Toxins

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Open AccessArticle

Effects of Bread Making and Wheat Germ Addition on the Natural Deoxynivalenol Content in Bread

by Isabel Giménez, Jesús Blesa, Marta Herrera and Agustín Ariño

Toxins 2014, 6(1), 394-401; https://doi.org/10.3390/toxins6010394 - 21 Jan 2014

Cited by 15 | Viewed by 7157

Deoxynivalenol (DON, vomitoxin) is a type-B trichothecene mycotoxin produced by several field fungi such as Fusarium graminearum and Fusarium culmorum and known to have various toxic effects. This study investigated the effect of the bread making process on the stability of DON in [...] Read more.

Deoxynivalenol (DON, vomitoxin) is a type-B trichothecene mycotoxin produced by several field fungi such as Fusarium graminearum and Fusarium culmorum and known to have various toxic effects. This study investigated the effect of the bread making process on the stability of DON in common bread and wheat germ-enriched bread using naturally contaminated ingredients at the level of 560 µg/kg. The concentration of DON and its evolution during bread making were determined by immunoaffinity column cleanup followed by liquid chromatography with diode array detection (HPLC-DAD). During the bread making process, DON was reduced by 2.1% after fermentation and dropped by 7.1% after baking, reaching a maximum reduction of 19.8% in the crust as compared with a decrease of 5.6% in the crumb. The addition of 15% wheat germ to the dough did not affect DON stability during bread making, showing an apparent increase of 3.5% after fermentation and a reduction by 10.2% after baking. Full article

(This article belongs to the Special Issue Recent Advances and Perspectives in Deoxynivalenol Research)

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Open AccessArticle

Active Immunity Induced by Passive IgG Post-Exposure Protection against Ricin

by Charles Chen Hu, Junfei Yin, Damon Chau, John W. Cherwonogrodzky and Wei-Gang Hu

Toxins 2014, 6(1), 380-393; https://doi.org/10.3390/toxins6010380 - 21 Jan 2014

Cited by 5 | Viewed by 6847

Abstract

Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab’)2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were [...] Read more.

Therapeutic antibodies can confer an instant protection against biothreat agents when administered. In this study, intact IgG and F(ab’)2 from goat anti-ricin hyperimmune sera were compared for the protection against lethal ricin mediated intoxication. Similar ricin-binding affinities and neutralizing activities in vitro were observed between IgG and F(ab’)2 when compared at the same molar concentration. In a murine ricin intoxication model, both IgG and F(ab’)2 could rescue 100% of the mice by one dose (3 nmol) administration of antibodies 1 hour after 5 × LD50 ricin challenge. Nine days later, when the rescued mice received a second ricin challenge (5 × LD50), only the IgG-treated mice survived; the F(ab’)2-treated mice did not. The experimental design excluded the possibility of residual goat IgG responsible for the protection against the second ricin challenge. Results confirmed that the active immunity against ricin in mice was induced quickly following the passive delivery of a single dose of goat IgG post-exposure. Furthermore, it was demonstrated that the induced active immunity against ricin in mice lasted at least 5 months. Therefore, passive IgG therapy not only provides immediate protection to the victim after ricin exposure, but also elicits an active immunity against ricin that subsequently results in long term protection. Full article

(This article belongs to the Special Issue Toxin-Antibody Interactions)

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Open AccessReview

A Review of the Evidence that Ochratoxin A Is an Nrf2 Inhibitor: Implications for Nephrotoxicity and Renal Carcinogenicity

by Alice Limonciel and Paul Jennings

Toxins 2014, 6(1), 371-379; https://doi.org/10.3390/toxins6010371 - 20 Jan 2014

Cited by 108 | Viewed by 10819

Abstract

Several studies have demonstrated that ochratoxin A (OTA) inhibits the nuclear factor, erythroid 2-like 2 (Nrf2) oxidative stress response pathway. At the cellular level this would attenuate (i) glutathione synthesis; (ii) recycling of oxidised glutathione; (iii) activity of oxidoreductases; and (iv) phase II [...] Read more.

Several studies have demonstrated that ochratoxin A (OTA) inhibits the nuclear factor, erythroid 2-like 2 (Nrf2) oxidative stress response pathway. At the cellular level this would attenuate (i) glutathione synthesis; (ii) recycling of oxidised glutathione; (iii) activity of oxidoreductases; and (iv) phase II metabolism inducibility. The effects combined would render the cell and tissue more vulnerable to oxidative stress. Indeed, Nrf2 knock out animals exhibit increased susceptibility to various types of chemical-induced injury. Several studies have shown that OTA exposure can inhibit Nrf2 responses. Such an action would initially lead to increased susceptibility to both physiological and chemical-induced cell stress. However, chronic exposure to OTA may also act as a selective pressure for somatic mutations in Nrf2 or its inhibitor Keap-1, leading to constitutive Nrf2 activation. Nrf2 overexpression confers a survival advantage and is often associated with cancer cell survival. Here we review the evidence for OTA’s role as an Nrf2 inhibitor and discuss the implications of this mechanism in nephrotoxicity and carcinogenicity. Full article

(This article belongs to the Special Issue Recent Advances in Ochratoxins Research)

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Open AccessArticle

Neuromuscular Activity of Micrurus laticollaris (Squamata: Elapidae) Venom in Vitro

by Alejandro Carbajal-Saucedo, Rafael Stuani Floriano, Cháriston André Dal Belo, Alejandro Olvera-Rodríguez, Alejandro Alagón and Léa Rodrigues-Simioni

Toxins 2014, 6(1), 359-370; https://doi.org/10.3390/toxins6010359 - 17 Jan 2014

Cited by 12 | Viewed by 6895

Abstract

In this work, we have examined the neuromuscular activity of Micrurus laticollaris (Mexican coral snake) venom (MLV) in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations, the MLV induced an irreversible concentration- and time-dependent (1–30 µg/mL) neuromuscular blockade, with 50% blockade occurring [...] Read more.

