle Lebein, a Snake Venom Disintegrin, Induces Apoptosis in Human Melanoma Cells
Toxins 2016, 8(7), 206; doi:10.3390/toxins8070206
Received: 4 May 2016 / Revised: 22 June 2016 / Accepted: 1 July 2016 / Published: 5 July 2016
Cited by 3 | PDF Full-text (2401 KB) | HTML Full-text | XML Full-text
Abstract
Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that
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Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that are free of resistance mechanisms and side effects. Anti-neoplasic properties have been highlighted for different disintegrins from snake venom including Lebein; however, the exact effect of Lebein on melanoma has not yet been defined. In this study, we showed that Lebein blocks melanoma cell proliferation and induces a more differentiated phenotype with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and microphthalmia-associated transcription factor (MITF) overexpression. Melanoma cells became detached but were less invasive with upregulation of E-cadherin after Lebein exposure. Lebein induced a caspase-independent apoptotic program with apoptosis inducing factor (AIF), BCL-2-associated X protein (BAX) and Bim overexpression together with downregulation of B-cell lymphoma-2 (BCL-2). It generated a distinct response in reactive oxygen species (ROS) generation and p53 levels depending on the p53 cell line status (wild type or mutant). Therefore, we propose Lebein as a new candidate for development of potential therapies for melanoma. Full article
(This article belongs to the Section Animal Venoms)
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Open AccessArticle Canopy Venom: Proteomic Comparison among New World Arboreal Pit-Viper Venoms
Toxins 2016, 8(7), 210; doi:10.3390/toxins8070210
Received: 22 August 2015 / Revised: 28 May 2016 / Accepted: 16 June 2016 / Published: 8 July 2016
Cited by 1 | PDF Full-text (2305 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Central and South American pitvipers, belonging to the genera Bothrops and Bothriechis, have independently evolved arboreal tendencies. Little is known regarding the composition and activity of their venoms. In order to close this knowledge gap, venom proteomics and toxin activity of species
[...] Read more.
Central and South American pitvipers, belonging to the genera Bothrops and Bothriechis, have independently evolved arboreal tendencies. Little is known regarding the composition and activity of their venoms. In order to close this knowledge gap, venom proteomics and toxin activity of species of Bothriechis, and Bothrops (including Bothriopsis) were investigated through established analytical methods. A combination of proteomics and bioactivity techniques was used to demonstrate a similar diversification of venom composition between large and small species within Bothriechis and Bothriopsis. Increasing our understanding of the evolution of complex venom cocktails may facilitate future biodiscoveries. Full article
(This article belongs to the collection Evolution of Venom Systems)
Open AccessCommunication Cells Deficient in the Fanconi Anemia Protein FANCD2 are Hypersensitive to the Cytotoxicity and DNA Damage Induced by Coffee and Caffeic Acid
Toxins 2016, 8(7), 211; doi:10.3390/toxins8070211
Received: 15 March 2016 / Revised: 11 June 2016 / Accepted: 1 July 2016 / Published: 8 July 2016
Cited by 1 | PDF Full-text (1720 KB) | HTML Full-text | XML Full-text
Abstract
Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder
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Epidemiological studies have found a positive association between coffee consumption and a lower risk of cardiovascular disorders, some cancers, diabetes, Parkinson and Alzheimer disease. Coffee consumption, however, has also been linked to an increased risk of developing some types of cancer, including bladder cancer in adults and leukemia in children of mothers who drink coffee during pregnancy. Since cancer is driven by the accumulation of DNA alterations, the ability of the coffee constituent caffeic acid to induce DNA damage in cells may play a role in the carcinogenic potential of this beverage. This carcinogenic potential may be exacerbated in cells with DNA repair defects. People with the genetic disease Fanconi Anemia have DNA repair deficiencies and are predisposed to several cancers, particularly acute myeloid leukemia. Defects in the DNA repair protein Fanconi Anemia D2 (FANCD2) also play an important role in the development of a variety of cancers (e.g., bladder cancer) in people without this genetic disease. This communication shows that cells deficient in FANCD2 are hypersensitive to the cytotoxicity (clonogenic assay) and DNA damage (γ-H2AX and 53BP1 focus assay) induced by caffeic acid and by a commercial lyophilized coffee extract. These data suggest that people with Fanconi Anemia, or healthy people who develop sporadic mutations in FANCD2, may be hypersensitive to the carcinogenic activity of coffee. Full article
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Open AccessArticle Distribution and Metabolism of Bt-Cry1Ac Toxin in Tissues and Organs of the Cotton Bollworm, Helicoverpa armigera
Toxins 2016, 8(7), 212; doi:10.3390/toxins8070212
Received: 6 June 2016 / Accepted: 30 June 2016 / Published: 7 July 2016
Cited by 3 | PDF Full-text (1327 KB) | HTML Full-text | XML Full-text
Abstract
Crystal (Cry) proteins derived from Bacillus thuringiensis (Bt) have been widely used in transgenic crops due to their toxicity against insect pests. However, the distribution and metabolism of these toxins in insect tissues and organs have remained obscure because the target
