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Toxins, Volume 6, Issue 3 (March 2014), Pages 784-1154

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Research

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Open AccessArticle Nerve Growth Factor from Cobra Venom Inhibits the Growth of Ehrlich Tumor in Mice
Toxins 2014, 6(3), 784-795; doi:10.3390/toxins6030784
Received: 12 November 2013 / Revised: 14 February 2014 / Accepted: 17 February 2014 / Published: 26 February 2014
Cited by 4 | PDF Full-text (543 KB) | HTML Full-text | XML Full-text
Abstract
The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores
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The effects of nerve growth factor (NGF) from cobra venom (cvNGF) on growth of Ehrlich ascites carcinoma (EAC) cells inoculated subcutaneously in mice have been studied. The carcinoma growth slows down, but does not stop, during a course of cvNGF injections and restores after the course has been discontinued. The maximal anti-tumor effect has been observed at a dose of 8 nmoles cvNGF/kg body weight. cvNGF does not impact on lifespan of mice with grafted EAC cells. K252a, a tyrosine kinase inhibitor, attenuates the anti-tumor effect of cvNGF indicating the involvement of TrkA receptors in the process. cvNGF has induced also increase in body weight of the experimental animals. In overall, cvNGF shows the anti-tumor and weight-increasing effects which are opposite to those described for mammalian NGF (mNGF). However in experiments on breast cancer cell line MCF-7 cvNGF showed the same proliferative effects as mNGF and had no cytotoxic action on tumor cells in vitro. These data suggest that cvNGF slows down EAC growth via an indirect mechanism in which TrkA receptors are involved. Full article
(This article belongs to the Section Animal Venoms)
Open AccessArticle Characterization of a Novel BmαTX47 Toxin Modulating Sodium Channels: The Crucial Role of Expression Vectors in Toxin Pharmacological Activity
Toxins 2014, 6(3), 816-829; doi:10.3390/toxins6030816
Received: 4 December 2013 / Revised: 30 December 2013 / Accepted: 20 January 2014 / Published: 26 February 2014
Cited by 3 | PDF Full-text (1589 KB) | HTML Full-text | XML Full-text
Abstract
Long-chain scorpion toxins with four disulfide bridges exhibit various pharmacological features towards the different voltage-gated sodium channel subtypes. However, the toxin production still remains a huge challenge. Here, we reported the effects of different expression vectors on the pharmacological properties of a novel
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Long-chain scorpion toxins with four disulfide bridges exhibit various pharmacological features towards the different voltage-gated sodium channel subtypes. However, the toxin production still remains a huge challenge. Here, we reported the effects of different expression vectors on the pharmacological properties of a novel toxin BmαTX47 from the scorpion Buthus martensii Karsch. The recombinant BmαTX47 was obtained using the expression vector pET-14b and pET-28a, respectively. Pharmacological experiments showed that the recombinant BmαTX47 was a new α-scorpion toxin which could inhibit the fast inactivation of rNav1.2, mNav1.4 and hNav1.5 channels. Importantly, the different expression vectors were found to strongly affect BmαTX47 pharmacological activities while toxins were obtained by the same expression and purification procedures. When 10 µM recombinant BmαTX47 from the pET-28a vector was applied, the values of I5ms/Ipeak for rNav1.2, mNav1.4 and hNav1.5 channels were 44.12% ± 3.17%, 25.40% ± 4.89% and 65.34% ± 3.86%, respectively, which were better than those values of 11.33% ± 1.46%, 15.96% ± 1.87% and 5.24% ± 2.38% for rNav1.2, mNav1.4 and hNav1.5 channels delayed by 10 µM recombinant BmαTX47 from the pET-14b vector. The dose-response experiments further indicated the EC50 values of recombinant BmαTX47 from the pET-28a vector were 7262.9 ± 755.9 nM for rNav1.2 channel and 1005.8 ± 118.6 nM for hNav1.5 channel, respectively. Together, these findings highlighted the important role of expression vectors in scorpion toxin pharmacological properties, which would accelerate the understanding of the structure-function relationships of scorpion toxins and promote the potential application of toxins in the near future. Full article
(This article belongs to the Special Issue Scorpion Toxins)
Open AccessArticle Fusarium Head Blight Control and Prevention of Mycotoxin Contamination in Wheat with Botanicals and Tannic Acid
Toxins 2014, 6(3), 830-849; doi:10.3390/toxins6030830
Received: 24 December 2013 / Revised: 5 February 2014 / Accepted: 13 February 2014 / Published: 26 February 2014
Cited by 6 | PDF Full-text (2116 KB) | HTML Full-text | XML Full-text
Abstract
Suspensions or solutions with 1% of Chinese galls (Galla chinensis, GC) or 1% of tannic acid (TA), inhibited germination of conidia or mycelium growth of Fusarium graminearum (FG) by 98%–100% or by 75%–80%, respectively, whereas dried bark from buckthorn (Frangula
