http://www.mdpi.com/journal/toxins/special_issues/toxins-novel-properties/ Dear Colleagues, Compounds expressed by microbes and plants originally described to possess toxic activities (e.g., cytotoxins, neurotoxins, enterotoxins, etc.) have proven to be remarkably multifunctional molecules. For example, the capacity of Shiga toxins, a family of cytotoxins expressed by enteric pathogens, to act as ribosome-inactivating proteins was characterized in the 1980’s. Yet, it has recently been shown that in addition to protein synthesis inhibition, Shiga toxins are capable of: i) mediating membrane curvature and invagination; ii) triggering protein kinase signaling cascades upon membrane receptor binding; iii) being routed to multiple intracellular compartments including lysosomes, the endoplasmic reticulum, and nuclear membranes; iv) mediating transcytotic transport across polarized epithelial monolayers without cytotoxicity; v) activating the ribotoxic stress response leading to MAPK activation; vi) activating the ER stress pathway leading to induction of transcription factors and chaperone expression; vii) inducing chemokine expression by human intestinal epithelial cells; viii) inducing cytokine expression by macrophages; ix) altering normal cell cycling; x) altering cytoskeletal elements; and xi) inducing apoptosis in some cell types and inhibiting spontaneous apoptosis in other cells. Thus, these “toxins” activate a myriad of biological processes, many of which may contribute to pathogenesis. The ability to genetically manipulate toxin genes to produce toxoids (mutations that attenuate toxicity) has revealed many heretofore uncharacterized biological properties of toxins. In this special issue of Toxins, we will explore recently described novel properties of well-characterized toxins, discuss their role in pathogenesis, and review potential clinical applications to prevent or ameliorate toxin-mediated disease. Prof. Dr. Vernon L. Tesh Guest Editor Submission All manuscripts should be submitted to toxins@mdpi.com with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website. Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed Open Access monthly journal published by MDPI. Please visit the Instructions for Authors page before submitting a manuscript. Article Processing Charges (APC) for publication in this Open Access journal will be waived for well-prepared manuscripts submitted before 30 June 2010. English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections. http://www.mdpi.com/2072-6651/3/10/1263/ Ribosome-inactivating (ribotoxic) xenobiotics are capable of using cleavage and modification to damage 28S ribosomal RNA, which leads to translational arrest. The blockage of global protein synthesis predisposes rapidly dividing tissues, including gut epithelia, to damage from various pathogenic processes, including epithelial inflammation and carcinogenesis. In particular, mucosal exposure to ribotoxic stress triggers integrated processes that are important for barrier regulation and re-constitution to maintain gut homeostasis. In the present study, various experimental models of the mucosal barrier were evaluated for their response to acute and chronic exposure to ribotoxic agents. Specifically, this review focuses on the regulation of epithelial junctions, epithelial transporting systems, epithelial cytotoxicity, and compensatory responses to mucosal insults. The primary aim is to characterize the mechanisms associated with the intestinal epithelial responses induced by ribotoxic stress and to discuss the implications of ribotoxic stressors as chemical modulators of mucosa-associated diseases such as ulcerative colitis and epithelial cancers. http://www.mdpi.com/2072-6651/3/10/1263/ Thu, 20 Oct 2011 00:00:00 CEST Toxins 2011-10-20 3 10 Review 1263 1277 2072-6651 Mucosal Injuries due to Ribosome-Inactivating Stress and the Compensatory Responses of the Intestinal Epithelial Barrier 2011-10-20 doi: 10.3390/toxins3101263 Yuseok Moon http://www.mdpi.com/2072-6651/3/7/884/ Pertussis toxin (PTX) is a typical A-B toxin. The A-protomer (S1 subunit) exhibits ADP-ribosyltransferase activity. The B-oligomer consists of four subunits (S2 to S5) and binds extracellular molecules that allow the toxin to enter the cells. The A-protomer ADP-ribosylates the α subunits of heterotrimeric Gi/o proteins, resulting in the receptors being uncoupled from the Gi/o proteins. The B-oligomer binds proteins expressed on the cell surface, such as Toll-like receptor 4, and activates an intracellular signal transduction cascade. Thus, PTX modifies cellular responses by at least two different signaling pathways; ADP-ribosylation of the Gαi/o proteins by the A-protomer (Gi/o protein-dependent action) and the interaction of the B-oligomer with cell surface proteins (Gi/o protein-independent action). http://www.mdpi.com/2072-6651/3/7/884/ Fri, 15 Jul 2011 00:00:00 CEST Toxins 2011-07-15 3 7 Article 884 899 2072-6651 Gi/o Protein-Dependent and -Independent Actions of Pertussis Toxin (PTX) 2011-07-15 doi: 10.3390/toxins3070884 Supachoke Mangmool Hitoshi Kurose http://www.mdpi.com/2072-6651/3/5/453/ Ricin is a highly toxic type II ribosome-inactivating protein that has potential as a biochemical weapon and as the toxic component of immunotoxins. The unfolded protein response (UPR) is a survival response that helps cells to recover from endoplasmic reticulum (ER) stress. Failure to recover from ER stress leads to apoptosis. In yeast, ricin-A-chain (RTA), the enzymatic component of ricin, inhibits UPR. Our goals were to determine if RTA inhibits UPR in two epithelial cell lines and if this affects RTA cytotoxicity. RTA alone did not induce UPR. However, RTA inhibited both phosphorylation of inositol-requiring enzyme 1 (IRE1) and splicing of X-box binding protein1 mRNA by the UPR-inducing agent tunicamycin (Tm). The ability of dithiothreitol (DTT) to activate eukaryotic translation initiation factor 2 alpha (eIF2α), a component of the PERK pathway, was also inhibited by RTA. Treatment with RTA in combination with Tm or DTT inhibited protein synthesis more than either agent did alone in one cell line, while caspase cleavage was enhanced by the treatment combination in both cell lines. These data indicate that RTA is more cytotoxic when UPR is inhibited. This ability to inhibit UPR may enhance the potential of RTA as a therapeutic immunotoxin in solid tumors. http://www.mdpi.com/2072-6651/3/5/453/ Tue, 10 May 2011 00:00:00 CEST Toxins 2011-05-10 3 5 Article 453 468 2072-6651 Inhibition of the Unfolded Protein Response by Ricin A-Chain Enhances Its Cytotoxicity in Mammalian Cells 2011-05-10 doi: 10.3390/toxins3050453 Chao-Ting Wang Amanda E. Jetzt Ju-Shun Cheng Wendie S. Cohick http://www.mdpi.com/2072-6651/2/8/1997/ We have shown previously that neurons in the mouse spinal cord express Gb3. We show in this article that distribution of anti-Gb3-Ab reactivity occurs in many different types of neurons of different areas of the central nervous system (CNS). The immunoreactive neurons are in olfactory bulbs, cerebral cortex, hippocampus, striatum, amygdala, thalamus, hypothalamus, cerebellum, and medulla oblongata. In several different circumventricular organs where vessels do not have the blood-brain-barrier (BBB) structure, anti-Gb3-Ab is not positive for vessel structures, while neurons at these regions are positive. Also, within the ventricular area, ependymal cells in the third ventricle express Gb3, as revealed by anti-Gb3-Ab staining and intensity analysis. http://www.mdpi.com/2072-6651/2/8/1997/ Wed, 04 Aug 2010 00:00:00 CEST Toxins 2010-08-04 2 8 Article 1997 2006 2072-6651 Distribution of Gb3 Immunoreactivity in the Mouse Central Nervous System 2010-08-04 doi: 10.3390/toxins2081997 Fumiko Obata Tom Obrig http://www.mdpi.com/2072-6651/2/7/1881/ Anthrax edema toxin (ET), a powerful adenylyl cyclase, is an important virulence factor of Bacillus anthracis. Until recently, only a modest amount of research was performed to understand the role this toxin plays in the organism’s immune evasion strategy. A new wave of studies have begun to elucidate the effects this toxin has on a variety of host cells. While efforts have been made to illuminate the effect ET has on cells of the adaptive immune system, such as T cells, the greatest focus has been on cells of the innate immune system, particularly the macrophage. Here we discuss the immunoevasive activities that ET exerts on macrophages, as well as new research on the effects of this toxin on B cells. http://www.mdpi.com/2072-6651/2/7/1881/ Mon, 19 Jul 2010 00:00:00 CEST Toxins 2010-07-19 2 7 Review 1881 1897 2072-6651 Emergence of Anthrax Edema Toxin as a Master Manipulator of Macrophage and B Cell Functions 2010-07-19 doi: 10.3390/toxins2071881 Bryan T. Gnade Scott T. Moen Ashok K. Chopra Johnny W. Peterson Linsey A. Yeager http://www.mdpi.com/2072-6651/2/6/1515/ Despite efforts to improve hygenic conditions and regulate food and drinking water safety, the enteric pathogens, Shiga toxin-producing Escherichia coli (STEC) and Shigella dysenteriae serotype 1 remain major public health concerns due to widespread outbreaks and the severity of extra-intestinal diseases they cause, including acute renal failure and central nervous system complications. Shiga toxins are the key virulence factors expressed by these pathogens mediating extra-intestinal disease. Delivery of the toxins to the endoplasmic reticulum (ER) results in host cell protein synthesis inhibition, activation of the ribotoxic stress response, the ER stress response, and in some cases, the induction of apoptosis. Intrinsic and/or extrinsic apoptosis inducing pathways are involved in executing cell death following intoxication. In this review we provide an overview of the current understanding Shiga toxin intracellular trafficking, host cellular responses to the toxin and ER stress-induced apoptosis with an emphasis on recent findings. http://www.mdpi.com/2072-6651/2/6/1515/ Thu, 17 Jun 2010 00:00:00 CEST Toxins 2010-06-17 2 6 Review 1515 1535 