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Crystal (Cry) proteins derived from Bacillus thuringiensis (Bt) have been widely used in transgenic crops due to their toxicity against insect pests. However, the distribution and metabolism of these toxins in insect tissues and organs have remained obscure because the target insects do not ingest much toxin. In this study, several Cry1Ac-resistant strains of Helicoverpa armigera, fed artificial diets containing high doses of Cry1Ac toxin, were used to investigate the distribution and metabolism of Cry1Ac in their bodies. Cry1Ac was only detected in larvae, not in pupae or adults. Also, Cry1Ac passed through the midgut into other tissues, such as the hemolymph and fat body, but did not reach the larval integument. Metabolic tests revealed that Cry1Ac degraded most rapidly in the fat body, followed by the hemolymph, peritrophic membrane and its contents. The toxin was metabolized slowly in the midgut, but was degraded in all locations within 48 h. These findings will improve understanding of the functional mechanism of Bt toxins in target insects and the biotransfer and the bioaccumulation of Bt toxins in arthropod food webs in the Bt crop ecosystem. Full article
(This article belongs to the Section Bacterial Toxins)
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Open AccessArticle Baltikinin: A New Myotropic Tryptophyllin-3 Peptide Isolated from the Skin Secretion of the Purple-Sided Leaf Frog, Phyllomedusa baltea
Toxins 2016, 8(7), 213; doi:10.3390/toxins8070213
Received: 14 May 2016 / Revised: 1 July 2016 / Accepted: 4 July 2016 / Published: 8 July 2016
Cited by 2 | PDF Full-text (1880 KB) | HTML Full-text | XML Full-text
Abstract
Here we report the identification of a novel tryptophyllin-3 peptide with arterial smooth muscle relaxation activity from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea. This new peptide was named baltikinin and had the following primary structure, pGluDKPFGPPPIYPV, as determined
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Here we report the identification of a novel tryptophyllin-3 peptide with arterial smooth muscle relaxation activity from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea. This new peptide was named baltikinin and had the following primary structure, pGluDKPFGPPPIYPV, as determined by tandem mass spectrometry (MS/MS) fragmentation sequencing and from cloned skin precursor-encoding cDNA. A synthetic replicate of baltikinin was found to have a similar potency to bradykinin in relaxing arterial smooth muscle (half maximal effective concentration (EC50) is 7.2 nM). These data illustrate how amphibian skin secretions can continue to provide novel potent peptides that act through functional targets in mammalian tissues. Full article
(This article belongs to the Section Animal Venoms)
Open AccessArticle Respiratory Effects of Sarafotoxins from the Venom of Different Atractaspis Genus Snake Species
Toxins 2016, 8(7), 215; doi:10.3390/toxins8070215
Received: 10 May 2016 / Revised: 23 June 2016 / Accepted: 4 July 2016 / Published: 11 July 2016
PDF Full-text (506 KB) | HTML Full-text | XML Full-text
Abstract
Sarafotoxins (SRTX) are endothelin-like peptides extracted from the venom of snakes belonging to the Atractaspididae family. A recent in vivo study on anesthetized and ventilated animals showed that sarafotoxin-b (SRTX-b), extracted from the venom of Atractaspis engaddensis, decreases cardiac output by inducing
[...] Read more.
Sarafotoxins (SRTX) are endothelin-like peptides extracted from the venom of snakes belonging to the Atractaspididae family. A recent in vivo study on anesthetized and ventilated animals showed that sarafotoxin-b (SRTX-b), extracted from the venom of Atractaspis engaddensis, decreases cardiac output by inducing left ventricular dysfunction while sarafotoxin-m (SRTX-m), extracted from the venom of Atractaspis microlepidota microlepidota, induces right ventricular dysfunction with increased airway pressure. The aim of the present experimental study was to compare the respiratory effects of SRTX-m and SRTX-b. Male Wistar rats were anesthetized, tracheotomized and mechanically ventilated. They received either a 1 LD50 IV bolus of SRTX-b (n = 5) or 1 LD50 of SRTX-m (n = 5). The low-frequency forced oscillation technique was used to measure respiratory impedance. Airway resistance (Raw), parenchymal damping (G) and elastance (H) were determined from impedance data, before and 5 min after SRTX injection. SRTX-m and SRTX-b injections induced acute hypoxia and metabolic acidosis with an increased anion gap. Both toxins markedly increased Raw, G and H, but with a much greater effect of SRTX-b on H, which may have been due to pulmonary edema in addition to bronchoconstriction. Therefore, despite their structural analogy, these two toxins exert different effects on respiratory function. These results emphasize the role of the C-terminal extension in the in vivo effect of these toxins. Full article
(This article belongs to the Section Animal Venoms)
Open AccessFeature PaperArticle Insights into the Evolution of a Snake Venom Multi-Gene Family from the Genomic Organization of Echis ocellatus SVMP Genes
Toxins 2016, 8(7), 216; doi:10.3390/toxins8070216
Received: 12 June 2016 / Revised: 29 June 2016 / Accepted: 6 July 2016 / Published: 12 July 2016
Cited by 2 | PDF Full-text (9042 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The molecular events underlying the evolution of the Snake Venom Metalloproteinase (SVMP) family from an A Disintegrin And Metalloproteinase (ADAM) ancestor remain poorly understood. Comparative genomics may provide decisive information to reconstruct the evolutionary history of this multi-locus toxin family. Here, we report
[...] Read more.
