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Lethal Toxin (lethal + toxin)
Selected AbstractsTotal Synthesis of Polycavernoside A (I), a Lethal Toxin of the Red Alga Polycavernosa tsudai.CHEMINFORM, Issue 49 2005Paul R. Blakemore No abstract is available for this article. [source] Fish venom: pharmacological features and biological significanceFISH AND FISHERIES, Issue 2 2009Gisha Sivan Abstract Nearly 1200 species of marine fish are venomous and they account for two-third of the population of venomous vertebrates. Fish venoms are focused as a potential source of pharmacological agents and physiological tools that have evolved to target vital processes in the human body that appear to have more electivity than many drugs. Fish venoms possess cardiovascular, neuromuscular, oedematic and cytolytic activity. Lethal toxins have been isolated and purified, with some having LD50 values comparable to that of snake venoms. Cardiovascular activity seems to be the dominant effect of fish venoms in experimental models. Piscine venom acts both pre- and post-junctionally to produce depolarization of cell membranes. Studies on cytolytic activity of fish venom found that it produces lysis by forming hydrophilic pores in cell membranes which then result in cell lysis. Almost all fish venoms with neuromuscular activity also possesses cytolytic activity, and it is very likely that the two activities are related. Fish venom is known to induce intense and sustained edematogenic response. As piscine venoms have evolved for the same purpose, they show a number of similarities pharmacologically and it seems likely that most of the biological activities of any given toxin can be traced back to its cytolytic activity. A variety of toxins have been isolated from piscine venom. Although there is a complex balance between the components present in the venom of different fish, all of them seem to share similar activity , functionally and pharmacologically as well as structurally. [source] Role of the monomeric GTPase Rho in hematopoietic progenitor cell migration and transplantationEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2006Stephan Göttig Abstract To investigate the role of the monomeric guanosine triphosphatase (GTPase) Rho on migration of hematopoietic progenitor cells (HPC), we employed different clostridial toxins which inhibit the Rho family of GTPases. Pretreatment with C2I-C3, a cell-accessible C3 transferase fusion protein that targets Rho, increased chemokinetic migration of the factor-dependent multipotent cell line Factor Dependent Cell Paterson with mixed lineage differentiation potential (FDCP-mix) and of primary lineage marker-depleted HPC in vitro. In contrast, treatment with lethal toxin (LT) from Clostridium sordellii, which predominantly inactivates Rac, and with toxin,B from C.,difficile, which inactivates Rho, Rac and Cdc42, decreased in vitro migration. When HPC pretreated with LT or toxin,B were transplanted into mice, homing to the bone marrow was impaired, whereas C2I-C3 treatment did not alter HPC homing. However, in a competitive hematopoietic repopulation experiment in C57BL/6 mice, pretreatment of bone marrow cells with any of the inhibitors, including the Rho inhibitor C2I-C3, resulted in suppressed donor-type hematopoiesis. Our data indicate that whereas Rac supports HPC cell cycling, migration, short-term homing and hematopoietic regeneration, Rho coordinates down-regulation of HPC migration and is required for hematopoietic regeneration. [source] Proteomic analysis of the response of the human neutrophil-like cell line NB-4 after exposure to anthrax lethal toxinPROTEOMICS - CLINICAL APPLICATIONS, Issue 10 2007Jun X. Wheeler Abstract We used 2-D DIGE to analyze the early response of NB-4 cells, a human promyelotic leukemia cell line, exposed to lethal toxin from Bacillus anthracis at the proteome level. After a 2,h exposure, cells were still viable and 43% of spots (n,=,1042) showed a significant change in protein level. We identified 59 spots whose expression had changed significantly, and these reflected cytoskeleton damage, mitochondrial lysis and endoplasmic reticulum stress. Actin filament assembly was disrupted as evidenced by an increase in both actin subunits and phosphorylated cofilin, whilst levels of tropomyosin, tropomodulin and actin related protein 2/3 complex subunit decreased. Lower levels of ATP synthase subunits and mitochondrial inner membrane protein were identified as markers of mitochondrial lysis. Levels of various stress response proteins rose and, uniquely, levels of Ca2+ binding proteins such as translationally controlled tumor protein rose and hippocalcin-like protein 1 decreased. This response may have mitigated effects brought about by mitochondrial lysis and endoplasmic reticulum stress, and delayed or prevented apoptosis in NB-4 cells. These results resemble findings of similar proteomics studies in murine macrophages, although quantitative differences were observed. [source] Anthrax lethal toxin promotes dephosphorylation of TTP and formation of processing bodiesCELLULAR MICROBIOLOGY, Issue 4 2010Edith M. C. Chow Summary Anthrax lethal toxin (LeTx) is