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Toxins, Volume 3, Issue 3 (March 2011) – 10 articles , Pages 163-344

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398 KiB  
Review
Brown Spider (Loxosceles genus) Venom Toxins: Tools for Biological Purposes
by Olga Meiri Chaim, Dilza Trevisan-Silva, Daniele Chaves-Moreira, Ana Carolina M. Wille, Valéria Pereira Ferrer, Fernando Hitomi Matsubara, Oldemir Carlos Mangili, Rafael Bertoni da Silveira, Luiza Helena Gremski, Waldemiro Gremski, Andrea Senff-Ribeiro and Silvio Sanches Veiga
Toxins 2011, 3(3), 309-344; https://doi.org/10.3390/toxins3030309 - 22 Mar 2011
Cited by 85 | Viewed by 17880
Abstract
Venomous animals use their venoms as tools for defense or predation. These venoms are complex mixtures, mainly enriched of proteic toxins or peptides with several, and different, biological activities. In general, spider venom is rich in biologically active molecules that are useful in [...] Read more.
Venomous animals use their venoms as tools for defense or predation. These venoms are complex mixtures, mainly enriched of proteic toxins or peptides with several, and different, biological activities. In general, spider venom is rich in biologically active molecules that are useful in experimental protocols for pharmacology, biochemistry, cell biology and immunology, as well as putative tools for biotechnology and industries. Spider venoms have recently garnered much attention from several research groups worldwide. Brown spider (Loxosceles genus) venom is enriched in low molecular mass proteins (5–40 kDa). Although their venom is produced in minute volumes (a few microliters), and contain only tens of micrograms of protein, the use of techniques based on molecular biology and proteomic analysis has afforded rational projects in the area and permitted the discovery and identification of a great number of novel toxins. The brown spider phospholipase-D family is undoubtedly the most investigated and characterized, although other important toxins, such as low molecular mass insecticidal peptides, metalloproteases and hyaluronidases have also been identified and featured in literature. The molecular pathways of the action of these toxins have been reported and brought new insights in the field of biotechnology. Herein, we shall see how recent reports describing discoveries in the area of brown spider venom have expanded biotechnological uses of molecules identified in these venoms, with special emphasis on the construction of a cDNA library for venom glands, transcriptome analysis, proteomic projects, recombinant expression of different proteic toxins, and finally structural descriptions based on crystallography of toxins. Full article
(This article belongs to the Special Issue Spider Venoms)
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366 KiB  
Review
Mechanism of Diphtheria Toxin Catalytic Domain Delivery to the Eukaryotic Cell Cytosol and the Cellular Factors that Directly Participate in the Process
by John R. Murphy
Toxins 2011, 3(3), 294-308; https://doi.org/10.3390/toxins3030294 - 21 Mar 2011
Cited by 131 | Viewed by 21537
Abstract
Research on diphtheria and anthrax toxins over the past three decades has culminated in a detailed understanding of their structure function relationships (e.g., catalytic (C), transmembrane (T), and receptor binding (R) domains), as well as the identification of their eukaryotic cell surface receptor, [...] Read more.
Research on diphtheria and anthrax toxins over the past three decades has culminated in a detailed understanding of their structure function relationships (e.g., catalytic (C), transmembrane (T), and receptor binding (R) domains), as well as the identification of their eukaryotic cell surface receptor, an understanding of the molecular events leading to the receptor-mediated internalization of the toxin into an endosomal compartment, and the pH triggered conformational changes required for pore formation in the vesicle membrane. Recently, a major research effort has been focused on the development of a detailed understanding of the molecular interactions between each of these toxins and eukaryotic cell factors that play an essential role in the efficient translocation of their respective catalytic domains through the trans-endosomal vesicle membrane pore and delivery into the cell cytosol. In this review, I shall focus on recent findings that have led to a more detailed understanding of the mechanism by which the diphtheria toxin catalytic domain is delivered to the eukaryotic cell cytosol. While much work remains, it is becoming increasingly clear that the entry process is facilitated by specific interactions with a number of cellular factors in an ordered sequential fashion. In addition,since diphtheria, anthrax lethal factor and anthrax edema factor all carry multiple coatomer I complex binding motifs and COPI complex has been shown to play an essential role in entry process, it is likely that the initial steps in catalytic domain entry of these divergent toxins follow a common mechanism. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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1431 KiB  
Review
From Toxins Targeting Ligand Gated Ion Channels to Therapeutic Molecules
by Adak Nasiripourdori, Valérie Taly, Thomas Grutter and Antoine Taly
Toxins 2011, 3(3), 260-293; https://doi.org/10.3390/toxins3030260 - 21 Mar 2011
Cited by 25 | Viewed by 17643
Abstract
Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to [...] Read more.