The molecular events underlying the evolution of the Snake Venom Metalloproteinase (SVMP) family from an A Disintegrin And Metalloproteinase (ADAM) ancestor remain poorly understood. Comparative genomics may provide decisive information to reconstruct the evolutionary history of this multi-locus toxin family. Here, we report the genomic organization of Echis ocellatus genes encoding SVMPs from the PII and PI classes. Comparisons between them and between these genes and the genomic structures of Anolis carolinensis ADAM28 and E. ocellatus PIII-SVMP EOC00089 suggest that insertions and deletions of intronic regions played key roles along the evolutionary pathway that shaped the current diversity within the multi-locus SVMP gene family. In particular, our data suggest that emergence of EOC00028-like PI-SVMP from an ancestral PII(e/d)-type SVMP involved splicing site mutations that abolished both the 3′ splice AG acceptor site of intron 12* and the 5′ splice GT donor site of intron 13*, and resulted in the intronization of exon 13* and the consequent destruction of the structural integrity of the PII-SVMP characteristic disintegrin domain. Full article
(This article belongs to the Special Issue Snake Venom Metalloproteinases) Printed Edition available
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Open AccessArticle Biosorption of B-aflatoxins Using Biomasses Obtained from Formosa Firethorn [Pyracantha koidzumii (Hayata) Rehder]
Toxins 2016, 8(7), 218; doi:10.3390/toxins8070218
Received: 13 April 2016 / Revised: 5 July 2016 / Accepted: 6 July 2016 / Published: 13 July 2016
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Abstract
Mycotoxin adsorption onto biomaterials is considered as a promising alternative for decontamination without harmful chemicals. In this research, the adsorption of B-aflatoxins (AFB1 and AFB2) using Pyracantha koidzumii biomasses (leaves, berries and the mixture of leaves/berries) from aqueous solutions was
[...] Read more.
Mycotoxin adsorption onto biomaterials is considered as a promising alternative for decontamination without harmful chemicals. In this research, the adsorption of B-aflatoxins (AFB1 and AFB2) using Pyracantha koidzumii biomasses (leaves, berries and the mixture of leaves/berries) from aqueous solutions was explored. The biosorbent was used at 0.5% (w/v) in samples spiked with 100 ng/mL of B-aflatoxin standards and incubated at 40 °C for up to 24 h. A standard biosorption methodology was employed and aflatoxins were quantified by an immunoaffinity column and UPLC methodologies. The biosorbent-aflatoxin interaction mechanism was investigated from a combination of zeta potential (ζ), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The highest aflatoxin uptakes were 86% and 82% at 6 h using leaves and the mixture of leaves/berries biomasses, respectively. A moderate biosorption of 46% was attained when using berries biomass. From kinetic studies, the biosorption process is described using the first order adsorption model. Evidence from FTIR spectra suggests the participation of hydroxyl, amine, carboxyl, amide, phosphate and ketone groups in the biosorption and the mechanism was proposed to be dominated by the electrostatic interaction between the negatively charged functional groups and the positively charged aflatoxin molecules. Biosorption by P. koidzumii biomasses has been demonstrated to be an alternative to conventional systems for B-aflatoxins removal. Full article
(This article belongs to the collection Understanding Mycotoxin Occurrence in Food and Feed Chains)
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Open AccessArticle Anti-Inflammatory Activity of Cyanobacterial Serine Protease Inhibitors Aeruginosin 828A and Cyanopeptolin 1020 in Human Hepatoma Cell Line Huh7 and Effects in Zebrafish (Danio rerio)
Toxins 2016, 8(7), 219; doi:10.3390/toxins8070219
Received: 20 May 2016 / Revised: 21 June 2016 / Accepted: 5 July 2016 / Published: 14 July 2016
PDF Full-text (2536 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Intensive growth of cyanobacteria in freshwater promoted by eutrophication can lead to release of toxic secondary metabolites that may harm aquatic organisms and humans. The serine protease inhibitor aeruginosin 828A was isolated from a microcystin-deficient Planktothrix strain. We assessed potential molecular effects of
[...] Read more.
Intensive growth of cyanobacteria in freshwater promoted by eutrophication can lead to release of toxic secondary metabolites that may harm aquatic organisms and humans. The serine protease inhibitor aeruginosin 828A was isolated from a microcystin-deficient Planktothrix strain. We assessed potential molecular effects of aeruginosin 828A in comparison to another cyanobacterial serine protease inhibitor, cyanopeptolin 1020, in human hepatoma cell line Huh7, in zebrafish embryos and liver organ cultures. Aeruginosin 828A and cyanopeptolin 1020 promoted anti-inflammatory activity, as indicated by transcriptional down-regulation of interleukin 8 and tumor necrosis factor α in stimulated cells at concentrations of 50 and 100 µmol·L−1 aeruginosin 828A, and 100 µmol·L−1 cyanopeptolin 1020. Aeruginosin 828A induced the expression of CYP1A in Huh7 cells but did not affect enzyme activity. Furthermore, hatched zebrafish embryos and zebrafish liver organ cultures were exposed to aeruginosin 828A. The transcriptional responses were compared to those of cyanopeptolin 1020 and microcystin-LR. Aeruginosin 828A had only minimal effects on endoplasmic reticulum stress. In comparison to cyanopeptolin 1020 our data indicate that transcriptional effects of aeruginosin 828A in zebrafish are very minor. The data further demonstrate that pathways that are influenced by microcystin-LR are not affected by aeruginosin 828A. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
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Open AccessArticle Semicarbazone EGA Inhibits Uptake of Diphtheria Toxin into Human Cells and Protects Cells from Intoxication
Toxins 2016, 8(7), 221; doi:10.3390/toxins8070221
Received: 6 May 2016 / Revised: 25 June 2016 / Accepted: 7 July 2016 / Published: 15 July 2016
Cited by 3 | PDF Full-text (2143 KB) | HTML Full-text | XML Full-text
Abstract
Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA
[...] Read more.