2072-6651 Shiga Toxins: Intracellular Trafficking to the ER Leading to Activation of Host Cell Stress Responses 2010-06-17 doi: 10.3390/toxins2061515 Lee Cherla Tesh http://www.mdpi.com/2072-6651/2/6/1500/ Ricin exhibits well characterized ribotoxic actions that lead to the inhibition of protein synthesis and the phosphorylation of stress activated protein kinases (SAPKs). Proinflammatory effects of ricin are thought to be caused by upregulation of genes encoding proinflammatory transcripts as a result of the activation of c-Jun N-terminal kinase (JNK) and p38 MAPK. We reported previously that macrophages and interleukin-1β (IL-1β) signaling are required for murine host immune responses to ricin delivered to the lungs. Here we report that ricin-mediated IL-1β release from bone-marrow derived macrophages is dependent on the NALP3 inflammasome, a scaffolding complex that mediates pro-IL-1β cleavage to active IL-1β by caspase-1. Release of IL-1β from macrophages was suppressed by the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC) and high extracellular K+, which are two agents known to inhibit NALP3/cryopyrin/CIAS1 inflammasome formation. By employing inhibitors of p38 MAPK and JNK, we demonstrated that ricin-mediated release of IL-1β was enhanced, rather than suppressed, by inhibition of SAPK phosphorylation. In contrast, proteasomal inhibitors bortezomib and MG-132 completely suppressed ricin-induced IL-1β release from macrophages. These data suggest that ricin-mediated translational inhibition itself, by fostering the disappearance of labile protein(s) that normally suppress inflammasome formation, may constitute the mechanism underlying IL-1-dependent inflammatory signaling by ricin. http://www.mdpi.com/2072-6651/2/6/1500/ Thu, 17 Jun 2010 00:00:00 CEST Toxins 2010-06-17 2 6 Article 1500 1514 2072-6651 Ricin Toxin Activates the NALP3 Inflammasome 2010-06-17 doi: 10.3390/toxins2061500 Lindauer Wong Magun http://www.mdpi.com/2072-6651/2/6/1357/ The hypothalamic-pituitary-adrenal (HPA) axis activation and glucocorticoid responses are critical for survival from a number of bacterial, viral and toxic insults, demonstrated by the fact that removal of the HPA axis or GR blockade enhances mortality rates. Replacement with synthetic glucocorticoids reverses these effects by providing protection against lethal effects. Glucocorticoid resistance/insensitivity is a common problem in the treatment of many diseases. Much research has focused on the molecular mechanism behind this resistance, but an area that has been neglected is the role of infectious agents and toxins. We have recently shown that the anthrax lethal toxin is able to repress glucocorticoid receptor function. Data suggesting that the glucocorticoid receptor may be a target for a variety of toxins is reviewed here. These studies have important implications for glucocorticoid therapy. http://www.mdpi.com/2072-6651/2/6/1357/ Wed, 09 Jun 2010 00:00:00 CEST Toxins 2010-06-09 2 6 Review 1357 1380 2072-6651 The Glucocorticoid Receptor: A Revisited Target for Toxins 2010-06-09 doi: 10.3390/toxins2061357 Webster Marketon Sternberg http://www.mdpi.com/2072-6651/2/6/1300/ The trichothecene mycotoxin deoxynivalenol (DON) is commonly encountered in human cereal foods throughout the world as a result of infestation of grains in the field and in storage by the fungus Fusarium. Significant questions remain regarding the risks posed to humans from acute and chronic DON ingestion, and how to manage these risks without imperiling access to nutritionally important food commodities. Modulation of the innate immune system appears particularly critical to DON’s toxic effects. Specifically, DON induces activation of mitogen-activated protein kinases (MAPKs) in macrophages and monocytes, which mediate robust induction of proinflammatory gene expression—effects that can be recapitulated in intact animals. The initiating mechanisms for DON-induced ribotoxic stress response appear to involve the (1) activation of constitutive protein kinases on the damaged ribosome and (2) autophagy of the chaperone GRP78 with consequent activation of the ER stress response. Pathological sequelae resulting from chronic low dose exposure include anorexia, impaired weight gain, growth hormone dysregulation and aberrant IgA production whereas acute high dose exposure evokes gastroenteritis, emesis and a shock-like syndrome. Taken together, the capacity of DON to evoke ribotoxic stress in mononuclear phagocytes contributes significantly to its acute and chronic toxic effects in vivo. It is anticipated that these investigations will enable the identification of robust biomarkers of effect that will be applicable to epidemiological studies of the human health effects of this common mycotoxin. http://www.mdpi.com/2072-6651/2/6/1300/ Tue, 01 Jun 2010 00:00:00 CEST Toxins 2010-06-01 2 6 Review 1300 1317 2072-6651 Deoxynivalenol-Induced Proinflammatory Gene Expression: Mechanisms and Pathological Sequelae 2010-06-01 doi: 10.3390/toxins2061300 Pestka