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Suspensions or solutions with 1% of Chinese galls (Galla chinensis, GC) or 1% of tannic acid (TA), inhibited germination of conidia or mycelium growth of Fusarium graminearum (FG) by 98%–100% or by 75%–80%, respectively, whereas dried bark from buckthorn (Frangula alnus, FA) showed no effect at this concentration. In climate chamber experiments where the wheat variety “Apogee” was artificially inoculated with FG and F. crookwellense (FCr) and treated with 5% suspensions of TA, GC and FA, the deoxynivalenol (DON) content in grains was reduced by 81%, 67% and 33%, respectively. In field experiments with two commercial wheat varieties and artificial or semi-natural inoculations, mean DON reductions of 66% (TA) and 58% (FA), respectively, were obtained. Antifungal toxicity can explain the high efficacies of TA and GC but not those of FA. The Fusarium head blight (FHB) and mycotoxin reducing effect of FA is probably due to elicitation of resistance in wheat plants. With semi-natural inoculation, a single FA application in the first half of the flowering period performed best. However, we assume that applications of FA at the end of ear emergence and a treatment, triggered by an infection period, with TA or GC during flowering, might perform better than synthetic fungicides. Full article
(This article belongs to the Special Issue Recent Advances and Perspectives in Deoxynivalenol Research)
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Open AccessArticle Elapid Snake Venom Analyses Show the Specificity of the Peptide Composition at the Level of Genera Naja and Notechis
Toxins 2014, 6(3), 850-868; doi:10.3390/toxins6030850
Received: 3 November 2013 / Revised: 24 January 2014 / Accepted: 5 February 2014 / Published: 28 February 2014
Cited by 6 | PDF Full-text (1208 KB) | HTML Full-text | XML Full-text
Abstract
Elapid snake venom is a highly valuable, but till now mainly unexplored, source of pharmacologically important peptides. We analyzed the peptide fractions with molecular masses up to 10 kDa of two elapid snake venoms—that of the African cobra, N. m. mossambica (genus Naja
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Elapid snake venom is a highly valuable, but till now mainly unexplored, source of pharmacologically important peptides. We analyzed the peptide fractions with molecular masses up to 10 kDa of two elapid snake venoms—that of the African cobra, N. m. mossambica (genus Naja), and the Peninsula tiger snake, N. scutatus, from Kangaroo Island (genus Notechis). A combination of chromatographic methods was used to isolate the peptides, which were characterized by combining complimentary mass spectrometric techniques. Comparative analysis of the peptide compositions of two venoms showed specificity at the genus level. Three-finger (3-F) cytotoxins, bradykinin-potentiating peptides (BPPs) and a bradykinin inhibitor were isolated from the Naja venom. 3-F neurotoxins, Kunitz/basic pancreatic trypsin inhibitor (BPTI)-type inhibitors and a natriuretic peptide were identified in the N. venom. The inhibiting activity of the peptides was confirmed in vitro with a selected array of proteases. Cytotoxin 1 (P01467) from the Naja venom might be involved in the disturbance of cellular processes by inhibiting the cell 20S-proteasome. A high degree of similarity between BPPs from elapid and viperid snake venoms was observed, suggesting that these molecules play a key role in snake venoms and also indicating that these peptides were recruited into the snake venom prior to the evolutionary divergence of the snakes. Full article
(This article belongs to the collection Evolution of Venom Systems)
Open AccessArticle Electrophysiological Characterization of Ts6 and Ts7, K+ Channel Toxins Isolated through an Improved Tityus serrulatus Venom Purification Procedure
Toxins 2014, 6(3), 892-913; doi:10.3390/toxins6030892
Received: 12 December 2013 / Revised: 24 January 2014 / Accepted: 17 February 2014 / Published: 28 February 2014
Cited by 16 | PDF Full-text (1306 KB) | HTML Full-text | XML Full-text
Abstract
In Brazil, Tityus serrulatus (Ts) is the species responsible for most of the scorpion related accidents. Among the Ts toxins, the neurotoxins with action on potassium channels (α-KTx) present high interest, due to their effect in the envenoming process and the ion channel
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In Brazil, Tityus serrulatus (Ts) is the species responsible for most of the scorpion related accidents. Among the Ts toxins, the neurotoxins with action on potassium channels (α-KTx) present high interest, due to their effect in the envenoming process and the ion channel specificity they display. The α-KTx toxins family is the most relevant because its toxins can be used as therapeutic tools for specific target cells. The improved isolation method provided toxins with high resolution, obtaining pure Ts6 and Ts7 in two chromatographic steps. The effects of Ts6 and Ts7 toxins were evaluated in 14 different types of potassium channels using the voltage-clamp technique with two-microelectrodes. Ts6 toxin shows high affinity for Kv1.2, Kv1.3 and Shaker IR, blocking these channels in low concentrations. Moreover, Ts6 blocks the Kv1.3 channel in picomolar concentrations with an IC50 of 0.55 nM and therefore could be of valuable assistance to further designing immunosuppressive therapeutics. Ts7 toxin blocks multiple subtypes channels, showing low selectivity among the channels analyzed. This work also stands out in its attempt to elucidate the residues important for interacting with each channel and, in the near future, to model a desired drug. Full article
(This article belongs to the Special Issue Scorpion Toxins)
Open AccessArticle Immune Checkpoint Blockade in Cancer Treatment: A Double-Edged Sword Cross-Targeting the Host as an “Innocent Bystander”
Toxins 2014, 6(3), 914-933; doi:10.3390/toxins6030914
Received: 27 November 2013 / Revised: 21 January 2014 / Accepted: 18 February 2014 / Published: 3 March 2014
Cited by 16 | PDF Full-text (3904 KB) | HTML Full-text | XML Full-text
Abstract
Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific “immune-related adverse events” (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account
[...] Read more.