composed of protective antigen (PA) and lethal factor (LF) , PA is the receptor-binding moiety and LF is a protease that cleaves mitogen-activated protein kinase kinases (MAPKKs). LeTx subverts the immune response to Bacillus anthracis in several ways, such as downregulating interleukin-8 (IL-8) by increasing the rate of IL-8 mRNA degradation. Many transcripts are regulated through cis -acting elements that bind proteins that either impede or promote degradation. Some of these RNA-binding proteins are regulated by MAPKs and previous work has demonstrated that interfering with MAPK signalling decreases the half-life of IL-8 mRNA. Here, we have localized a segment within the IL-8 3, untranslated region responsible for LeTx-induced transcript destabilization and show that this is caused by inhibition of the p38, ERK and JNK pathways. TTP, an RNA-binding protein involved in IL-8 mRNA decay, became hypophosphorylated in LeTx-treated cells and knock-down of TTP prevented LeTx from destabilizing the IL-8 transcript. Cells that were treated with LeTx exhibited increased localization of TTP to Processing bodies, which are structures that accumulate transcripts targeted for degradation. We furthermore observed that LeTx promoted the formation of Processing bodies, revealing a link between the toxin and a major mRNA decay pathway. [source] Anthrax toxins inhibit immune cell chemotaxis by perturbing chemokine receptor signallingCELLULAR MICROBIOLOGY, Issue 4 2007Silvia Rossi Paccani Summary Pathogenic strains of Bacillus anthracis produce two potent toxins, lethal toxin (LT), a metalloprotease that cleaves mitogen-activated protein kinase kinases, and oedema toxin (ET), a calcium/calmodulin-dependent adenylate cyclase. Emerging evidence indicates a role for both toxins in suppressing the initiation of both innate and adaptive immune responses, which are essential to keep the infection under control. Here we show that LT and ET inhibit chemotaxis of T-cells and macrophages by subverting signalling by both CXC and CC chemokine receptors. The data highlight a novel strategy of immunosuppression by B. anthracis based on inhibition of immune cell homing. [source] Murine splenocytes produce inflammatory cytokines in a MyD88-dependent response to Bacillus anthracis sporesCELLULAR MICROBIOLOGY, Issue 2 2007Ian J. Glomski Summary Bacillus anthracis is a sporulating Gram-positive bacterium that causes the disease anthrax. The highly stable spore is the infectious form of the bacterium that first interacts with the prospective host, and thus the interaction between the host and spore is vital to the development of disease. We focused our study on the response of murine splenocytes to the B. anthracis spore by using paraformaldehyde-inactivated spores (FIS), a treatment that prevents germination and production of products associated with vegetative bacilli. We found that murine splenocytes produce IL-12 and IFN-, in response to FIS. The IL-12 was secreted by CD11b cells, which functioned to induce the production of IFN-, by CD49b (DX5) NK cells. The production of these cytokines by splenocytes was not dependent on TLR2, TLR4, TLR9, Nod1, or Nod2; however, it was dependent on the signalling adapter protein MyD88. Unlike splenocytes, Nod1- and Nod2-transfected HEK cells were activated by FIS. Both IL-12 and IFN-, secretion were inhibited by treatment with B. anthracis lethal toxin. These observations suggest that the innate immune system recognizes spores with a MyD88-dependent receptor (or receptors) and responds by secreting inflammatory cytokines, which may ultimately aid in resisting infection. [source] Modification of epithelial cell barrier permeability and intercellular junctions by Clostridium sordellii lethal toxinsCELLULAR MICROBIOLOGY, Issue 7 2006Catherine Boehm Summary Clostridium sordellii lethal toxin (LT) is a glucosyltransferase which inactivates small GTPases from the Rho and Ras families. In the present work, we studied the effects of two variants, LT82 and LT9048, on the integrity of epithelial cell barrier using polarized MCCD (Mouse Cortical Collecting Duct) and MDCK (Madin-Darby Canine Kidney) cells. Our results demonstrate for the first time that LTs have very limited effects on tight junctions. In contrast, we show that both toxins modified the paracellular permeability within 2,4 h. Concomitantly LT82 and LT9048 induced a disorganization of basolateral actin filaments, without modifying apical actin. Both toxins mainly altered adherens junctions by removing E-cadherin-catenin complexes from the membrane to the cytosol. Similar effects on adherens junctions have been observed with other toxins, which directly or indirectly depolymerize actin. Thereby, Rac, a common substrate of both LTs, might play a central role in LT-dependent adherens junction alteration. Here, we show that adherens junction perturbation induced by LTs results neither from a direct effect of toxins on adherens junction proteins nor from an actin-independent Rac pathway, but rather from a Rac-dependent disorganization of basolateral actin cytoskeleton. This further supports that a dynamic equilibrium of cortical actin filaments is essential