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Toxins, Volume 8, Issue 2 (February 2016)

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Open AccessArticle Insight into the Mode of Action of Haedoxan A from Phryma leptostachya
Received: 12 December 2015 / Revised: 14 February 2016 / Accepted: 15 February 2016 / Published: 22 February 2016
Cited by 1 | Viewed by 1306 | PDF Full-text (3635 KB) | HTML Full-text | XML Full-text
Abstract
Haedoxan A (HA) is a major active ingredient in the herbaceous perennial plant lopseed (Phryma leptostachya L.), which is used as a natural insecticide against insect pests in East Asia. Here, we report that HA delayed the decay rate of evoked excitatory [...] Read more.
Haedoxan A (HA) is a major active ingredient in the herbaceous perennial plant lopseed (Phryma leptostachya L.), which is used as a natural insecticide against insect pests in East Asia. Here, we report that HA delayed the decay rate of evoked excitatory junctional potentials (EJPs) and increased the frequency of miniature EJPs (mEJPs) on the Drosophila neuromuscular junction. HA also caused a significant hyperpolarizing shift of the voltage dependence of fast inactivation of insect sodium channels expressed in Xenopus oocytes. Our results suggest that HA acts on both axonal conduction and synaptic transmission, which can serve as a basis for elucidating the mode of action of HA for further designing and developing new effective insecticides. Full article
(This article belongs to the Section Plant Toxins)
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Open AccessReview Bee Venom Phospholipase A2: Yesterday’s Enemy Becomes Today’s Friend
Received: 11 November 2015 / Revised: 26 January 2016 / Accepted: 14 February 2016 / Published: 22 February 2016
Cited by 14 | Viewed by 2699 | PDF Full-text (549 KB) | HTML Full-text | XML Full-text
Abstract
Bee venom therapy has been used to treat immune-related diseases such as arthritis for a long time. Recently, it has revealed that group III secretory phospholipase A2 from bee venom (bee venom group III sPLA2) has in vitro and in [...] Read more.
Bee venom therapy has been used to treat immune-related diseases such as arthritis for a long time. Recently, it has revealed that group III secretory phospholipase A2 from bee venom (bee venom group III sPLA2) has in vitro and in vivo immunomodulatory effects. A growing number of reports have demonstrated the therapeutic effects of bee venom group III sPLA2. Notably, new experimental data have shown protective immune responses of bee venom group III sPLA2 against a wide range of diseases including asthma, Parkinson’s disease, and drug-induced organ inflammation. It is critical to evaluate the beneficial and adverse effects of bee venom group III sPLA2 because this enzyme is known to be the major allergen of bee venom that can cause anaphylactic shock. For many decades, efforts have been made to avoid its adverse effects. At high concentrations, exposure to bee venom group III sPLA2 can result in damage to cellular membranes and necrotic cell death. In this review, we summarized the current knowledge about the therapeutic effects of bee venom group III sPLA2 on several immunological diseases and described the detailed mechanisms of bee venom group III sPLA2 in regulating various immune responses and physiopathological changes. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Open AccessArticle Venom of Parasitoid Pteromalus puparum Impairs Host Humoral Antimicrobial Activity by Decreasing Host Cecropin and Lysozyme Gene Expression
Received: 13 November 2015 / Revised: 30 January 2016 / Accepted: 4 February 2016 / Published: 20 February 2016
Cited by 3 | Viewed by 1992 | PDF Full-text (1226 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Insect host/parasitoid interactions are co-evolved systems in which host defenses are balanced by parasitoid mechanisms to disable or hide from host immune effectors. Here, we report that Pteromalus puparum venom impairs the antimicrobial activity of its host Pieris rapae. Inhibition zone results [...] Read more.