Targeted immune checkpoint blockade augments anti-tumor immunity and induces durable responses in patients with melanoma and other solid tumors. It also induces specific “immune-related adverse events” (irAEs). IrAEs mainly include gastrointestinal, dermatological, hepatic and endocrinological toxicities. Off-target effects that arise appear to account for much of the toxicity of the immune checkpoint blockade. These unique “innocent bystander” effects are likely a direct result of breaking immune tolerance upon immune check point blockade and require specific treatment guidelines that include symptomatic therapies or systemic corticosteroids. What do we need going forward to limit immune checkpoint blockade-induced toxicity? Most importantly, we need a better understanding of the roles played by these agents in normal tissues, so that we can begin to predict potentially problematic side effects on the basis of their selectivity profile. Second, we need to focus on the predictive factors of the response and toxicity of the host rather than serially focusing on individual agents. Third, rigorous biomarker-driven clinical trials are needed to further elucidate the mechanisms of both the benefit and toxicity. We will summarize the double-edged sword effect of immunotherapeutics in cancer treatment. Full article
(This article belongs to the collection Toxicity and Therapeutic Interventions in the Immune System)
Open AccessArticle Deoxynivalenol in the Gastrointestinal Tract of Immature Gilts under per os Toxin Application
Toxins 2014, 6(3), 973-987; doi:10.3390/toxins6030973
Received: 7 November 2013 / Revised: 13 February 2014 / Accepted: 17 February 2014 / Published: 5 March 2014
Cited by 14 | PDF Full-text (288 KB) | HTML Full-text | XML Full-text
Abstract
Deoxynivalenol is also known as vomitoxin due to its impact on livestock through interference with animal growth and acceptance of feed. At the molecular level, deoxynivalenol disrupts normal cell function by inhibiting protein synthesis via binding to the ribosome and by activating critical
[...] Read more.
Deoxynivalenol is also known as vomitoxin due to its impact on livestock through interference with animal growth and acceptance of feed. At the molecular level, deoxynivalenol disrupts normal cell function by inhibiting protein synthesis via binding to the ribosome and by activating critical cellular kinases involved in signal transduction related to proliferation, differentiation and apoptosis. Because of concerns related to deoxynivalenol, the United States FDA has instituted advisory levels of 5 µg/g for grain products for most animal feeds and 10 µg/g for grain products for cattle feed. The aim of the study was to determine the effect of low doses of deoxynivalenol applied per os on the presence of this mycotoxin in selected tissues of the alimentary canal of gilts. The study was performed on 39 animals divided into two groups (control, C; n = 21 and experimental, E; n = 18), of 20 kg body weight at the beginning of the experiment. Gilts received the toxin in doses of 12 µg/kg b.w./day (experimental group) or placebo (control group) over a period of 42 days. Three animals from two experimental groups were sacrificed on days 1, 7, 14, 21, 28, 35 and 42, excluding day 1 when only three control group animals were scarified. Tissues samples were prepared for high performance liquid chromatography (HPLC) analyses with the application of solid phase extraction (SPE). The results show that deoxynivalenol doses used in our study, even when applied for a short period, resulted in its presence in gastrointestinal tissues. The highest concentrations of deoxynivalenol reported in small intestine samples ranged from 7.2 (in the duodenum) to 18.6 ng/g (in the ileum) and in large intestine samples from 1.8 (in transverse the colon) to 23.0 ng/g (in the caecum). In liver tissues, the deoxynivalenol contents ranged from 6.7 to 8.8 ng/g. Full article
(This article belongs to the Special Issue Recent Advances and Perspectives in Deoxynivalenol Research)
Open AccessArticle The Venom of the Spider Selenocosmia Jiafu Contains Various Neurotoxins Acting on Voltage-Gated Ion Channels in Rat Dorsal Root Ganglion Neurons
Toxins 2014, 6(3), 988-1001; doi:10.3390/toxins6030988
Received: 27 January 2014 / Revised: 10 February 2014 / Accepted: 17 February 2014 / Published: 5 March 2014
Cited by 4 | PDF Full-text (1495 KB) | HTML Full-text | XML Full-text
Abstract
Selenocosmia jiafu is a medium-sized theraphosid spider and an attractive source of venom, because it can be bred in captivity and it produces large amounts of venom. We performed reversed-phase high-performance liquid chromatography (RP-HPLC) and matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses and