Ligand-gated ion channels (LGIC) play a central role in inter-cellular communication. This key function has two consequences: (i) these receptor channels are major targets for drug discovery because of their potential involvement in numerous human brain diseases; (ii) they are often found to be the target of plant and animal toxins. Together this makes toxin/receptor interactions important to drug discovery projects. Therefore, toxins acting on LGIC are presented and their current/potential therapeutic uses highlighted. Full article
(This article belongs to the Special Issue Toxins as Therapeutics)
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475 KiB  
Review
Aggregatibacter actinomycetemcomitans Leukotoxin: A Powerful Tool with Capacity to Cause Imbalance in the Host Inflammatory Response
by Anders Johansson
Toxins 2011, 3(3), 242-259; https://doi.org/10.3390/toxins3030242 - 21 Mar 2011
Cited by 120 | Viewed by 23185
Abstract
Aggregatibacter actinomycetemcomitans has been described as a member of the indigenous oral microbiota of humans, and is involved in the pathology of periodontitis and various non-oral infections. This bacterium selectively kills human leukocytes through expression of leukotoxin, a large pore-forming protein that belongs [...] Read more.
Aggregatibacter actinomycetemcomitans has been described as a member of the indigenous oral microbiota of humans, and is involved in the pathology of periodontitis and various non-oral infections. This bacterium selectively kills human leukocytes through expression of leukotoxin, a large pore-forming protein that belongs to the Repeat in Toxin (RTX) family. The specificity of the toxin is related to its prerequisite for a specific target cell receptor, LFA-1, which is solely expressed on leukocytes. The leukotoxin causes death of different leukocyte populations in a variety of ways. It activates a rapid release of lysosomal enzymes and MMPs from neutrophils and causes apoptosis in lymphocytes. In the monocytes/macrophages, the toxin activates caspase-1, a cysteine proteinase, which causes a proinflammatory response by the activation and secretion of IL-1β and IL-18. A specific clone (JP2) of A. actinomycetemcomitans with enhanced leukotoxin expression significantly correlates to disease onset in infected individuals. Taken together, the mechanisms by which this toxin kills leukocytes are closely related to the pathogenic mechanisms of inflammatory disorders, such as periodontitis. Therapeutic strategies targeting the cellular and molecular inflammatory host response in periodontal diseases might be a future treatment alternative. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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1086 KiB  
Article
Arf6-Dependent Intracellular Trafficking of Pasteurella multocida Toxin and pH-Dependent Translocation from Late Endosomes
by Tana L. Repella, Mengfei Ho, Tracy P. M. Chong, Yuka Bannai and Brenda A. Wilson
Toxins 2011, 3(3), 218-241; https://doi.org/10.3390/toxins3030218 - 16 Mar 2011
Cited by 23 | Viewed by 11852
Abstract
The potent mitogenic toxin from Pasteurella multocida (PMT) is the major virulence factor associated with a number of epizootic and zoonotic diseases caused by infection with this respiratory pathogen. PMT is a glutamine-specific protein deamidase that acts on its intracellular G-protein targets to [...] Read more.