Insect host/parasitoid interactions are co-evolved systems in which host defenses are balanced by parasitoid mechanisms to disable or hide from host immune effectors. Here, we report that Pteromalus puparum venom impairs the antimicrobial activity of its host Pieris rapae. Inhibition zone results showed that bead injection induced the antimicrobial activity of the host hemolymph but that venom inhibited it. The cDNAs encoding cecropin and lysozyme were screened. Relative quantitative PCR results indicated that all of the microorganisms and bead injections up-regulated the transcript levels of the two genes but that venom down-regulated them. At 8 h post bead challenge, there was a peak in the transcript level of the cecropin gene, whereas the peak of lysozyme gene occurred at 24 h. The transcripts levels of the two genes were higher in the granulocytes and fat body than in other tissues. RNA interference decreased the transcript levels of the two genes and the antimicrobial activity of the pupal hemolymph. Venom injections similarly silenced the expression of the two genes during the first 8 h post-treatment in time- and dose-dependent manners, after which the silence effects abated. Additionally, recombinant cecropin and lysozyme had no significant effect on the emergence rate of pupae that were parasitized by P. puparum females. These findings suggest one mechanism of impairing host antimicrobial activity by parasitoid venom. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Open AccessCase Report Long-Term Blood Pressure Control Effect of Celiac Plexus Block with Botulinum Toxin
Received: 31 December 2015 / Revised: 31 January 2016 / Accepted: 14 February 2016 / Published: 19 February 2016
Cited by 5 | Viewed by 1625 | PDF Full-text (796 KB) | HTML Full-text | XML Full-text
Abstract
Celiac plexus block (CPB) is one of the main treatment options for patients resistant to conventional antihypertensive drugs. We present a case of resistant hypertension (RHTN) that was treated with CPB using botulinum toxin. An 18-year-old male patient with RHTN, who suffered from [...] Read more.
Celiac plexus block (CPB) is one of the main treatment options for patients resistant to conventional antihypertensive drugs. We present a case of resistant hypertension (RHTN) that was treated with CPB using botulinum toxin. An 18-year-old male patient with RHTN, who suffered from persistent hypertension even after combination therapy and a renal denervation procedure, was referred to our pain center for CPB. CPB using botulinum toxin following the use of only local anesthetics resulted in control of systolic blood pressure (BP) at ~150 mmHg for at least three months. Full article
(This article belongs to the Section Bacterial Toxins)
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Open AccessArticle Combined Effects of Lipophilic Phycotoxins (Okadaic Acid, Azapsiracid-1 and Yessotoxin) on Human Intestinal Cells Models
Received: 14 October 2015 / Revised: 29 January 2016 / Accepted: 1 February 2016 / Published: 19 February 2016
Cited by 5 | Viewed by 1763 | PDF Full-text (901 KB) | HTML Full-text | XML Full-text
Abstract
Phycotoxins are monitored in seafood because they can cause food poisonings in humans. Phycotoxins do not only occur singly but also as mixtures in shellfish. The aim of this study was to evaluate the in vitro toxic interactions of binary combinations of three [...] Read more.
Phycotoxins are monitored in seafood because they can cause food poisonings in humans. Phycotoxins do not only occur singly but also as mixtures in shellfish. The aim of this study was to evaluate the in vitro toxic interactions of binary combinations of three lipophilic phycotoxins commonly found in Europe (okadaic acid (OA), yessotoxin (YTX) and azaspiracid-1 (AZA-1)) using the neutral red uptake assay on two human intestinal cell models, Caco-2 and the human intestinal epithelial crypt-like cells (HIEC). Based on the cytotoxicity of individual toxins, we studied the interactions between toxins in binary mixtures using the combination index-isobologram equation, a method widely used in pharmacology to study drug interactions. This method quantitatively classifies interactions between toxins in mixtures as synergistic, additive or antagonistic. AZA-1/OA, and YTX/OA mixtures showed increasing antagonism with increasing toxin concentrations. In contrast, the AZA-1/YTX mixture showed increasing synergism with increasing concentrations, especially for mixtures with high YTX concentrations. These results highlight the hazard potency of AZA-1/YTX mixtures with regard to seafood intoxication. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
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Open AccessReview Heterologous Expression of Toxins from Bacterial Toxin-Antitoxin Systems in Eukaryotic Cells: Strategies and Applications
Received: 17 January 2016 / Revised: 3 February 2016 / Accepted: 15 February 2016 / Published: 19 February 2016
Cited by 9 | Viewed by 2817 | PDF Full-text (1106 KB) | HTML Full-text | XML Full-text
Abstract
Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the [...] Read more.