Diphtheria toxin is a single-chain protein toxin that invades human cells by receptor-mediated endocytosis. In acidic endosomes, its translocation domain inserts into endosomal membranes and facilitates the transport of the catalytic domain (DTA) from endosomal lumen into the host cell cytosol. Here, DTA ADP-ribosylates elongation factor 2 inhibits protein synthesis and leads to cell death. The compound 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA) has been previously shown to protect cells from various bacterial protein toxins which deliver their enzymatic subunits from acidic endosomes to the cytosol, including Bacillus anthracis lethal toxin and the binary clostridial actin ADP-ribosylating toxins C2, iota and Clostridium difficile binary toxin (CDT). Here, we demonstrate that EGA also protects human cells from diphtheria toxin by inhibiting the pH-dependent translocation of DTA across cell membranes. The results suggest that EGA might serve for treatment and/or prevention of the severe disease diphtheria. Full article
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Open AccessArticle Mapping Protein–Protein Interactions of the Resistance-Related Bacterial Zeta Toxin–Epsilon Antitoxin Complex (ε2ζ2) with High Affinity Peptide Ligands Using Fluorescence Polarization
Toxins 2016, 8(7), 222; doi:10.3390/toxins8070222
Received: 14 May 2016 / Revised: 29 June 2016 / Accepted: 5 July 2016 / Published: 16 July 2016
PDF Full-text (4352 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Toxin–antitoxin systems constitute a native survival strategy of pathogenic bacteria and thus are potential targets of antibiotic drugs. Here, we target the Zeta–Epsilon toxin–antitoxin system, which is responsible for the stable maintenance of certain multiresistance plasmids in Gram-positive bacteria. Peptide ligands were designed
[...] Read more.
Toxin–antitoxin systems constitute a native survival strategy of pathogenic bacteria and thus are potential targets of antibiotic drugs. Here, we target the Zeta–Epsilon toxin–antitoxin system, which is responsible for the stable maintenance of certain multiresistance plasmids in Gram-positive bacteria. Peptide ligands were designed on the basis of the ε2ζ2 complex. Three α helices of Zeta forming the protein–protein interaction (PPI) site were selected and peptides were designed conserving the residues interacting with Epsilon antitoxin while substituting residues binding intramolecularly to other parts of Zeta. Designed peptides were synthesized with an N-terminal fluoresceinyl-carboxy-residue for binding assays and provided active ligands, which were used to define the hot spots of the ε2ζ2 complex. Further shortening and modification of the binding peptides provided ligands with affinities <100 nM, allowing us to determine the most relevant PPIs and implement a robust competition binding assay. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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Open AccessArticle Interaction between TNF and BmooMP-Alpha-I, a Zinc Metalloprotease Derived from Bothrops moojeni Snake Venom, Promotes Direct Proteolysis of This Cytokine: Molecular Modeling and Docking at a Glance
Toxins 2016, 8(7), 223; doi:10.3390/toxins8070223
Received: 17 December 2015 / Revised: 4 July 2016 / Accepted: 7 July 2016 / Published: 20 July 2016
PDF Full-text (4470 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Tumor necrosis factor (TNF) is a major cytokine in inflammatory processes and its deregulation plays a pivotal role in several diseases. Here, we report that a zinc metalloprotease extracted from Bothrops moojeni venom (BmooMP-alpha-I) inhibits TNF directly by promoting its degradation. This inhibition
[...] Read more.
Tumor necrosis factor (TNF) is a major cytokine in inflammatory processes and its deregulation plays a pivotal role in several diseases. Here, we report that a zinc metalloprotease extracted from Bothrops moojeni venom (BmooMP-alpha-I) inhibits TNF directly by promoting its degradation. This inhibition was demonstrated by both in vitro and in vivo assays, using known TLR ligands. These findings are supported by molecular docking results, which reveal interaction between BmooMP-alpha-I and TNF. The major cluster of interaction between BmooMP-alpha-I and TNF was confirmed by the structural alignment presenting Ligand Root Mean Square Deviation LRMS = 1.05 Å and Interactive Root Mean Square Deviation IRMS = 1.01 Å, this result being compatible with an accurate complex. Additionally, we demonstrated that the effect of this metalloprotease on TNF is independent of cell cytotoxicity and it does not affect other TLR-triggered cytokines, such as IL-12. Together, these results indicate that this zinc metalloprotease is a potential tool to be further investigated for the treatment of inflammatory disorders involving TNF deregulation. Full article
(This article belongs to the Special Issue Venomics, Venom Proteomics and Venom Transcriptomics)
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Open AccessCommunication No Association between Mycotoxin Exposure and Autism: A Pilot Case-Control Study in School-Aged Children
Toxins 2016, 8(7), 224; doi:10.3390/toxins8070224
Received: 22 May 2016 / Revised: 6 July 2016 / Accepted: 8 July 2016 / Published: 20 July 2016
Cited by 2 | PDF Full-text (251 KB) | HTML Full-text | XML Full-text
Abstract
Evaluation of environmental risk factors in the development of autism spectrum disorder (ASD) is needed for a more complete understanding of disease etiology and best approaches for prevention, diagnosis, and treatment. A pilot experiment in 54 children (n = 25 ASD, n
[...] Read more.