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Selenocosmia jiafu is a medium-sized theraphosid spider and an attractive source of venom, because it can be bred in captivity and it produces large amounts of venom. We performed reversed-phase high-performance liquid chromatography (RP-HPLC) and matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analyses and showed that S. jiafu venom contains hundreds of peptides with a predominant mass of 3000–4500 Da. Patch clamp analyses indicated that the venom could inhibit voltage-gated Na+, K+ and Ca2+ channels in rat dorsal root ganglion (DRG) neurons. The venom exhibited inhibitory effects on tetrodotoxin-resistant (TTX-R) Na+ currents and T-type Ca2+ currents, suggesting the presence of antagonists to both channel types and providing a valuable tool for the investigation of these channels and for drug development. Intra-abdominal injection of the venom had severe toxic effects on cockroaches and caused death at higher concentrations. The LD50 was 84.24 μg/g of body weight in the cockroach. However, no visible symptoms or behavioral changes were detected after intraperitoneal injection of the venom into mice even at doses up to 10 mg/kg body weight. Our results provide a basis for further case-by-case investigations of peptide toxins from this venom. Full article
(This article belongs to the Section Animal Venoms)
Open AccessArticle The Effects of the Toxic Cyanobacterium Limnothrix (Strain AC0243) on Bufo marinus Larvae
Toxins 2014, 6(3), 1021-1035; doi:10.3390/toxins6031021
Received: 31 October 2013 / Revised: 17 February 2014 / Accepted: 20 February 2014 / Published: 6 March 2014
Cited by 3 | PDF Full-text (2466 KB) | HTML Full-text | XML Full-text
Abstract
Limnothrix (strain AC0243) is a cyanobacterium, which has only recently been identified as toxin producing. Under laboratory conditions, Bufo marinus larvae were exposed to 100,000 cells mL−1 of Limnothrix (strain AC0243) live cultures for seven days. Histological examinations were conducted post mortem
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Limnothrix (strain AC0243) is a cyanobacterium, which has only recently been identified as toxin producing. Under laboratory conditions, Bufo marinus larvae were exposed to 100,000 cells mL−1 of Limnothrix (strain AC0243) live cultures for seven days. Histological examinations were conducted post mortem and revealed damage to the notochord, eyes, brain, liver, kidney, pancreas, gastrointestinal tract, and heart. The histopathological results highlight the toxicological impact of this strain, particularly during developmental stages. Toxicological similarities to β-N-Methylamino-L-alanine are discussed. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
Open AccessArticle In-vitro Neurotoxicity of Two Malaysian Krait Species (Bungarus candidus and Bungarus fasciatus) Venoms: Neutralization by Monovalent and Polyvalent Antivenoms from Thailand
Toxins 2014, 6(3), 1036-1048; doi:10.3390/toxins6031036
Received: 15 January 2014 / Revised: 28 February 2014 / Accepted: 7 March 2014 / Published: 12 March 2014
Cited by 4 | PDF Full-text (753 KB) | HTML Full-text | XML Full-text
Abstract
Bungarus candidus and Bungarus fasciatus are two species of krait found in Southeast Asia. Envenoming by these snakes is often characterized by neurotoxicity and, without treatment, causes considerable morbidity and mortality. In this study, the in vitro neurotoxicity of each species, and the
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Bungarus candidus and Bungarus fasciatus are two species of krait found in Southeast Asia. Envenoming by these snakes is often characterized by neurotoxicity and, without treatment, causes considerable morbidity and mortality. In this study, the in vitro neurotoxicity of each species, and the effectiveness of two monovalent antivenoms and a polyvalent antivenom, against the neurotoxic effects of the venoms, were examined in a skeletal muscle preparation. Both venoms caused concentration-dependent inhibition of indirect twitches, and attenuated responses to exogenous nicotinic receptor agonists, in the chick biventer preparation, with B. candidus venom being more potent than B. fasciatus venom. SDS-PAGE and western blot analysis indicated different profiles between the venoms. Despite these differences, most proteins bands were recognized by all three antivenoms. Antivenom, added prior to the venoms, attenuated the neurotoxic effect of the venoms. Interestingly, the respective monovalent antivenoms did not neutralize the effects of the venom from the other Bungarus species indicating a relative absence of cross-neutralization. Addition of a high concentration of polyvalent antivenom, at the t90 time point after addition of venom, partially reversed the neurotoxicity of B. fasciatus venom but not B. candidus venom. The monovalent antivenoms had no significant effect when added at the t90 time point. This study showed that B. candidus and B. fasciatus venoms display marked in vitro neurotoxicity in the chick biventer preparation and administration of antivenoms at high dose is necessary to prevent or reverse neurotoxicity. Full article
