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Toxins, Volume 2, Issue 1 (January 2010), Pages 1-204

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Research

Jump to: Review, Other

Open AccessArticle Protein Domain Analysis of C. botulinum Type A Neurotoxin and Its Relationship with Other Botulinum Serotypes
Toxins 2010, 2(1), 1-9; doi:10.3390/toxins2010001
Received: 2 December 2009 / Revised: 23 December 2009 / Accepted: 23 December 2009 / Published: 24 December 2009
Cited by 2 | PDF Full-text (206 KB) | HTML Full-text | XML Full-text
Abstract
Botulinum neurotoxins (BoNTs) are highly potent poisons produced by seven serotypes of Clostridium botulinum. The mechanism of neurotoxin action is a multistep process which leads to the cleavage of one of three different SNARE proteins essential for synaptic vesicle fusion and [...] Read more.
Botulinum neurotoxins (BoNTs) are highly potent poisons produced by seven serotypes of Clostridium botulinum. The mechanism of neurotoxin action is a multistep process which leads to the cleavage of one of three different SNARE proteins essential for synaptic vesicle fusion and transmission of the nerve signals to muscles: synaptobrevin, syntaxin, or SNAP-25. In order to understand the precise mechanism of neurotoxin in a host, the domain structure of the neurotoxin was analyzed among different serotypes of C. botulinum. The results indicate that neurotoxins type A, C, D, E and F contain a coiled-coil domain while types B and type G neurotoxin do not. Interestingly, phylogenetic analysis based on neurotoxin sequences has further confirmed that serotypes B and G are closely related. These results suggest that neurotoxin has multi-domain structure, and coiled-coil domain plays an important role in oligomerisation of the neurotoxin. Domain analysis may help to identify effective antibodies to treat Botulinum toxin intoxication. Full article
(This article belongs to the Special Issue Neurotoxins of Biological Origin)
Open AccessArticle The Versatility of the Helicobacter pylori Vacuolating Cytotoxin VacA in Signal Transduction and Molecular Crosstalk
Toxins 2010, 2(1), 69-92; doi:10.3390/toxins2010069
Received: 3 December 2009 / Revised: 31 December 2009 / Accepted: 14 January 2010 / Published: 15 January 2010
Cited by 9 | PDF Full-text (1833 KB) | HTML Full-text | XML Full-text
Abstract
By modulating important properties of eukaryotic cells, many bacterial protein toxins highjack host signalling pathways to create a suitable niche for the pathogen to colonize and persist. Helicobacter pylori VacA is paradigm of pore-forming toxins which contributes to the pathogenesis of peptic [...] Read more.
By modulating important properties of eukaryotic cells, many bacterial protein toxins highjack host signalling pathways to create a suitable niche for the pathogen to colonize and persist. Helicobacter pylori VacA is paradigm of pore-forming toxins which contributes to the pathogenesis of peptic ulceration. Several cellular receptors have been described for VacA, which exert different effects on epithelial and immune cells. The crystal structure of VacA p55 subunit might be important for elucidating details of receptor interaction and pore formation. Here we discuss the multiple signalling activities of this important toxin and the molecular crosstalk between VacA and other virulence factors. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins)
Open AccessArticle Calprotectin (S100A8/S100A9) and Myeloperoxidase: Co-Regulators of Formation of Reactive Oxygen Species
Toxins 2010, 2(1), 95-115; doi:10.3390/toxins2010095
Received: 12 December 2009 / Accepted: 18 January 2010 / Published: 20 January 2010
Cited by 4 | PDF Full-text (616 KB) | HTML Full-text | XML Full-text
Abstract
Inflammatory mediators trigger polymorphonuclear neutrophils (PMN) to produce reactive oxygen species (ROS: O2-, H2O2, ∙OH). Mediated by myeloperoxidase in PMN, HOCl is formed, detectable in a chemiluminescence (CL) assay. We have shown that the abundant cytosolic [...] Read more.
Inflammatory mediators trigger polymorphonuclear neutrophils (PMN) to produce reactive oxygen species (ROS: O2-, H2O2, ∙OH). Mediated by myeloperoxidase in PMN, HOCl is formed, detectable in a chemiluminescence (CL) assay. We have shown that the abundant cytosolic PMN protein calprotectin (S100A8/A9) similarly elicits CL in response to H2O2 in a cell-free system. Myeloperoxidase and calprotectin worked synergistically. Calprotectin-induced CL increased, whereas myeloperoxidase-triggered CL decreased with pH > 7.5. Myeloperoxidase needed NaCl for CL, calprotectin did not. 4-hydroxybenzoic acid, binding ∙OH, almost abrogated calprotectin CL, but moderately increased myeloperoxidase activity. The combination of native calprotectin, or recombinant S100A8/A9 proteins, with NaOCl markedly enhanced CL. NaOCl may be the synergistic link between myeloperoxidase and calprotectin. Surprisingly- and unexplained- at higher concentration of S100A9 the stimulation vanished, suggesting a switch from pro-oxidant to anti-oxidant function. We propose that the ∙OH is predominant in ROS production by calprotectin, a function not described before. Full article
(This article belongs to the collection Toxicity and Therapeutic Interventions in the Immune System)
Figures