Toxin-antitoxin (TA) systems are found in nearly all prokaryotic genomes and usually consist of a pair of co-transcribed genes, one of which encodes a stable toxin and the other, its cognate labile antitoxin. Certain environmental and physiological cues trigger the degradation of the antitoxin, causing activation of the toxin, leading either to the death or stasis of the host cell. TA systems have a variety of functions in the bacterial cell, including acting as mediators of programmed cell death, the induction of a dormant state known as persistence and the stable maintenance of plasmids and other mobile genetic elements. Some bacterial TA systems are functional when expressed in eukaryotic cells and this has led to several innovative applications, which are the subject of this review. Here, we look at how bacterial TA systems have been utilized for the genetic manipulation of yeasts and other eukaryotes, for the containment of genetically modified organisms, and for the engineering of high expression eukaryotic cell lines. We also examine how TA systems have been adopted as an important tool in developmental biology research for the ablation of specific cells and the potential for utility of TA systems in antiviral and anticancer gene therapies. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System in Bacteria)
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Open AccessReview Lolitrem B and Indole Diterpene Alkaloids Produced by Endophytic Fungi of the Genus Epichloë and Their Toxic Effects in Livestock
Received: 15 January 2016 / Revised: 29 January 2016 / Accepted: 3 February 2016 / Published: 15 February 2016
Cited by 15 | Viewed by 1849 | PDF Full-text (1160 KB) | HTML Full-text | XML Full-text
Abstract
Different group of alkaloids are produced during the symbiotic development of fungal endophytes of the genus Epichloë in grass. The structure and toxicity of the compounds vary considerably in mammalian herbivores and in crop pests. Alkaloids of the indole-diterpene group, of which lolitrem [...] Read more.
Different group of alkaloids are produced during the symbiotic development of fungal endophytes of the genus Epichloë in grass. The structure and toxicity of the compounds vary considerably in mammalian herbivores and in crop pests. Alkaloids of the indole-diterpene group, of which lolitrem B is the most toxic, were first characterized in endophyte-infected perennial ryegrass, and are responsible for “ryegrass staggers.” Ergot alkaloids, of which ergovaline is the most abundant ergopeptide alkaloid produced, are also found in ryegrass, but generally at a lower rate than lolitrem B. Other alkaloids such as lolines and peramine are toxic for crop pests but have weak toxicological properties in mammals. The purpose of this review is to present indole-diterpene alkaloids produced in endophyte infected ryegrass from the first characterization of ryegrass staggers to the determination of the toxicokinetics of lolitrem B and of their mechanism of action in mammals, focusing on the different factors that could explain the worldwide distribution of the disease. Other indole diterpene alkaloids than lolitrem B that can be found in Epichloë infected ryegrass, and their tremorgenic properties, are presented in the last section of this review. Full article
(This article belongs to the collection Toxicity of Natural Alkaloids)
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Open AccessArticle Functional Genomic Analysis of Aspergillus flavus Interacting with Resistant and Susceptible Peanut
Received: 30 December 2015 / Revised: 30 January 2016 / Accepted: 5 February 2016 / Published: 15 February 2016
Cited by 10 | Viewed by 2886 | PDF Full-text (1299 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
In the Aspergillus flavus (A. flavus)–peanut pathosystem, development and metabolism of the fungus directly influence aflatoxin contamination. To comprehensively understand the molecular mechanism of A. flavus interaction with peanut, RNA-seq was used for global transcriptome profiling of A. flavus during interaction with [...] Read more.
In the Aspergillus flavus (A. flavus)–peanut pathosystem, development and metabolism of the fungus directly influence aflatoxin contamination. To comprehensively understand the molecular mechanism of A. flavus interaction with peanut, RNA-seq was used for global transcriptome profiling of A. flavus during interaction with resistant and susceptible peanut genotypes. In total, 67.46 Gb of high-quality bases were generated for A. flavus-resistant (af_R) and -susceptible peanut (af_S) at one (T1), three (T2) and seven (T3) days post-inoculation. The uniquely mapped reads to A. flavus reference genome in the libraries of af_R and af_S at T2 and T3 were subjected to further analysis, with more than 72% of all obtained genes expressed in the eight libraries. Comparison of expression levels both af_R vs. af_S and T2 vs. T3 uncovered 1926 differentially expressed genes (DEGs). DEGs associated with mycelial growth, conidial development and aflatoxin biosynthesis were up-regulated in af_S compared with af_R, implying that A. flavus mycelia more easily penetrate and produce much more aflatoxin in susceptible than in resistant peanut. Our results serve as a foundation for understanding the molecular mechanisms of aflatoxin production differences between A. flavus-R and -S peanut, and offer new clues to manage aflatoxin contamination in crops. Full article
(This article belongs to the collection Aflatoxins)
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Open AccessFeature PaperReview Mycotoxin Contamination in the EU Feed Supply Chain: A Focus on Cereal Byproducts
Received: 1 October 2015 / Revised: 28 January 2016 / Accepted: 4 February 2016 / Published: 15 February 2016
Cited by 54 | Viewed by 3289 | PDF Full-text (827 KB) | HTML Full-text | XML Full-text
Abstract
Mycotoxins represent a risk to the feed supply chain with an impact on economies and international trade. A high percentage of feed samples have been reported to be contaminated with more than one mycotoxin. In most cases, the concentrations were low enough to [...] Read more.