(This article belongs to the Section Animal Venoms)
Open AccessArticle Identification of a Key Residue for Oligomerisation and Pore-Formation of Clostridium perfringens NetB
Toxins 2014, 6(3), 1049-1061; doi:10.3390/toxins6031049
Received: 20 December 2013 / Revised: 26 February 2014 / Accepted: 3 March 2014 / Published: 12 March 2014
Cited by 4 | PDF Full-text (1073 KB) | HTML Full-text | XML Full-text
Abstract
Necrotic enteritis toxin B (NetB) is a β-pore-forming toxin produced by Clostridium perfringens and has been identified as a key virulence factor in the pathogenesis of avian necrotic enteritis, a disease causing significant economic damage to the poultry industry worldwide. In this study,
[...] Read more.
Necrotic enteritis toxin B (NetB) is a β-pore-forming toxin produced by Clostridium perfringens and has been identified as a key virulence factor in the pathogenesis of avian necrotic enteritis, a disease causing significant economic damage to the poultry industry worldwide. In this study, site-directed mutagenesis was used to identify amino acids that play a role in NetB oligomerisation and pore-formation. NetB K41H showed significantly reduced toxicity towards LMH cells and human red blood cells relative to wild type toxin. NetB K41H was unable to oligomerise and form pores in liposomes. These findings suggest that NetB K41H could be developed as a genetic toxoid vaccine to protect against necrotic enteritis. Full article
(This article belongs to the Section Bacterial Toxins)
Open AccessArticle Influence of Two Depuration Periods on the Activity and Transcription of Antioxidant Enzymes in Tilapia Exposed to Repeated Doses of Cylindrospermopsin under Laboratory Conditions
Toxins 2014, 6(3), 1062-1079; doi:10.3390/toxins6031062
Received: 12 November 2013 / Revised: 25 February 2014 / Accepted: 27 February 2014 / Published: 13 March 2014
Cited by 6 | PDF Full-text (908 KB) | HTML Full-text | XML Full-text
Abstract
The cyanobacterial toxin Cylindrospermopsin (CYN), a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and
[...] Read more.
The cyanobacterial toxin Cylindrospermopsin (CYN), a potent protein synthesis inhibitor, is increasingly being found in freshwater bodies infested by cyanobacterial blooms worldwide. Moreover, it has been reported to be implicated in human intoxications and animal mortality. Recently, the alteration of the activity and gene expression of some glutathione related enzymes in tilapias (Oreochromis niloticus) exposed to a single dose of CYN has been reported. However, little is known about the effects induced by repeated doses of this toxin in tilapias exposed by immersion and the potential reversion of these biochemical alterations after two different depuration periods (3 or 7 days). In the present study, tilapias were exposed by immersion to repeated doses of a CYN-containing culture of Aphanizomenon ovalisporum during 14 days, and then were subjected to depuration periods (3 or 7 days) in clean water in order to examine the potential reversion of the effects observed. The activity and relative mRNA expression by real-time polymerase chain reaction (PCR) of the antioxidant enzymes glutathione peroxidase (GPx) and soluble glutathione-S-transferases (sGST), and also the sGST protein abundance by Western blot analysis were evaluated in liver and kidney of fish. Results showed significant alterations in most of the parameters evaluated and their recovery after 3 days (GPx activity, sGST relative abundance) or 7 days (GPx gene expression, sGST activity). These findings not only confirm the oxidative stress effects produced in fish by cyanobacterial cells containing CYN, but also show the effectiveness of depuration processes in mitigating the CYN-containing culture toxic effects. Full article
(This article belongs to the collection Marine and Freshwater Toxins)
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Open AccessArticle Zearalenone, an Estrogenic Mycotoxin, Is an Immunotoxic Compound
Toxins 2014, 6(3), 1080-1095; doi:10.3390/toxins6031080
Received: 28 January 2014 / Revised: 27 February 2014 / Accepted: 3 March 2014 / Published: 13 March 2014
Cited by 15 | PDF Full-text (581 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this study was to assess the toxic effects of zearalenone (ZEA) on the immune function. Ovariectomised rats were treated daily by gavage with 3.0 mg/kg of ZEA for 28 days. Body weight gain, food consumption, haemotological parameters, lymphoid organs, and
[...] Read more.