for functional E-cadherin organization in epithelia. [source] Structure Determination of an Organometallic 1-(Diazenylaryl)ethanol: A Novel Toxin Subclass from the Web of the Spider Nephila clavipesCHEMISTRY & BIODIVERSITY, Issue 6 2004Maurício, Ribeiro Marques A novel chemical subclass of toxin, [1-(3-diazenylphenyl)ethanol]iron, was identified among the compounds present in the web of the spider Nephila clavipes. This type of compound is not common among natural products, mainly in spider-venom toxins; it was shown to be a potent paralytic and/or lethal toxin applied by the spider over its web to ensure prey capture only by topical application. The structure was elucidated by means of ESI mass spectrometry, 1H-NMR spectroscopy, high-resolution (HR) mass spectrometry, and ICP spectrometry. The structure of [1-(3-diazenylphenyl)ethanol]iron and the study of its insecticidal action may be used as a starting point for the development of new drugs for pest control in agriculture. [source] Effect of Clostridium perfringens epsilon toxin on MDCK cellsFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2 2001Erika Borrmann Abstract Epsilon toxin is one of the major lethal toxins produced by Clostridium perfringens type D and B. It is responsible for a rapidly fatal disease in sheep and other farm animals. Many facts have been published about the physical properties and the biological activities of the toxin, but the molecular mechanism of the action inside the cells remains unclear. We have found that the C. perfringens epsilon toxin caused a significant decrease of the cell numbers and a significant enlargement of the mean cell volume of MDCK cells. The flow cytometric analysis of DNA content revealed the elongation of the S phase and to a smaller extent of the G2+M phase of toxin-treated MDCK cells in comparison to untreated MDCK cells. The results of ultrastructural studies showed that the mitosis is disturbed and blocked at a very early stage, and confirmed the toxin influence on the cell cycle of MDCK cells. [source] Small peptides, big world: biotechnological potential in neglected bioactive peptides from arthropod venoms,JOURNAL OF PEPTIDE SCIENCE, Issue 11 2005Adriano M. C. Pimenta Abstract Until recently, a toxinologist's tasks involved the search for highly toxic or lethal toxins in animal venoms that could explain the harmful effects in clinically observed symptoms. Most of these toxins were put on evidence using a function to structure approach, in which a biological phenomena observation usually guided the isolation and characterization of the causative molecule. Paving this way, many toxins were promptly purified because of their readily observed effect. Nevertheless, small molecules with micro-effects that are not easily visualized can be relatively neglected or poorly studied. This situation has changed now with the advent of the sensitivity, resolution and accuracy of techniques such as mass spectrometry and proteomic approaches used in toxinology. Taking advantage of these methodologies, small peptides with ,newly exploited' biological activities such as vasoactive, hormone-like, antimicrobial and others have been recently given much more attention, enlarging the known repertoire of bioactive molecules found in animal venoms. This article aims to review current knowledge on small biologically active peptides (<3 kDa) found in arthropod venoms and discuss their potentialities as new drug candidates or therapeutic lead compounds. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [source] Modification of epithelial cell barrier permeability and intercellular junctions by Clostridium sordellii lethal toxinsCELLULAR MICROBIOLOGY, Issue 7 2006Catherine Boehm Summary Clostridium sordellii lethal toxin (LT) is a glucosyltransferase which inactivates small GTPases from the Rho and Ras families. In the present work, we studied the effects of two variants, LT82 and LT9048, on the integrity of epithelial cell barrier using polarized MCCD (Mouse Cortical Collecting Duct) and MDCK (Madin-Darby Canine Kidney) cells. Our results demonstrate for the first time that LTs have very limited effects on tight junctions. In contrast, we show that both toxins modified the paracellular permeability within 2,4 h. Concomitantly LT82 and LT9048 induced a disorganization of basolateral actin filaments, without modifying apical actin. Both toxins mainly altered adherens junctions by removing E-cadherin-catenin complexes from the membrane to the cytosol. Similar effects on adherens junctions have been observed with other toxins, which directly or indirectly depolymerize actin. Thereby, Rac, a common substrate of both LTs, might play a central role in LT-dependent adherens junction alteration. Here, we show that adherens junction perturbation induced by LTs results neither from a direct effect of toxins on adherens junction proteins nor from an actin-independent Rac pathway, but rather from a Rac-dependent disorganization of basolateral actin cytoskeleton. This further supports that a dynamic equilibrium of cortical actin filaments is essential for functional E-cadherin organization in epithelia. [source] | ||||||||||||||||