Mycotoxins represent a risk to the feed supply chain with an impact on economies and international trade. A high percentage of feed samples have been reported to be contaminated with more than one mycotoxin. In most cases, the concentrations were low enough to ensure compliance with the European Union (EU) guidance values or maximum admitted levels. However, mycotoxin co-contamination might still exert adverse effects on animals due to additive/synergistic interactions. Studies on the fate of mycotoxins during cereal processing, such as milling, production of ethanol fuels, and beer brewing, have shown that mycotoxins are concentrated into fractions that are commonly used as animal feed. Published data show a high variability in mycotoxin repartitioning, mainly due to the type of mycotoxins, the level and extent of fungal contamination, and a failure to understand the complexity of food processing technologies. Precise knowledge of mycotoxin repartitioning during technological processes is critical and may provide a sound technical basis for feed managers to conform to legislation requirements and reduce the risk of severe adverse market and trade repercussions. Regular, economical and straightforward feed testing is critical to reach a quick and accurate diagnosis of feed quality. The use of rapid methods represents a future challenge. Full article
(This article belongs to the collection Understanding Mycotoxin Occurrence in Food and Feed Chains)
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Open AccessArticle An Insight into the Triabin Protein Family of American Hematophagous Reduviids: Functional, Structural and Phylogenetic Analysis
Received: 14 November 2015 / Revised: 24 December 2015 / Accepted: 18 January 2016 / Published: 15 February 2016
Cited by 6 | Viewed by 1843 | PDF Full-text (5216 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
A transcriptomic analysis of the saliva of T. pallidipennis together with a short proteomic analysis were carried out to reveal novel primary structures of the lipocalin/triabin protein families in this reduviid. Although triabins share some structural characteristics to lipocalins and they are classified [...] Read more.
A transcriptomic analysis of the saliva of T. pallidipennis together with a short proteomic analysis were carried out to reveal novel primary structures of the lipocalin/triabin protein families in this reduviid. Although triabins share some structural characteristics to lipocalins and they are classified as in the calcyn/lipocalin superfamily, triabins differ from lipocalins in the direction of β-strands in the general conformation of the β-barrel. The triabin protein family encompasses a wide variety of proteins, which disrupt the hemostasis of warm-blooded animals. Likewise, the function of proteins classified as triabins includes proteins that are carriers of small molecules, protease inhibitors, binders of specific cell-surface receptors as well as proteins that form complexes with other macromolecules. For example, triabin and pallidipin from the saliva of T. pallidipennis are thrombin and platelet aggregation inhibitors, respectively; triplatin from T. infestans binds to thromboxane A2; and nitrophorin from Rhodnius prolixus carries nitric oxide. Therefore, based on 42 new transcriptome sequences of triabins from the salivary glands of T. pallidipennis reported at present, and on triabin sequences of other American hematophagous reduviids already reported in the literature, subfamilies of triabins were proposed following phylogenetic analyses and functional characterization of triabin members. Eight subfamilies of proteins were recognized with known functions, which were the nitrophorin and amine binding proteins, Rhodnius prolixus aggregation inhibitor, triafestin, triatin, dipetalodipin and pallidipin, triplatin and infestilin, dimiconin and triabin, and procalin subfamilies. Interestingly, 70% of the analyzed sequences came from these eight subfamilies because there was no biological function associated with them, implying the existence of a vast number of proteins with potential novel biological activities. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Open AccessReview Venoms of Heteropteran Insects: A Treasure Trove of Diverse Pharmacological Toolkits
Received: 21 December 2015 / Revised: 25 January 2016 / Accepted: 26 January 2016 / Published: 12 February 2016
Cited by 15 | Viewed by 2860 | PDF Full-text (2807 KB) | HTML Full-text | XML Full-text
Abstract
The piercing-sucking mouthparts of the true bugs (Insecta: Hemiptera: Heteroptera) have allowed diversification from a plant-feeding ancestor into a wide range of trophic strategies that include predation and blood-feeding. Crucial to the success of each of these strategies is the injection of venom. [...] Read more.