The aim of this study was to assess the toxic effects of zearalenone (ZEA) on the immune function. Ovariectomised rats were treated daily by gavage with 3.0 mg/kg of ZEA for 28 days. Body weight gain, food consumption, haemotological parameters, lymphoid organs, and their cellularities were evaluated. Moreover, acquired immune responses and macrophage activity were also assessed. ZEA promoted reduction in body weight gain, which is not fully explained by diminished food consumption. Despite no effect on haematological parameters, ZEA caused thymic atrophy with histological and thymocyte phenotype changes and decrease in the B cell percentage in the spleen. With respect to acquired and innate immune responses, no statistically significant differences in delayed-type hypersensitivity were noticed; however, in the ZEA-treated rats, antibody production and peroxide release by macrophages were impaired. The observed results could be related to ZEA activity on ERs; thus, ZEA is an immunotoxic compound similar to estrogen and some endocrine disruptors. Full article
Open AccessArticle Stimulation of Erythrocyte Cell Membrane Scrambling by Mushroom Tyrosinase
Toxins 2014, 6(3), 1096-1108; doi:10.3390/toxins6031096
Received: 5 February 2014 / Revised: 24 February 2014 / Accepted: 5 March 2014 / Published: 18 March 2014
Cited by 6 | PDF Full-text (258 KB) | HTML Full-text | XML Full-text
Abstract
Background: Mushroom tyrosinase, a copper containing enzyme, modifies growth and survival of tumor cells. Mushroom tyrosinase may foster apoptosis, an effect in part due to interference with mitochondrial function. Erythrocytes lack mitochondria but are able to undergo apoptosis-like suicidal cell death or eryptosis,
[...] Read more.
Background: Mushroom tyrosinase, a copper containing enzyme, modifies growth and survival of tumor cells. Mushroom tyrosinase may foster apoptosis, an effect in part due to interference with mitochondrial function. Erythrocytes lack mitochondria but are able to undergo apoptosis-like suicidal cell death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling leading to phosphatidylserine-exposure at the erythrocyte surface. Signaling involved in the triggering of eryptosis include increase of cytosolic Ca2+-activity ([Ca2+]i) and activation of sphingomyelinase with subsequent formation of ceramide. The present study explored, whether tyrosinase stimulates eryptosis. Methods: Cell volume has been estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, [Ca2+]i from Fluo3-fluorescence, and ceramide abundance from binding of fluorescent antibodies in flow cytometry. Results: A 24 h exposure to mushroom tyrosinase (7 U/mL) was followed by a significant increase of [Ca2+]i, a significant increase of ceramide abundance, and a significant increase of annexin-V-binding. The annexin-V-binding following tyrosinase treatment was significantly blunted but not abrogated in the nominal absence of extracellular Ca2+. Tyrosinase did not significantly modify forward scatter. Conclusions: Tyrosinase triggers cell membrane scrambling, an effect, at least partially, due to entry of extracellular Ca2+ and ceramide formation. Full article
Open AccessArticle Toxins Produced by Valsa mali var. mali and Their Relationship with Pathogenicity
Toxins 2014, 6(3), 1139-1154; doi:10.3390/toxins6031139
Received: 22 January 2014 / Revised: 11 March 2014 / Accepted: 12 March 2014 / Published: 21 March 2014
Cited by 3 | PDF Full-text (1696 KB) | HTML Full-text | XML Full-text
Abstract
Valsa mali var. mali (Vmm), the causal agent of apple tree canker disease, produces various toxic compounds, including protocatechuic acid, p-hydroxybenzoic acid, p-hydroxyacetophenone, 3-(p-hydroxyphenyl)propanoic acid and phloroglucinol. Here, we examined the relationship between toxin production and the
[...] Read more.