The potent mitogenic toxin from Pasteurella multocida (PMT) is the major virulence factor associated with a number of epizootic and zoonotic diseases caused by infection with this respiratory pathogen. PMT is a glutamine-specific protein deamidase that acts on its intracellular G-protein targets to increase intracellular calcium, cytoskeletal, and mitogenic signaling. PMT enters cells through receptor-mediated endocytosis and then translocates into the cytosol through a pH-dependent process that is inhibited by NH4Cl or bafilomycin A1. However, the detailed mechanisms that govern cellular entry, trafficking, and translocation of PMT remain unclear. Co-localization studies described herein revealed that while PMT shares an initial entry pathway with transferrin (Tfn) and cholera toxin (CT), the trafficking pathways of Tfn, CT, and PMT subsequently diverge, as Tfn is trafficked to recycling endosomes, CT is trafficked retrograde to the ER, and PMT is trafficked to late endosomes. Our studies implicate the small regulatory GTPase Arf6 in the endocytic trafficking of PMT. Translocation of PMT from the endocytic vesicle occurs through a pH-dependent process that is also dependent on both microtubule and actin dynamics, as evidenced by inhibition of PMT activity in our SRE-based reporter assay, with nocodazole and cytochalasin D, respectively, suggesting that membrane translocation and cytotoxicity of PMT is dependent on its transfer to late endosomal compartments. In contrast, disruption of Golgi-ER trafficking with brefeldin A increased PMT activity, suggesting that inhibiting PMT trafficking to non-productive compartments that do not lead to translocation, while promoting formation of an acidic tubulovesicle system more conducive to translocation, enhances PMT translocation and activity. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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254 KiB  
Article
Post-Intoxication Inhibition of Botulinum Neurotoxin Serotype A within Neurons by Small-Molecule, Non-Peptidic Inhibitors
by Gordon Ruthel, James C. Burnett, Jonathan E. Nuss, Laura M. Wanner, Lyal E. Tressler, Edna Torres-Melendez, Sarah J. Sandwick, Cary J. Retterer and Sina Bavari
Toxins 2011, 3(3), 207-217; https://doi.org/10.3390/toxins3030207 - 15 Mar 2011
Cited by 23 | Viewed by 9671
Abstract
Botulinum neurotoxins (BoNTs) comprise seven distinct serotypes that inhibit the release of neurotransmitter across neuromuscular junctions, resulting in potentially fatal flaccid paralysis. BoNT serotype A (BoNT/A), which targets synaptosomal-associated protein of 25kDa (SNAP-25), is particularly long-lived within neurons and requires a longer time [...] Read more.
Botulinum neurotoxins (BoNTs) comprise seven distinct serotypes that inhibit the release of neurotransmitter across neuromuscular junctions, resulting in potentially fatal flaccid paralysis. BoNT serotype A (BoNT/A), which targets synaptosomal-associated protein of 25kDa (SNAP-25), is particularly long-lived within neurons and requires a longer time for recovery of neuromuscular function. There are currently no treatments available to counteract BoNT/A after it has entered the neuronal cytosol. In this study, we examined the ability of small molecule non-peptidic inhibitors (SMNPIs) to prevent SNAP-25 cleavage post-intoxication of neurons. The progressive cleavage of SNAP-25 observed over 5 h following 1 h BoNT/A intoxication was prevented by addition of SMNPIs. In contrast, anti-BoNT/A neutralizing antibodies that strongly inhibited SNAP-25 cleavage when added during intoxication were completely ineffective when added post-intoxication. Although Bafilomycin A1, which blocks entry of BoNT/A into the cytosol by preventing endosomal acidification, inhibited SNAP-25 cleavage post-intoxication, the degree of inhibition was significantly reduced versus addition both during and after intoxication. Post-intoxication application of SMNPIs, on the other hand, was nearly as effective as application both during and after intoxication. Taken together, the results indicate that competitive SMNPIs of BoNT/A light chain can be effective within neurons post-intoxication. Full article
(This article belongs to the Special Issue Development of Botulinum Toxin Drugs)
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140 KiB  
Review
Imaging of Convection Enhanced Delivery of Toxins in Humans
by Ankit I. Mehta, Bryan D. Choi, Raghu Raghavan, Martin Brady, Allan H. Friedman, Darell D. Bigner, Ira Pastan and John H. Sampson
Toxins 2011, 3(3), 201-206; https://doi.org/10.3390/toxins3030201 - 15 Mar 2011
Cited by 18 | Viewed by 8902
Abstract
Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated [...] Read more.
Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field. Full article
(This article belongs to the Special Issue Immunotoxins)
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190 KiB  
Review
Monitoring Radiographic Brain Tumor Progression
by Ankit I. Mehta, Charles W. Kanaly, Allan H. Friedman, Darell D. Bigner and John H. Sampson
Toxins 2011, 3(3), 191-200; https://doi.org/10.3390/toxins3030191 - 15 Mar 2011
Cited by 25 | Viewed by 8205
Abstract
Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability to [...] Read more.
Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability to detect tumor progression radiographically remains inadequate. Despite the advanced imaging techniques, detecting tumor progression continues to be a clinical challenge. Here we review the different criteria used to detect tumor progression, and highlight the inherent challenges with detection of progression. Full article
(This article belongs to the Special Issue Immunotoxins)
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457 KiB  
Review
The Biology of the Cytolethal Distending Toxins
by Lina Guerra, Ximena Cortes-Bratti, Riccardo Guidi and Teresa Frisan
Toxins 2011, 3(3), 172-190; https://doi.org/10.3390/toxins3030172 - 7 Mar 2011
Cited by 108 | Viewed by 15351
Abstract
The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B2 toxin, where the CdtA and CdtC subunits are required to [...] Read more.
The cytolethal distending toxins (CDTs), produced by a variety of Gram-negative pathogenic bacteria, are the first bacterial genotoxins described, since they cause DNA damage in the target cells. CDT is an A-B2 toxin, where the CdtA and CdtC subunits are required to mediate the binding on the surface of the target cells, allowing internalization of the active CdtB subunit, which is functionally homologous to the mammalian deoxyribonuclease I. The nature of the surface receptor is still poorly characterized, however binding of CDT requires intact lipid rafts, and its internalization occurs via dynamin-dependent endocytosis. The toxin is retrograde transported through the Golgi complex and the endoplasmic reticulum, and subsequently translocated into the nuclear compartment, where it exerts the toxic activity. Cellular intoxication induces DNA damage and activation of the DNA damage responses, which results in arrest of the target cells in the G1 and/or G2 phases of the cell cycle and activation of DNA repair mechanisms. Cells that fail to repair the damage will senesce or undergo apoptosis. This review will focus on the well-characterized aspects of the CDT biology and discuss the questions that still remain unanswered. Full article
(This article belongs to the Special Issue Cellular Microbiology of Bacterial Toxins)
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216 KiB  
Communication
Mycobiota and Aflatoxin B1 in Feed for Farmed Sea Bass (Dicentrarchus labrax)
by Inês Filipa Martins Almeida, Hermínia Marina Lourdes Martins, Sara Maria Oliveira Santos, Maria Suzana Freitas, José Manuel Gaspar Nunes da Costa and Fernando Manuel D´Almeida Bernardo
Toxins 2011, 3(3), 163-171; https://doi.org/10.3390/toxins3030163 - 25 Feb 2011
Cited by 30 | Viewed by 10018
Abstract
The safety characteristics of feed used in fish and crustacean aquaculture systems are an essential tool to assure the productivity of those animal exploitations. Safety of feed may be affected by different hazards, including biological and chemical groups. The aim of this preliminary [...] Read more.
The safety characteristics of feed used in fish and crustacean aquaculture systems are an essential tool to assure the productivity of those animal exploitations. Safety of feed may be affected by different hazards, including biological and chemical groups. The aim of this preliminary study was to evaluate fungi contamination and the presence of aflatoxins in 87 samples of feed for sea bass, collected in Portugal. Molds were found in 35 samples (40.2%) in levels ranging from 1 to 3.3 log10 CFU∙g−1. Six genera of molds were found. Aspergillus flavus was the most frequent, found in all positive samples, with a range from 2 to 3.2 log10 CFU∙g−1. Aspergillus niger was found in 34 samples (39.1%), ranging from 1 to 2.7 log10 CFU∙g−1. Aspergillus glaucus was found in 26 samples (29.9%) with levels between 1 and 2.4 log10 CFU∙g−1. Penicillium spp. and Cladosporium spp. were both found in 25 samples (28.7%). Fusarium spp. was found in 22 samples (25.3%), ranging from 1 to 2.3 log10 CFU∙g−1. All feed samples were screened for aflatoxins using a HPLC technique, with a detection limit of 1.0 μg∙kg−1. All samples were aflatoxin negative. Full article
(This article belongs to the Special Issue Aflatoxins 2011)
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