The piercing-sucking mouthparts of the true bugs (Insecta: Hemiptera: Heteroptera) have allowed diversification from a plant-feeding ancestor into a wide range of trophic strategies that include predation and blood-feeding. Crucial to the success of each of these strategies is the injection of venom. Here we review the current state of knowledge with regard to heteropteran venoms. Predaceous species produce venoms that induce rapid paralysis and liquefaction. These venoms are powerfully insecticidal, and may cause paralysis or death when injected into vertebrates. Disulfide-rich peptides, bioactive phospholipids, small molecules such as N,N-dimethylaniline and 1,2,5-trithiepane, and toxic enzymes such as phospholipase A2, have been reported in predatory venoms. However, the detailed composition and molecular targets of predatory venoms are largely unknown. In contrast, recent research into blood-feeding heteropterans has revealed the structure and function of many protein and non-protein components that facilitate acquisition of blood meals. Blood-feeding venoms lack paralytic or liquefying activity but instead are cocktails of pharmacological modulators that disable the host haemostatic systems simultaneously at multiple points. The multiple ways venom is used by heteropterans suggests that further study will reveal heteropteran venom components with a wide range of bioactivities that may be recruited for use as bioinsecticides, human therapeutics, and pharmacological tools. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Open AccessArticle Acetylated Deoxynivalenol Generates Differences of Gene Expression that Discriminate Trichothecene Toxicity
Received: 11 December 2015 / Accepted: 3 February 2016 / Published: 6 February 2016
Cited by 3 | Viewed by 1861 | PDF Full-text (2992 KB) | HTML Full-text | XML Full-text
Abstract
Deoxynivalenol (DON), which is a toxic secondary metabolite generated by Fusarium species, is synthesized through two separate acetylation pathways. Both acetylation derivatives, 3-acetyl-DON (3ADON) and 15-acetyl-DON (15ADON), also contaminate grain and corn widely. These derivatives are deacetylated via a variety of processes after [...] Read more.
Deoxynivalenol (DON), which is a toxic secondary metabolite generated by Fusarium species, is synthesized through two separate acetylation pathways. Both acetylation derivatives, 3-acetyl-DON (3ADON) and 15-acetyl-DON (15ADON), also contaminate grain and corn widely. These derivatives are deacetylated via a variety of processes after ingestion, so it has been suggested that they have the same toxicity as DON. However, in the intestinal entry region such as the duodenum, the derivatives might come into contact with intestinal epithelium cells because metabolism by microflora or import into the body has not progressed. Therefore, the differences of toxicity between DON and these derivatives need to be investigated. Here, we observed gene expression changes in the yeast pdr5Δ mutant strain under concentration-dependent mycotoxin exposure conditions. 15ADON exposure induced significant gene expression changes and DON exposure generally had a similar but smaller effect. However, the glucose transporter genes HXT2 and HXT4 showed converse trends. 3ADON also induced a different expression trend in these genes than DON and 15ADON. These differences in gene expression suggest that DON and its derivatives have different effects on cells. Full article
(This article belongs to the collection Fusarium Toxins – Relevance for Human and Animal Health)
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Open AccessEditorial Announcing the 2016 Toxins Travel Awards for Post-Doctoral Fellows and Ph.D. Students
Received: 1 February 2016 / Accepted: 1 February 2016 / Published: 6 February 2016
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Abstract
With the goal of promoting the development of early career investigators in the field of toxinology, Toxins welcomed applications for the 2016 Toxins Travel Awards for post-doctoral fellows and Ph.D. students. [...] Full article
Open AccessFeature PaperArticle Teratogenicity of Ochratoxin A and the Degradation Product, Ochratoxin α, in the Zebrafish (Danio rerio) Embryo Model of Vertebrate Development
Received: 11 December 2015 / Revised: 13 January 2016 / Accepted: 19 January 2016 / Published: 5 February 2016
Cited by 8 | Viewed by 2611 | PDF Full-text (405 KB) | HTML Full-text | XML Full-text
Abstract
Ochratoxins, and particularly ochratoxin A (OTA), are toxic fungal-derived contaminants of food and other agricultural products. Growing evidence supports the degradation of OTA by chemical, enzymatic and/or microbial means as a potential approach to remove this mycotoxin from food products. In particular, hydrolysis [...] Read more.