Open AccessArticle PP2A Inhibition Assay Using Recombinant Enzyme for Rapid Detection of Okadaic Acid and Its Analogs in Shellfish
Toxins 2010, 2(1), 195-204; doi:10.3390/toxins2010195
Received: 27 November 2009 / Revised: 18 January 2010 / Accepted: 19 January 2010 / Published: 25 January 2010
Cited by 12 | PDF Full-text (325 KB) | HTML Full-text | XML Full-text
Abstract
Okadaic acid and its analogs (OAs) responsible for diarrhetic shellfish poisoning (DSP) strongly inhibit protein phosphatase 2A (PP2A) and thus are quantifiable by measuring the extent of the enzyme inhibition. In this study, we evaluated the suitability of the catalytic subunit of [...] Read more.
Okadaic acid and its analogs (OAs) responsible for diarrhetic shellfish poisoning (DSP) strongly inhibit protein phosphatase 2A (PP2A) and thus are quantifiable by measuring the extent of the enzyme inhibition. In this study, we evaluated the suitability of the catalytic subunit of recombinant human PP2A (rhPP2Ac) for use in a microplate OA assay. OA, dinophysistoxin-1(DTX1), and hydrolyzate of 7-O-palmitoyl-OA strongly inhibited rhPP2Ac activity with IC50 values of 0.095, 0.104, and 0.135 nM, respectively. The limits of detection and quantitation for OA in the digestive gland of scallops and mussels were 0.0348 μg/g and 0.0611 μg/g respectively, and, when converted to the whole meat basis, are well below the regulation level proposed by EU (0.16 μg/g whole meat). A good correlation with LC-MS data was demonstrated, the correlation coefficient being 0.996 with the regression slope of 1.097. Full article
(This article belongs to the Special Issue Marine Biotoxins: Novel Issues about Old Compounds)

Review

Jump to: Research, Other

Open AccessReview Structure and Function of Snake Venom Proteins Affecting Platelet Plug Formation
Toxins 2010, 2(1), 10-23; doi:10.3390/toxins2010010
Received: 1 December 2009 / Revised: 18 December 2009 / Accepted: 24 December 2009 / Published: 28 December 2009
Cited by 4 | PDF Full-text (2695 KB) | HTML Full-text | XML Full-text
Abstract
Many snake venom proteins have been isolated that affect platelet plug formation by interacting either with platelet integrins, membrane glycoprotein Ib (GPIb), or plasma von Willebrand factor (VWF). Among them, disintegrins purified from various snake venoms are strong inhibitors of platelet aggregation. [...] Read more.
Many snake venom proteins have been isolated that affect platelet plug formation by interacting either with platelet integrins, membrane glycoprotein Ib (GPIb), or plasma von Willebrand factor (VWF). Among them, disintegrins purified from various snake venoms are strong inhibitors of platelet aggregation. Botrocetin and bitiscetin derived from Bothrops jararaca and Bitis arietans venom, respectively, induce VWF-dependent platelet agglutination in vitro. Several GPIb-binding proteins have also been isolated from snake venoms. In this review, we focus on the structure and function of those snake venom proteins that influence platelet plug formation. These proteins are potentially useful as reagents for the sub-diagnosis of platelet disorder or von Willebrand disease, as well as for clinical and basic research of thrombosis and hemostasis. Full article
(This article belongs to the Special Issue Animal Venoms)
Open AccessReview Sensing the Deadliest Toxin: Technologies for Botulinum Neurotoxin Detection
Toxins 2010, 2(1), 24-53; doi:10.3390/toxins2010024
Received: 1 December 2009 / Revised: 17 December 2009 / Accepted: 22 December 2009 / Published: 7 January 2010
Cited by 28 | PDF Full-text (1534 KB) | HTML Full-text | XML Full-text | Correction | Supplementary Files
Abstract
Sensitive and rapid detection of botulinum neurotoxins (BoNTs), the most poisonous substances known to date, is essential for studies of medical applications of BoNTs and detection of poisoned food, as well as for response to potential bioterrorist threats. Currently, the most common [...] Read more.
Sensitive and rapid detection of botulinum neurotoxins (BoNTs), the most poisonous substances known to date, is essential for studies of medical applications of BoNTs and detection of poisoned food, as well as for response to potential bioterrorist threats. Currently, the most common method of BoNT detection is the mouse bioassay. While this assay is sensitive, it is slow, quite expensive, has limited throughput and requires sacrificing animals. Herein, we discuss and compare recently developed alternative in vitro detection methods and assess their ability to supplement or replace the mouse bioassay in the analysis of complex matrix samples. Full article
(This article belongs to the Special Issue Neurotoxins of Biological Origin)
Figures