Evaluation of environmental risk factors in the development of autism spectrum disorder (ASD) is needed for a more complete understanding of disease etiology and best approaches for prevention, diagnosis, and treatment. A pilot experiment in 54 children (n = 25 ASD, n = 29 controls; aged 12.4 ± 3.9 years) screened for 87 urinary mycotoxins via liquid chromatography-tandem mass spectrometry to assess current exposure. Zearalenone, zearalenone-4-glucoside, 3-acetyldeoxynivalenol, and altenuene were detected in 9/54 (20%) samples, most near the limit of detection. No mycotoxin/group of mycotoxins was associated with ASD-diagnosed children. To identify potential correlates of mycotoxin presence in urine, we further compared the nine subjects where a urinary mycotoxin was confirmed to the remaining 45 participants and found no difference based on the presence or absence of mycotoxin for age (t-test; p = 0.322), gender (Fisher’s exact test; p = 0.456), exposure or not to selective serotonin reuptake inhibitors (Fisher’s exact test; p = 0.367), or to other medications (Fisher’s exact test; p = 1.00). While no positive association was found, more sophisticated sample preparation techniques and instrumentation, coupled with selectivity for a smaller group of mycotoxins, could improve sensitivity and detection. Further, broadening sampling to in utero (mothers) and newborn-toddler years would cover additional exposure windows. Full article
(This article belongs to the Section Mycotoxins)
Open AccessArticle A Theoretical Study of 8-Chloro-9-Hydroxy-Aflatoxin B1, the Conversion Product of Aflatoxin B1 by Neutral Electrolyzed Water
Toxins 2016, 8(7), 225; doi:10.3390/toxins8070225
Received: 18 June 2016 / Accepted: 14 July 2016 / Published: 21 July 2016
Cited by 5 | PDF Full-text (4020 KB) | HTML Full-text | XML Full-text
Abstract
Theoretical studies of 8-chloro-9-hydroxy-aflatoxin B1 (2) were carried out by Density Functional Theory (DFT). This molecule is the reaction product of the treatment of aflatoxin B1 (1) with hypochlorous acid, from neutral electrolyzed water. Determination of the
[...] Read more.
Theoretical studies of 8-chloro-9-hydroxy-aflatoxin B1 (2) were carried out by Density Functional Theory (DFT). This molecule is the reaction product of the treatment of aflatoxin B1 (1) with hypochlorous acid, from neutral electrolyzed water. Determination of the structural, electronic and spectroscopic properties of the reaction product allowed its theoretical characterization. In order to elucidate the formation process of 2, two reaction pathways were evaluated—the first one considering only ionic species (Cl+ and OH) and the second one taking into account the entire hypochlorous acid molecule (HOCl). Both pathways were studied theoretically in gas and solution phases. In the first suggested pathway, the reaction involves the addition of chlorenium ion to 1 forming a non-classic carbocation assisted by anchimeric effect of the nearest aromatic system, and then a nucleophilic attack to the intermediate by the hydroxide ion. In the second studied pathway, as a first step, the attack of the double bond from the furanic moiety of 1 to the hypochlorous acid is considered, accomplishing the same non-classical carbocation, and again in the second step, a nucleophilic attack by the hydroxide ion. In order to validate both reaction pathways, the atomic charges, the highest occupied molecular orbital and the lowest unoccupied molecular orbital were obtained for both substrate and product. The corresponding data imply that the C9 atom is the more suitable site of the substrate to interact with the hydroxide ion. It was demonstrated by theoretical calculations that a vicinal and anti chlorohydrin is produced in the terminal furan ring. Data of the studied compound indicate an important reduction in the cytotoxic and genotoxic potential of the target molecule, as demonstrated previously by our research group using different in vitro assays. Full article
(This article belongs to the Section Mycotoxins)
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Open AccessArticle Type II Toxin–Antitoxin Systems in the Unicellular Cyanobacterium Synechocystis sp. PCC 6803
Toxins 2016, 8(7), 228; doi:10.3390/toxins8070228
Received: 20 June 2016 / Accepted: 11 July 2016 / Published: 21 July 2016
Cited by 4 | PDF Full-text (3449 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bacterial toxin–antitoxin (TA) systems are genetic elements, which are encoded by plasmid as well as chromosomal loci. They mediate plasmid and genomic island maintenance through post-segregational killing mechanisms but may also have milder effects, acting as mobile stress response systems that help certain
[...] Read more.
Bacterial toxin–antitoxin (TA) systems are genetic elements, which are encoded by plasmid as well as chromosomal loci. They mediate plasmid and genomic island maintenance through post-segregational killing mechanisms but may also have milder effects, acting as mobile stress response systems that help certain cells of a population in persisting adverse growth conditions. Very few cyanobacterial TA system have been characterized thus far. In this work, we focus on the cyanobacterium Synechocystis 6803, a widely used model organism. We expand the number of putative Type II TA systems from 36 to 69 plus seven stand-alone components. Forty-seven TA pairs are located on the chromosome and 22 are plasmid-located. Different types of toxins are associated with various antitoxins in a mix and match principle. According to protein domains and experimental data, 81% of all toxins in Synechocystis 6803 likely exhibit RNase activity, suggesting extensive potential for toxicity-related RNA degradation and toxin-mediated transcriptome remodeling. Of particular interest is the Ssr8013–Slr8014 system encoded on plasmid pSYSG, which is part of a larger defense island or the pSYSX system Slr6056–Slr6057, which is linked to a bacterial ubiquitin-like system. Consequently, Synechocystis 6803 is one of the most prolific sources of new information about these genetic elements. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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Review

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Open AccessReview A Review of the Methods for Detection of Staphylococcus aureus Enterotoxins
Toxins 2016, 8(7), 176; doi:10.3390/toxins8070176
Received: 17 March 2016 / Accepted: 30 May 2016 / Published: 24 June 2016
Cited by 9 | PDF Full-text (1491 KB) | HTML Full-text | XML Full-text
Abstract
Food safety has attracted extensive attention around the world, and food-borne diseases have become one of the major threats to health. Staphylococcus aureus is a major food-borne pathogen worldwide and a frequent contaminant of foodstuffs. Staphylococcal enterotoxins (SEs) produced by some S. aureus
[...] Read more.