Ochratoxins, and particularly ochratoxin A (OTA), are toxic fungal-derived contaminants of food and other agricultural products. Growing evidence supports the degradation of OTA by chemical, enzymatic and/or microbial means as a potential approach to remove this mycotoxin from food products. In particular, hydrolysis of OTA to ochratoxin α (OTα) and phenylalanine is the presumptive product of degradation in most cases. In the current study, we employed the zebrafish (Danio rerio) embryo, as a model of vertebrate development to evaluate, the teratogenicity of OTA and OTα. These studies show that OTA is potently active in the zebrafish embryo toxicity assay (ZETA), and that toxicity is both concentration- and time-dependent with discernible and quantifiable developmental toxicity observed at nanomolar concentrations. On the other hand, OTα had no significant effect on embryo development at all concentrations tested supporting a decreased toxicity of this degradation product. Taken together, these results suggest that ZETA is a useful, and highly sensitive, tool for evaluating OTA toxicity, as well as its degradation products, toward development of effective detoxification strategies. Specifically, the results obtained with ZETA, in the present study, further demonstrate the toxicity of OTA, and support its degradation via hydrolysis to OTα as an effective means of detoxification. Full article
(This article belongs to the collection Ochratoxins-Collection)
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Open AccessArticle A New Member of Gamma-Conotoxin Family Isolated from Conus princeps Displays a Novel Molecular Target
Received: 3 November 2015 / Revised: 22 January 2016 / Accepted: 25 January 2016 / Published: 5 February 2016
Cited by 3 | Viewed by 1792 | PDF Full-text (2559 KB) | HTML Full-text | XML Full-text
Abstract
A novel conotoxin, named as PiVIIA, was isolated from the venom of Conus princeps, a marine predatory cone snail collected in the Pacific Southern Coast of Mexico. Chymotryptic digest of the S-alkylated peptide in combination with liquid chromatography coupled to tandem mass [...] Read more.
A novel conotoxin, named as PiVIIA, was isolated from the venom of Conus princeps, a marine predatory cone snail collected in the Pacific Southern Coast of Mexico. Chymotryptic digest of the S-alkylated peptide in combination with liquid chromatography coupled to tandem mass spectrometry, were used to define the sequencing of this peptide. Eleven N-terminal amino acids were verified by automated Edman degradation. PiVIIA is a 25-mer peptide (CDAOTHYCTNYWγCCSGYCγHSHCW) with six cysteine residues forming three disulphide bonds, a hydroxyproline (O) and two gamma carboxyglutamic acid (γ) residues. Based on the arrangement of six Cys residues (C-C-CC-C-C), this conotoxin might belong to the O2-superfamily. Moreover, PiVIIA has a conserved motif (-γCCS-) that characterizes γ-conotoxins from molluscivorous Conus. Peptide PiVIIA has 45% sequence identity with γ-PnVIIA—the prototype of this family. Biological activity of PiVIIA was assessed by voltage-clamp recording in rat dorsal root ganglion neurons. Perfusion of PiVIIA in the µM range produces a significant increase in the Ca2+ currents, without significantly modifying the Na+, K+ or proton-gated acid sensing ionic currents. These results indicate that PiVIIA is a new conotoxin whose activity deserves further studies to define its potential use as a positive modulator of neuronal activity. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
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Open AccessArticle Apoptosis Activation in Human Lung Cancer Cell Lines by a Novel Synthetic Peptide Derived from Conus californicus Venom
Received: 28 November 2015 / Revised: 26 January 2016 / Accepted: 28 January 2016 / Published: 5 February 2016
Cited by 10 | Viewed by 2150 | PDF Full-text (3925 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Lung cancer is one of the most common types of cancer in men and women and a leading cause of death worldwide resulting in more than one million deaths per year. The venom of marine snails Conus contains up to 200 pharmacologically active [...] Read more.