Open AccessReview Reciprocal Interactions between Lactoferrin and Bacterial Endotoxins and Their Role in the Regulation of the Immune Response
Toxins 2010, 2(1), 54-68; doi:10.3390/toxins2010054
Received: 1 December 2009 / Revised: 23 December 2009 / Accepted: 25 December 2009 / Published: 8 January 2010
Cited by 13 | PDF Full-text (640 KB) | HTML Full-text | XML Full-text
Abstract
Lactoferrin (Lf), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of the mammalian innate immune system. Lf’s multiple activities rely not only on its capacity to bind iron, but also to interact with molecular and cellular components of [...] Read more.
Lactoferrin (Lf), an iron-binding glycoprotein expressed in most biological fluids, represents a major component of the mammalian innate immune system. Lf’s multiple activities rely not only on its capacity to bind iron, but also to interact with molecular and cellular components of both host and pathogens. Lf can bind and sequester lipopolysaccharide (LPS), thus preventing pro-inflammatory pathway activation, sepsis and tissue damage. However, Lf-bound LPS may retain the capacity to induce cell activation via Toll-like receptor 4-dependent and -independent mechanisms. This review discusses the complex interplay between Lf and LPS and its relevance in the regulation of the immune response. Full article
(This article belongs to the collection Toxicity and Therapeutic Interventions in the Immune System)
Open AccessReview Cytotoxic Necrotizing Factors (CNFs)−A Growing Toxin Family
Toxins 2010, 2(1), 116-127; doi:10.3390/toxins2010116
Received: 14 December 2009 / Revised: 15 January 2010 / Accepted: 20 January 2010 / Published: 21 January 2010
Cited by 13 | PDF Full-text (394 KB) | HTML Full-text | XML Full-text
Abstract
The Escherichia coli Cytotoxic Necrotizing Factors, CNF1, CNF2, CNF3 and CNFY from Yersinia pseudotuberculosis belong to a family of deamidating toxins. CNFs deamidate glutamine 63/61 in the switch II region of Rho GTPases that is essential for GTP hydrolysing activity. Deamidation leads [...] Read more.
The Escherichia coli Cytotoxic Necrotizing Factors, CNF1, CNF2, CNF3 and CNFY from Yersinia pseudotuberculosis belong to a family of deamidating toxins. CNFs deamidate glutamine 63/61 in the switch II region of Rho GTPases that is essential for GTP hydrolysing activity. Deamidation leads to constitutive activation of Rho GTPases. However, cellular mechanisms like proteasomal degradation of the activated Rho proteins restrict the action of the GTPases. This review describes the differences between the toxin family members concerning expression, cellular entry and substrate specificity. Full article
(This article belongs to the Special Issue Bacterial Protein Toxins)
Open AccessReview Curcumin―The Paradigm of a Multi-Target Natural Compound with Applications in Cancer Prevention and Treatment
Toxins 2010, 2(1), 128-162; doi:10.3390/toxins2010128
Received: 28 December 2009 / Revised: 11 January 2010 / Accepted: 12 January 2010 / Published: 21 January 2010
Cited by 78 | PDF Full-text (631 KB) | HTML Full-text | XML Full-text
Abstract
As cancer is a multifactor disease, it may require treatment with compounds able to target multiple intracellular components. We summarize here how curcumin is able to modulate many components of intracellular signaling pathways implicated in inflammation, cell proliferation and invasion and to [...] Read more.
As cancer is a multifactor disease, it may require treatment with compounds able to target multiple intracellular components. We summarize here how curcumin is able to modulate many components of intracellular signaling pathways implicated in inflammation, cell proliferation and invasion and to induce genetic modulations eventually leading to tumor cell death. Clinical applications of this natural compound were initially limited by its low solubility and bioavailability in both plasma and tissues but combination with adjuvant and delivery vehicles was reported to largely improve bio-availability of curcumin. Moreover, curcumin was reported to act in synergism with several natural compounds or synthetic agents commonly used in chemotherapy. Based on this, curcumin could thus be considered as a good candidate for cancer prevention and treatment when used alone or in combination with other conventional treatments. Full article
Open AccessReview Bothrops lanceolatus Bites: Guidelines for Severity Assessment and Emergent Management
Toxins 2010, 2(1), 163-173; doi:10.3390/toxins2010163
Received: 6 December 2009 / Revised: 13 January 2010 / Accepted: 19 January 2010 / Published: 22 January 2010
Cited by 7 | PDF Full-text (370 KB) | HTML Full-text | XML Full-text
Abstract