Valsa mali var. mali (Vmm), the causal agent of apple tree canker disease, produces various toxic compounds, including protocatechuic acid, p-hydroxybenzoic acid, p-hydroxyacetophenone, 3-(p-hydroxyphenyl)propanoic acid and phloroglucinol. Here, we examined the relationship between toxin production and the pathogenicity of Vmm strains and determined their bioactivities in several assays, for further elucidating the pathogenesis mechanisms of Vmm and for developing new procedures to control this disease. The toxins were quantified with the high performance liquid chromatography (HPLC) method, and the results showed that the strain with attenuated virulence produced low levels of toxins with only three to four kinds of compounds being detectable. In contrast, higher amounts of toxins were produced by the more aggressive strain, and all five compounds were detected. This indicated a significant correlation between the pathogenicity of Vmm strains and their ability to produce toxins. However, this correlation only existed in planta, but not in vitro. During the infection of Vmm, protocatechuic acid was first detected at three days post inoculation (dpi), and the others at seven or 11 dpi. In addition, all compounds produced noticeable symptoms on host plants at concentrations of 2.5 to 40 mmol/L, with protocatechuic acid being the most effective compound, whereas 3-(p-hydroxyphenyl)propanoic acid or p-hydroxybenzoic acid were the most active compounds on non-host plants. Full article
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Review

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Open AccessReview Overview of Scorpion Species from China and Their Toxins
Toxins 2014, 6(3), 796-815; doi:10.3390/toxins6030796
Received: 13 December 2013 / Revised: 16 January 2014 / Accepted: 18 January 2014 / Published: 26 February 2014
Cited by 9 | PDF Full-text (531 KB) | HTML Full-text | XML Full-text
Abstract
Scorpions are one of the most ancient groups of terrestrial animals. They have maintained a steady morphology over more than 400 million years of evolution. Their venom arsenals for capturing prey and defending against predators may play a critical role in their ancient
[...] Read more.
Scorpions are one of the most ancient groups of terrestrial animals. They have maintained a steady morphology over more than 400 million years of evolution. Their venom arsenals for capturing prey and defending against predators may play a critical role in their ancient and conservative appearance. In the current review, we present the scorpion fauna of China: 53 species covering five families and 12 genera. We also systematically list toxins or genes from Chinese scorpion species, involving eight species covering four families. Furthermore, we review the diverse functions of typical toxins from Chinese scorpion species, involving Na+ channel modulators, K+ channel blockers, antimicrobial peptides and protease inhibitors. Using scorpion species and their toxins from China as an example, we build the bridge between scorpion species and their toxins, which helps us to understand the molecular and functional diversity of scorpion venom arsenal, the dynamic and functional evolution of scorpion toxins, and the potential relationships of scorpion species and their toxins. Full article
(This article belongs to the Special Issue Scorpion Toxins)
Open AccessReview Monoclonal Antibody Therapy and Renal Transplantation: Focus on Adverse Effects
Toxins 2014, 6(3), 869-891; doi:10.3390/toxins6030869
Received: 29 November 2013 / Revised: 7 February 2014 / Accepted: 21 February 2014 / Published: 28 February 2014
Cited by 8 | PDF Full-text (847 KB) | HTML Full-text | XML Full-text
Abstract
A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed
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A series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications. Full article
(This article belongs to the collection Toxicity and Therapeutic Interventions in the Immune System)
Open AccessReview The Aryl Hydrocarbon Receptor-Activating Effect of Uremic Toxins from Tryptophan Metabolism: A New Concept to Understand Cardiovascular Complications of Chronic Kidney Disease
Toxins 2014, 6(3), 934-949; doi:10.3390/toxins6030934
Received: 25 November 2013 / Revised: 19 February 2014 / Accepted: 24 February 2014 / Published: 4 March 2014
Cited by 23 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because
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Patients with chronic kidney disease (CKD) have a higher risk of cardiovascular diseases and suffer from accelerated atherosclerosis. CKD patients are permanently exposed to uremic toxins, making them good candidates as pathogenic agents. We focus here on uremic toxins from tryptophan metabolism because of their potential involvement in cardiovascular toxicity: indolic uremic toxins (indoxyl sulfate, indole-3 acetic acid, and indoxyl-β-d-glucuronide) and uremic toxins from the kynurenine pathway (kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and quinolinic acid). Uremic toxins derived from tryptophan are endogenous ligands of the transcription factor aryl hydrocarbon receptor (AhR). AhR, also known as the dioxin receptor, interacts with various regulatory and signaling proteins, including protein kinases and phosphatases, and Nuclear Factor-Kappa-B. AhR activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin and some polychlorinated biphenyls is associated with an increase in cardiovascular disease in humans and in mice. In addition, this AhR activation mediates cardiotoxicity, vascular inflammation, and a procoagulant and prooxidant phenotype of vascular cells. Uremic toxins derived from tryptophan have prooxidant, proinflammatory, procoagulant, and pro-apoptotic effects on cells involved in the cardiovascular system, and some of them are related with cardiovascular complications in CKD. We discuss here how the cardiovascular effects of these uremic toxins could be mediated by AhR activation, in a “dioxin-like” effect. Full article
(This article belongs to the Special Issue Uremic Toxins)