Lung cancer is one of the most common types of cancer in men and women and a leading cause of death worldwide resulting in more than one million deaths per year. The venom of marine snails Conus contains up to 200 pharmacologically active compounds that target several receptors in the cell membrane. Due to their diversity and specific binding properties, Conus toxins hold great potential as source of new drugs against cancer. We analyzed the cytotoxic effect of a 17-amino acid synthetic peptide (s-cal14.1a) that is based on a native toxin (cal14.1a) isolated from the sea snail Conus californicus. Cytotoxicity studies in four lung cancer cell lines were complemented with measurement of gene expression of apoptosis-related proteins Bcl-2, BAX and the pro-survival proteins NFκB-1 and COX-2, as well as quantification of caspase activity. Our results showed that H1299 and H1437 cell lines treated with s-call4.1a had decreased cell viability, activated caspases, and reduced expression of the pro-survival protein NFκB-1. To our knowledge, this is the first report describing activation of apoptosis in human lung cancer cell lines by s-cal14.1a and we offer insight into the possible mechanism of action. Full article
(This article belongs to the Special Issue Conotoxins: Novel Pharmacologies for Nervous System Disorders)
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Open AccessFeature PaperArticle Cancer Therapy by Catechins Involves Redox Cycling of Copper Ions and Generation of Reactive Oxygen Species
Received: 2 January 2016 / Revised: 23 January 2016 / Accepted: 26 January 2016 / Published: 4 February 2016
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Abstract
Catechins, the dietary phytochemicals present in green tea and other beverages, are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells. While it is believed that the antioxidant properties of catechins and related dietary agents may contribute to lowering the [...] Read more.
Catechins, the dietary phytochemicals present in green tea and other beverages, are considered to be potent inducers of apoptosis and cytotoxicity to cancer cells. While it is believed that the antioxidant properties of catechins and related dietary agents may contribute to lowering the risk of cancer induction by impeding oxidative injury to DNA, these properties cannot account for apoptosis induction and chemotherapeutic observations. Catechin (C), epicatechin (EC), epigallocatechin (EGC) and epigallocatechin-3-gallate (EGCG) are the four major constituents of green tea. In this article, using human peripheral lymphocytes and comet assay, we show that C, EC, EGC and EGCG cause cellular DNA breakage and can alternatively switch to a prooxidant action in the presence of transition metals such as copper. The cellular DNA breakage was found to be significantly enhanced in the presence of copper ions. Catechins were found to be effective in providing protection against oxidative stress induced by tertbutylhydroperoxide, as measured by oxidative DNA breakage in lymphocytes. The prooxidant action of catechins involved production of hydroxyl radicals through redox recycling of copper ions. We also determined that catechins, particularly EGCG, inhibit proliferation of breast cancer cell line MDA-MB-231 leading to a prooxidant cell death. Since it is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies, cancer cells would be more subject to redox cycling between copper ions and catechins to generate reactive oxygen species (ROS) responsible for DNA breakage. Such a copper dependent prooxidant cytotoxic mechanism better explains the anticancer activity and preferential cytotoxicity of dietary phytochemicals against cancer cells. Full article
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Open AccessArticle Structure-Activity Relationship of Chlorotoxin-Like Peptides
Received: 2 November 2015 / Revised: 18 January 2016 / Accepted: 19 January 2016 / Published: 2 February 2016
Cited by 7 | Viewed by 2102 | PDF Full-text (2792 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used [...] Read more.
Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na+, K+, Ca+, Cl, etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7) has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae) venom. This peptide demonstrates 66% with chlorotoxin (ClTx) and 82% with CFTR channel inhibitor (GaTx1) sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile) for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca)/dinitrophenyl (Dnp) as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM), indicating the importance of this toxin in diseases associated with decreased MMP2 activity. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Open AccessArticle Diminished but Not Abolished Effect of Two His351 Mutants of Anthrax Edema Factor in a Murine Model
Received: 28 October 2015 / Revised: 8 January 2016 / Accepted: 15 January 2016 / Published: 2 February 2016
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Abstract
Edema toxin (ET), which is composed of a potent adenylate cyclase (AC), edema factor (EF), and protective antigen (PA), is one of the major toxicity factors of Bacillus anthracis. In this study, we introduced mutations in full-length EF to generate alanine EF(H351A) [...] Read more.