Food safety has attracted extensive attention around the world, and food-borne diseases have become one of the major threats to health. Staphylococcus aureus is a major food-borne pathogen worldwide and a frequent contaminant of foodstuffs. Staphylococcal enterotoxins (SEs) produced by some S. aureus strains will lead to staphylococcal food poisoning (SFP) outbreaks. The most common symptoms caused by ingestion of SEs within food are nausea, vomiting, diarrhea and cramps. Children will suffer SFP by ingesting as little as 100 ng of SEs, and only a few micrograms of SEs are enough to cause SPF in vulnerable populations. Therefore, it is a great challenge and of urgent need to detect and identify SEs rapidly and accurately for governmental and non-governmental agencies, including the military, public health departments, and health care facilities. Herein, an overview of SE detection has been provided through a comprehensive literature survey. Full article
(This article belongs to the collection Staphylococcus aureus Toxins)
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Open AccessReview Ochratoxin A: 50 Years of Research
Toxins 2016, 8(7), 191; doi:10.3390/toxins8070191
Received: 26 April 2016 / Revised: 21 May 2016 / Accepted: 13 June 2016 / Published: 4 July 2016
Cited by 20 | PDF Full-text (3462 KB) | HTML Full-text | XML Full-text
Abstract
Since ochratoxin A (OTA) was discovered, it has been ubiquitous as a natural contaminant of moldy food and feed. The multiple toxic effects of OTA are a real threat for human beings and animal health. For example, OTA can cause porcine nephropathy but
[...] Read more.
Since ochratoxin A (OTA) was discovered, it has been ubiquitous as a natural contaminant of moldy food and feed. The multiple toxic effects of OTA are a real threat for human beings and animal health. For example, OTA can cause porcine nephropathy but can also damage poultries. Humans exposed to OTA can develop (notably by inhalation in the development of acute renal failure within 24 h) a range of chronic disorders such as upper urothelial carcinoma. OTA plays the main role in the pathogenesis of some renal diseases including Balkan endemic nephropathy, kidney tumors occurring in certain endemic regions of the Balkan Peninsula, and chronic interstitial nephropathy occurring in Northern African countries and likely in other parts of the world. OTA leads to DNA adduct formation, which is known for its genotoxicity and carcinogenicity. The present article discusses how renal carcinogenicity and nephrotoxicity cause both oxidative stress and direct genotoxicity. Careful analyses of the data show that OTA carcinogenic effects are due to combined direct and indirect mechanisms (e.g., genotoxicity, oxidative stress, epigenetic factors). Altogether this provides strong evidence that OTA carcinogenicity can also occur in humans. Full article
(This article belongs to the collection Ochratoxins-Collection)
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Open AccessReview Tumor Targeting and Drug Delivery by Anthrax Toxin
Toxins 2016, 8(7), 197; doi:10.3390/toxins8070197
Received: 26 April 2016 / Revised: 21 June 2016 / Accepted: 23 June 2016 / Published: 1 July 2016
Cited by 2 | PDF Full-text (1466 KB) | HTML Full-text | XML Full-text
Abstract
Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated
[...] Read more.
Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery. Full article
(This article belongs to the collection Immunotoxins 2016)
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Open AccessReview Therapeutic Effectiveness of Anticancer Phytochemicals on Cancer Stem Cells
Toxins 2016, 8(7), 199; doi:10.3390/toxins8070199
Received: 29 March 2016 / Revised: 17 June 2016 / Accepted: 23 June 2016 / Published: 30 June 2016
Cited by 6 | PDF Full-text (532 KB) | HTML Full-text | XML Full-text
Abstract
Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals
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Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals on heterogeneous cancer cell populations as well as on specific targeting of CSCs. Full article
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Open AccessReview Augmenting the Efficacy of Immunotoxins and Other Targeted Protein Toxins by Endosomal Escape Enhancers
Toxins 2016, 8(7), 200; doi:10.3390/toxins8070200
Received: 21 April 2016 / Revised: 14 June 2016 / Accepted: 17 June 2016 / Published: 1 July 2016
Cited by 6 | PDF Full-text (680 KB) | HTML Full-text | XML Full-text
Abstract
The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for
[...] Read more.
The toxic moiety of almost all protein-based targeted toxins must enter the cytosol of the target cell to mediate its fatal effect. Although more than 500 targeted toxins have been investigated in the past decades, no antibody-targeted protein toxin has been approved for tumor therapeutic applications by the authorities to date. Missing efficacy can be attributed in many cases to insufficient endosomal escape and therefore subsequent lysosomal degradation of the endocytosed toxins. To overcome this drawback, many strategies have been described to weaken the membrane integrity of endosomes. This comprises the use of lysosomotropic amines, carboxylic ionophores, calcium channel antagonists, various cell-penetrating peptides of viral, bacterial, plant, animal, human and synthetic origin, other organic molecules and light-induced techniques. Although the efficacy of the targeted toxins was typically augmented in cell culture hundred or thousand fold, in exceptional cases more than million fold, the combination of several substances harbors new problems including additional side effects, loss of target specificity, difficulties to determine the therapeutic window and cell type-dependent variations. This review critically scrutinizes the chances and challenges of endosomal escape enhancers and their potential role in future developments. Full article
(This article belongs to the collection Immunotoxins 2016)
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Open AccessReview Botulinum Toxin A for Bladder Pain Syndrome/Interstitial Cystitis
Toxins 2016, 8(7), 201; doi:10.3390/toxins8070201
Received: 31 January 2016 / Revised: 24 June 2016 / Accepted: 28 June 2016 / Published: 1 July 2016
Cited by 2 | PDF Full-text (204 KB) | HTML Full-text | XML Full-text
Abstract
Botulinum neurotoxin A (BoNT-A), derived from Clostridium botulinum, has been used clinically for several diseases or syndrome including chronic migraine, spasticity, focal dystonia and other neuropathic pain. Chronic pelvic or bladder pain is the one of the core symptoms of bladder pain syndrome/interstitial
[...] Read more.