Open AccessReview Staphylococcal Bicomponent Pore-Forming Toxins: Targets for Prophylaxis and Immunotherapy
Toxins 2014, 6(3), 950-972; doi:10.3390/toxins6030950
Received: 16 December 2013 / Revised: 22 February 2014 / Accepted: 26 February 2014 / Published: 4 March 2014
Cited by 6 | PDF Full-text (348 KB) | HTML Full-text | XML Full-text
Abstract
Staphylococccus aureus represents one of the most challenging human pathogens as well as a common colonizer of human skin and mucosal surfaces. S. aureus causes a wide range of diseases from skin and soft tissue infection (SSTI) to debilitating and life-threatening conditions such
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Staphylococccus aureus represents one of the most challenging human pathogens as well as a common colonizer of human skin and mucosal surfaces. S. aureus causes a wide range of diseases from skin and soft tissue infection (SSTI) to debilitating and life-threatening conditions such as osteomyelitis, endocarditis, and necrotizing pneumonia. The range of diseases reflects the remarkable diversity of the virulence factors produced by this pathogen, including surface antigens involved in the establishment of infection and a large number of toxins that mediate a vast array of cellular responses. The staphylococcal toxins are generally believed to have evolved to disarm the innate immune system, the first line of defense against this pathogen. This review focuses on recent advances on elucidating the biological functions of S. aureus bicomponent pore-forming toxins (BCPFTs) and their utility as targets for preventive and therapeutic intervention. These toxins are cytolytic to a variety of immune cells, primarily neutrophils, as well as cells with a critical barrier function. The lytic activity of BCPFTs towards immune cells implies a critical role in immune evasion, and a number of epidemiological studies and animal experiments relate these toxins to clinical disease, particularly SSTI and necrotizing pneumonia. Antibody-mediated neutralization of this lytic activity may provide a strategy for development of toxoid-based vaccines or immunotherapeutics for prevention or mitigation of clinical diseases. However, certain BCPFTs have been proposed to act as danger signals that may alert the immune system through an inflammatory response. The utility of a neutralizing vaccination strategy must be weighed against such immune-activating potential. Full article
(This article belongs to the collection Toxicity and Therapeutic Interventions in the Immune System)
Open AccessReview Multiple Toxin-Antitoxin Systems in Mycobacterium tuberculosis
Toxins 2014, 6(3), 1002-1020; doi:10.3390/toxins6031002
Received: 19 December 2013 / Revised: 20 February 2014 / Accepted: 24 February 2014 / Published: 6 March 2014
Cited by 30 | PDF Full-text (2015 KB) | HTML Full-text | XML Full-text
Abstract
The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the persistence
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The hallmark of Mycobacterium tuberculosis is its ability to persist for a long-term in host granulomas, in a non-replicating and drug-tolerant state, and later awaken to cause disease. To date, the cellular factors and the molecular mechanisms that mediate entry into the persistence phase are poorly understood. Remarkably, M. tuberculosis possesses a very high number of toxin-antitoxin (TA) systems in its chromosome, 79 in total, regrouping both well-known (68) and novel (11) families, with some of them being strongly induced in drug-tolerant persisters. In agreement with the capacity of stress-responsive TA systems to generate persisters in other bacteria, it has been proposed that activation of TA systems in M. tuberculosis could contribute to its pathogenesis. Herein, we review the current knowledge on the multiple TA families present in this bacterium, their mechanism, and their potential role in physiology and virulence. Full article
(This article belongs to the Special Issue Toxin-Antitoxin System)
Open AccessReview Presence of the Neurotoxin BMAA in Aquatic Ecosystems: What Do We Really Know?
Toxins 2014, 6(3), 1109-1138; doi:10.3390/toxins6031109
Received: 18 January 2014 / Revised: 28 February 2014 / Accepted: 4 March 2014 / Published: 21 March 2014
Cited by 26 | PDF Full-text (448 KB) | HTML Full-text | XML Full-text
Abstract
The neurotoxin β-N-methylamino-l-alanine (BMAA) is suspected to play a role in the neurological diseases amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease. BMAA production by cyanobacteria has been reported and contact with cyanobacteria infested waters or consumption of aquatic organisms are
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The neurotoxin β-N-methylamino-l-alanine (BMAA) is suspected to play a role in the neurological diseases amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease. BMAA production by cyanobacteria has been reported and contact with cyanobacteria infested waters or consumption of aquatic organisms are possible pathways to human exposure. However, there is little consensus regarding whether BMAA is present in cyanobacteria or not, and if so, at what concentrations. The aim of this review is to indicate the current state of knowledge on the presence of BMAA in aquatic ecosystems. Some studies have convincingly shown that BMAA can be present in aquatic samples at the µg/g dry weight level, which is around the detection limit of some equally credible studies in which no BMAA was detected. However, for the majority of the reviewed articles, it was unclear whether BMAA was correctly identified, either because inadequate analytical methods were used, or because poor reporting of analyses made it impossible to verify the results. Poor analysis, reporting and prolific errors have shaken the foundations of BMAA research. First steps towards estimation of human BMAA exposure are to develop and use selective, inter-laboratory validated methods and to correctly report the analytical work. Full article
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