Edema toxin (ET), which is composed of a potent adenylate cyclase (AC), edema factor (EF), and protective antigen (PA), is one of the major toxicity factors of Bacillus anthracis. In this study, we introduced mutations in full-length EF to generate alanine EF(H351A) and arginine EF(H351R) variants. In vitro activity analysis displayed that the adenylyl cyclase activity of both the mutants was significantly diminished compared with the wild-type EF. When the native and mutant toxins were administered subcutaneously in a mouse footpad edema model, severe acute swelling was evoked by wild-type ET, while the symptoms induced by mutant toxins were very minor. Systemic administration of these EF variants caused non-lethal hepatotoxicity. In addition, EF(H351R) exhibited slightly higher activity in causing more severe edema than EF(H351A). Our findings demonstrate that the toxicity of ET is not abolished by substitution of EF residue His351 by alanine or arginine. These results also indicate the potential of the mouse footpad edema model as a sensitive method for evaluating both ET toxicity and the efficacy of candidate therapeutic agents. Full article
(This article belongs to the collection Anthrax Toxins)
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Open AccessReview Roles of Anthrax Toxin Receptor 2 in Anthrax Toxin Membrane Insertion and Pore Formation
Received: 24 December 2015 / Revised: 18 January 2016 / Accepted: 19 January 2016 / Published: 22 January 2016
Cited by 4 | Viewed by 2288 | PDF Full-text (1522 KB) | HTML Full-text | XML Full-text
Abstract
Interaction between bacterial toxins and cellular surface receptors is an important component of the host-pathogen interaction. Anthrax toxin protective antigen (PA) binds to the cell surface receptor, enters the cell through receptor-mediated endocytosis, and forms a pore on the endosomal membrane that translocates [...] Read more.
Interaction between bacterial toxins and cellular surface receptors is an important component of the host-pathogen interaction. Anthrax toxin protective antigen (PA) binds to the cell surface receptor, enters the cell through receptor-mediated endocytosis, and forms a pore on the endosomal membrane that translocates toxin enzymes into the cytosol of the host cell. As the major receptor for anthrax toxin in vivo, anthrax toxin receptor 2 (ANTXR2) plays an essential role in anthrax toxin action by providing the toxin with a high-affinity binding anchor on the cell membrane and a path of entry into the host cell. ANTXR2 also acts as a molecular clamp by shifting the pH threshold of PA pore formation to a more acidic pH range, which prevents premature pore formation at neutral pH before the toxin reaches the designated intracellular location. Most recent studies have suggested that the disulfide bond in the immunoglobulin (Ig)-like domain of ANTXR2 plays an essential role in anthrax toxin action. Here we will review the roles of ANTXR2 in anthrax toxin action, with an emphasis on newly updated knowledge. Full article
(This article belongs to the collection Anthrax Toxins)
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Open AccessArticle Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice
Received: 2 December 2015 / Revised: 14 January 2016 / Accepted: 18 January 2016 / Published: 22 January 2016
Cited by 11 | Viewed by 2532 | PDF Full-text (1583 KB) | HTML Full-text | XML Full-text
Abstract
Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat [...] Read more.
Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT3 (MDL-72222, 15 μg) receptor antagonist, but not with α2-adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT3 receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Open AccessReview Differential Properties of Venom Peptides and Proteins in Solitary vs. Social Hunting Wasps
Received: 21 December 2015 / Revised: 13 January 2016 / Accepted: 14 January 2016 / Published: 22 January 2016
Cited by 19 | Viewed by 2341 | PDF Full-text (1487 KB) | HTML Full-text | XML Full-text
Abstract
The primary functions of venoms from solitary and social wasps are different. Whereas most solitary wasps sting their prey to paralyze and preserve it, without killing, as the provisions for their progeny, social wasps usually sting to defend their colonies from vertebrate predators. [...] Read more.
The primary functions of venoms from solitary and social wasps are different. Whereas most solitary wasps sting their prey to paralyze and preserve it, without killing, as the provisions for their progeny, social wasps usually sting to defend their colonies from vertebrate predators. Such distinctive venom properties of solitary and social wasps suggest that the main venom components are likely to be different depending on the wasps’ sociality. The present paper reviews venom components and properties of the Aculeata hunting wasps, with a particular emphasis on the comparative aspects of venom compositions and properties between solitary and social wasps. Common components in both solitary and social wasp venoms include hyaluronidase, phospholipase A2, metalloendopeptidase, etc. Although it has been expected that more diverse bioactive components with the functions of prey inactivation and physiology manipulation are present in solitary wasps, available studies on venom compositions of solitary wasps are simply too scarce to generalize this notion. Nevertheless, some neurotoxic peptides (e.g., pompilidotoxin and dendrotoxin-like peptide) and proteins (e.g., insulin-like peptide binding protein) appear to be specific to solitary wasp venom. In contrast, several proteins, such as venom allergen 5 protein, venom acid phosphatase, and various phospholipases, appear to be relatively more specific to social wasp venom. Finally, putative functions of main venom components and their application are also discussed. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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