Botulinum neurotoxin A (BoNT-A), derived from Clostridium botulinum, has been used clinically for several diseases or syndrome including chronic migraine, spasticity, focal dystonia and other neuropathic pain. Chronic pelvic or bladder pain is the one of the core symptoms of bladder pain syndrome/interstitial cystitis (BPS/IC). However, in the field of urology, chronic bladder or pelvic pain is often difficult to eradicate by oral medications or bladder instillation therapy. We are looking for new treatment modality to improve bladder pain or associated urinary symptoms such as frequency and urgency for patients with BPS/IC. Recent studies investigating the mechanism of the antinociceptive effects of BoNT A suggest that it can inhibit the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. In this review, we will examine the evidence supporting the use of BoNTs in bladder pain from basic science models and review the clinical studies on therapeutic applications of BoNT for BPS/IC. Full article
(This article belongs to the Special Issue Botulinum Toxin A on Lower Urinary Tract Dysfunction)
Open AccessFeature PaperReview Relationship between VacA Toxin and Host Cell Autophagy in Helicobacter pylori Infection of the Human Stomach: A Few Answers, Many Questions
Toxins 2016, 8(7), 203; doi:10.3390/toxins8070203
Received: 20 May 2016 / Revised: 14 June 2016 / Accepted: 17 June 2016 / Published: 1 July 2016
Cited by 3 | PDF Full-text (942 KB) | HTML Full-text | XML Full-text
Abstract
Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach of about half the global population and represents the greatest risk factor for gastric malignancy. The relevance of H. pylori for gastric cancer development is equivalent to that of tobacco smoking for lung
[...] Read more.
Helicobacter pylori is a Gram-negative bacterium that colonizes the stomach of about half the global population and represents the greatest risk factor for gastric malignancy. The relevance of H. pylori for gastric cancer development is equivalent to that of tobacco smoking for lung cancer. VacA toxin seems to play a pivotal role in the overall strategy of H. pylori towards achieving persistent gastric colonization. This strategy appears to involve the modulation of host cell autophagy. After an overview of autophagy and its role in infection and carcinogenesis, I critically review current knowledge about the action of VacA on host cell autophagy during H. pylori infection of the human stomach. Although VacA is a key player in modulation of H. pylori-induced autophagy, a few discrepancies in the data are also evident and many questions remain to be answered. We are thus still far from a definitive understanding of the molecular mechanisms through which VacA affects autophagy and the consequences of this toxin action on the overall pathogenic activity of H. pylori. Full article
(This article belongs to the Special Issue Vacuolating Toxin)
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Open AccessReview Regulation of Toxin Production in Clostridium perfringens
Toxins 2016, 8(7), 207; doi:10.3390/toxins8070207
Received: 20 March 2016 / Accepted: 24 June 2016 / Published: 5 July 2016
Cited by 6 | PDF Full-text (541 KB) | HTML Full-text | XML Full-text
Abstract
The Gram-positive anaerobic bacterium Clostridium perfringens is widely distributed in nature, especially in soil and the gastrointestinal tracts of humans and animals. C. perfringens causes gas gangrene and food poisoning, and it produces extracellular enzymes and toxins that are thought to act synergistically
[...] Read more.
The Gram-positive anaerobic bacterium Clostridium perfringens is widely distributed in nature, especially in soil and the gastrointestinal tracts of humans and animals. C. perfringens causes gas gangrene and food poisoning, and it produces extracellular enzymes and toxins that are thought to act synergistically and contribute to its pathogenesis. A complicated regulatory network of toxin genes has been reported that includes a two-component system for regulatory RNA and cell-cell communication. It is necessary to clarify the global regulatory system of these genes in order to understand and treat the virulence of C. perfringens. We summarize the existing knowledge about the regulatory mechanisms here. Full article
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Open AccessReview Staphylococcus aureus Toxins and Diabetic Foot Ulcers: Role in Pathogenesis and Interest in Diagnosis
Toxins 2016, 8(7), 209; doi:10.3390/toxins8070209
Received: 14 May 2016 / Revised: 29 June 2016 / Accepted: 1 July 2016 / Published: 7 July 2016
Cited by 6 | PDF Full-text (1356 KB) | HTML Full-text | XML Full-text
Abstract
Infection of foot ulcers is a common, often severe and costly complication in diabetes. Diabetic foot infections (DFI) are mainly polymicrobial, and Staphylococcus aureus is the most frequent pathogen isolated. The numerous virulence factors and toxins produced by S. aureus during an infection
[...] Read more.