Approximately 20–30 declared snakebite cases occurin Martinique each year. Bothrops lanceolatus, a member of the Crotalidae family, is considered to be the only involved snake. B. lanceolatus, commonly named “Fer-de-Lance”, is endemic and only found on this Caribbean island. Envenomation [...] Read more.
Approximately 20–30 declared snakebite cases occurin Martinique each year. Bothrops lanceolatus, a member of the Crotalidae family, is considered to be the only involved snake. B. lanceolatus, commonly named “Fer-de-Lance”, is endemic and only found on this Caribbean island. Envenomation local features include the presence of fang marks, swelling, pain, bleeding from punctures, and ecchymosis. Severe envenomation is associated with multiple systemic thromboses appearing within 48 h of the bite and resulting in cerebral, myocardial or pulmonary infarctions. Diagnosis requires first of all identification of the snake. Coagulation tests are helpful to identify thrombocytopenia or disseminated intravascular coagulation. A clinical score based on 4 grades is helpful to assess envonimation severity. A specific monovalent equine anti-venom (Bothrofav®, Sanofi-Pasteur, France) to neutralize B. lanceolatus venom is available. Its early administration within 6h from the biting in case of progressive local injures, general signs or coagulation disturbances is effective to prevent severe thrombosis and coagulopathy. Its tolerance is considered to be good. Despite an increasing incidence of bites, no deaths have been recently attributed to B. lanceolatus in Martinique, probably due to the currently recommended strategy of early antivenom administration when required. Full article
(This article belongs to the Special Issue Animal Venoms)
Open AccessReview The Protein Kinase C Agonist PEP005 (Ingenol 3-Angelate) in the Treatment of Human Cancer: A Balance between Efficacy and Toxicity
Toxins 2010, 2(1), 174-194; doi:10.3390/toxins2010174
Received: 30 November 2009 / Revised: 7 January 2010 / Accepted: 18 January 2010 / Published: 22 January 2010
Cited by 26 | PDF Full-text (457 KB) | HTML Full-text | XML Full-text
Abstract
The diterpene ester ingenol-3-angelate (referred to as PEP005) is derived from the plant Euphorbia peplus. Crude euphorbia extract causes local toxicity and transient inflammation when applied topically and has been used in the treatment of warts, skin keratoses and skin cancer. [...] Read more.
The diterpene ester ingenol-3-angelate (referred to as PEP005) is derived from the plant Euphorbia peplus. Crude euphorbia extract causes local toxicity and transient inflammation when applied topically and has been used in the treatment of warts, skin keratoses and skin cancer. PEP005 is a broad range activator of the classical (α, β, γ) and novel (δ, ε, η, θ) protein kinase C isoenzymes. Direct pro-apoptotic effects of this drug have been demonstrated in several malignant cells, including melanoma cell lines and primary human acute myelogenous leukemia cells. At micromolar concentrations required to kill melanoma cells this agent causes PKC-independent secondary necrosis. In contrast, the killing of leukemic cells occurs in the nanomolar range, requires activation of protein kinase C δ (PKCδ) and is specifically associated with translocation of PKCδ from the cytoplasm to the nuclear membrane. However, in addition to this pro-apoptotic effect the agent seems to have immunostimulatory effects, including: (i) increased chemokine release by malignant cells; (ii) a general increase in proliferation and cytokine release by activated T cells, including T cells derived from patients with chemotherapy-induced lymphopenia; (iii) local infiltration of neutrophils after topical application with increased antibody-dependent cytotoxicity; and (iv) development of specific anti-cancer immune responses by CD8+ T cells in animal models. Published studies mainly describe effects from in vitro investigations or after topical application of the agent, and careful evaluation of the toxicity after systemic administration is required before the possible use of this agent in the treatment of malignancies other than skin cancers. Full article
(This article belongs to the collection Toxicity and Therapeutic Interventions in the Immune System)

Other

Jump to: Research, Review

Open AccessCorrection Correction: Čapek, P., et al. Sensing the Deadliest Toxin: Technologies for Botulinum Neurotoxin Detection. Toxins 2010, 2, 24-53
Toxins 2010, 2(1), 93-94; doi:10.3390/toxins2010093
Received: 19 January 2010 / Accepted: 19 January 2010 / Published: 19 January 2010
Cited by 1 | PDF Full-text (73 KB) | HTML Full-text | XML Full-text
Abstract We realized that in our paper published recently in Toxins [1] limits of detection (LOD) of multiplexed fluorescent magnetic suspension assay [2] were incorrectly reported to be in the ng/mL range. [...] Full article

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