Infection of foot ulcers is a common, often severe and costly complication in diabetes. Diabetic foot infections (DFI) are mainly polymicrobial, and Staphylococcus aureus is the most frequent pathogen isolated. The numerous virulence factors and toxins produced by S. aureus during an infection are well characterized. However, some particular features could be observed in DFI. The aim of this review is to describe the role of S. aureus in DFI and the implication of its toxins in the establishment of the infection. Studies on this issue have helped to distinguish two S. aureus populations in DFI: toxinogenic S. aureus strains (harboring exfoliatin-, EDIN-, PVL- or TSST-encoding genes) and non-toxinogenic strains. Toxinogenic strains are often present in infections with a more severe grade and systemic impact, whereas non-toxinogenic strains seem to remain localized in deep structures and bone involving diabetic foot osteomyelitis. Testing the virulence profile of bacteria seems to be a promising way to predict the behavior of S. aureus in the chronic wounds. Full article
(This article belongs to the collection Staphylococcus aureus Toxins)
Open AccessReview Toxin-Antitoxin Modules Are Pliable Switches Activated by Multiple Protease Pathways
Toxins 2016, 8(7), 214; doi:10.3390/toxins8070214
Received: 14 May 2016 / Revised: 24 June 2016 / Accepted: 27 June 2016 / Published: 9 July 2016
Cited by 6 | PDF Full-text (3965 KB) | HTML Full-text | XML Full-text
Abstract
Toxin-antitoxin (TA) modules are bacterial regulatory switches that facilitate conflicting outcomes for cells by promoting a pro-survival phenotypic adaptation and/or by directly mediating cell death, all through the toxin activity upon degradation of antitoxin. Intensive study has revealed specific details of TA module
[...] Read more.
Toxin-antitoxin (TA) modules are bacterial regulatory switches that facilitate conflicting outcomes for cells by promoting a pro-survival phenotypic adaptation and/or by directly mediating cell death, all through the toxin activity upon degradation of antitoxin. Intensive study has revealed specific details of TA module functions, but significant gaps remain about the molecular details of activation via antitoxin degradation used by different bacteria and in different environments. This review summarizes the current state of knowledge about the interaction of antitoxins with cellular proteases Lon and ClpP to mediate TA module activation. An understanding of these processes can answer long-standing questions regarding stochastic versus specific activation of TA modules and provide insight into the potential for manipulation of TA modules to alter bacterial growth. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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Open AccessReview Impact of CDT Toxin on Human Diseases
Toxins 2016, 8(7), 220; doi:10.3390/toxins8070220
Received: 10 February 2016 / Revised: 1 July 2016 / Accepted: 6 July 2016 / Published: 15 July 2016
Cited by 3 | PDF Full-text (1467 KB) | HTML Full-text | XML Full-text
Abstract
Cytolethal distending toxin (CDT) is found in Gram-negative bacteria, especially in certain Proteobacteria such as the Pasteurellaceae family, including Haemophilus ducreyi and Aggregatibacter (Actinobacillus) actinomycetemcomitans, in the Enterobacteriaceae family and the Campylobacterales order, including the Campylobacter and Helicobacter species. In vitro and
[...] Read more.
Cytolethal distending toxin (CDT) is found in Gram-negative bacteria, especially in certain Proteobacteria such as the Pasteurellaceae family, including Haemophilus ducreyi and Aggregatibacter (Actinobacillus) actinomycetemcomitans, in the Enterobacteriaceae family and the Campylobacterales order, including the Campylobacter and Helicobacter species. In vitro and in vivo studies have clearly shown that this toxin has a strong effect on cellular physiology (inflammation, immune response modulation, tissue damage). Some works even suggest a potential involvement of CDT in cancers. In this review, we will discuss these different aspects. Full article
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Open AccessReview Toxin-Antitoxin Systems in Clinical Pathogens
Toxins 2016, 8(7), 227; doi:10.3390/toxins8070227
Received: 9 May 2016 / Accepted: 7 July 2016 / Published: 20 July 2016
Cited by 6 | PDF Full-text (1155 KB) | HTML Full-text | XML Full-text
Abstract
Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. Although not essential for normal cell growth, TA systems are implicated in multiple cellular functions associated with survival under stress conditions. Clinical strains of bacteria are currently causing major human health problems as a
[...] Read more.
Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. Although not essential for normal cell growth, TA systems are implicated in multiple cellular functions associated with survival under stress conditions. Clinical strains of bacteria are currently causing major human health problems as a result of their multidrug resistance, persistence and strong pathogenicity. Here, we present a review of the TA systems described to date and their biological role in human pathogens belonging to the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) and others of clinical relevance (Escherichia coli, Burkholderia spp., Streptococcus spp. and Mycobacterium tuberculosis). Better understanding of the mechanisms of action of TA systems will enable the development of new lines of treatment for infections caused by the above-mentioned pathogens. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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Other

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Open AccessOpinion How Safe Is Safe for Marine Toxins Monitoring?
Toxins 2016, 8(7), 208; doi:10.3390/toxins8070208
Received: 22 April 2016 / Revised: 27 June 2016 / Accepted: 1 July 2016 / Published: 6 July 2016
Cited by 3 | PDF Full-text (388 KB) | HTML Full-text | XML Full-text
Abstract
Current regulation for marine toxins requires a monitoring method based on mass spectrometric analysis. This method is pre-targeted, hence after searching for pre-assigned masses, it identifies those compounds that were pre-defined with available calibrants. Therefore, the scope for detecting novel toxins which are
[...] Read more.
Current regulation for marine toxins requires a monitoring method based on mass spectrometric analysis. This method is pre-targeted, hence after searching for pre-assigned masses, it identifies those compounds that were pre-defined with available calibrants. Therefore, the scope for detecting novel toxins which are not included in the monitoring protocol are very limited. In addition to this, there is a poor comprehension of the toxicity of some marine toxin groups. Also, the validity of the current approach is questioned by the lack of sufficient calibrants, and by the insufficient coverage by current legislation of the toxins reported to be present in shellfish. As an example, tetrodotoxin, palytoxin analogs, or cyclic imines are mentioned as indicators of gaps in the system that require a solid comprehension to assure consumers are protected. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
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