In this work, we have examined the neuromuscular activity of Micrurus laticollaris (Mexican coral snake) venom (MLV) in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations, the MLV induced an irreversible concentration- and time-dependent (1–30 µg/mL) neuromuscular blockade, with 50% blockade occurring between 8 and 30 min. Muscle contractures evoked by exogenous acetylcholine were completely abolished by MLV, whereas those of KCl were also significantly altered (86% ± 11%, 53% ± 11%, 89% ± 5% and 89% ± 7% for one, three, 10 and 30 µg of venom/mL, respectively; n = 4; p < 0.05). In mouse phrenic nerve-diaphragm preparations, MLV (1–10 µg/mL) promoted a slight increase in the amplitude of twitch-tension (3 µg/mL), followed by neuromuscular blockade (n = 4); the highest concentration caused complete inhibition of the twitches (time for 50% blockade = 26 ± 3 min), without exhibiting a previous neuromuscular facilitation. The venom (3 µg/mL) induced a biphasic modulation in the frequency of miniature end-plate potentials (MEPPs)/min, causing a significant increase after 15 min, followed by a decrease after 60 min (from 17 ± 1.4 (basal) to 28 ± 2.5 (t₁₅) and 12 ± 2 (t₆₀)). The membrane resting potential of mouse diaphragm preparations pre-exposed or not to d-tubocurarine (5 µg/mL) was also significantly less negative with MLV (10 µg/mL). Together, these results indicate that M. laticollaris venom induces neuromuscular blockade by a combination of pre- and post-synaptic activities. Full article

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Open AccessReview

Regulating Toxin-Antitoxin Expression: Controlled Detonation of Intracellular Molecular Timebombs

by Finbarr Hayes and Barbara Kędzierska

Toxins 2014, 6(1), 337-358; https://doi.org/10.3390/toxins6010337 - 15 Jan 2014

Cited by 76 | Viewed by 9283

Abstract

Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, [...] Read more.

Genes for toxin-antitoxin (TA) complexes are widely disseminated in bacteria, including in pathogenic and antibiotic resistant species. The toxins are liberated from association with the cognate antitoxins by certain physiological triggers to impair vital cellular functions. TAs also are implicated in antibiotic persistence, biofilm formation, and bacteriophage resistance. Among the ever increasing number of TA modules that have been identified, the most numerous are complexes in which both toxin and antitoxin are proteins. Transcriptional autoregulation of the operons encoding these complexes is key to ensuring balanced TA production and to prevent inadvertent toxin release. Control typically is exerted by binding of the antitoxin to regulatory sequences upstream of the operons. The toxin protein commonly works as a transcriptional corepressor that remodels and stabilizes the antitoxin. However, there are notable exceptions to this paradigm. Moreover, it is becoming clear that TA complexes often form one strand in an interconnected web of stress responses suggesting that their transcriptional regulation may prove to be more intricate than currently understood. Furthermore, interference with TA gene transcriptional autoregulation holds considerable promise as a novel antibacterial strategy: artificial release of the toxin factor using designer drugs is a potential approach to induce bacterial suicide from within. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System)

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Open AccessArticle

Stereoselective Luche Reduction of Deoxynivalenol and Three of Its Acetylated Derivatives at C8

by Philipp Fruhmann, Christian Hametner, Hannes Mikula, Gerhard Adam, Rudolf Krska and Johannes Fröhlich

Toxins 2014, 6(1), 325-336; https://doi.org/10.3390/toxins6010325 - 10 Jan 2014

Cited by 11 | Viewed by 14049

Abstract

The trichothecene mycotoxin deoxynivalenol (DON) is a well known and common contaminant in food and feed. Acetylated derivatives and other biosynthetic precursors can occur together with the main toxin. A key biosynthetic step towards DON involves an oxidation of the 8-OH group of [...] Read more.

The trichothecene mycotoxin deoxynivalenol (DON) is a well known and common contaminant in food and feed. Acetylated derivatives and other biosynthetic precursors can occur together with the main toxin. A key biosynthetic step towards DON involves an oxidation of the 8-OH group of 7,8-dihydroxycalonectrin. Since analytical standards for the intermediates are not available and these intermediates are therefore rarely studied, we aimed for a synthetic method to invert this reaction, making a series of calonectrin-derived precursors accessible. We did this by developing an efficient protocol for stereoselective Luche reduction at C8. This method was used to access 3,7,8,15-tetrahydroxyscirpene, 3-deacetyl-7,8-dihydroxycalonectrin, 15-deacetyl-7,8-dihydroxycalonectrin and 7,8-dihydroxycalonectrin, which were characterized using several NMR techniques. Beside the development of a method which could basically be used for all type B trichothecenes, we opened a synthetic route towards different acetylated calonectrins. Full article

(This article belongs to the Special Issue Recent Advances and Perspectives in Deoxynivalenol Research)

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Graphical abstract

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Open AccessReview

Toxin-Antitoxin Systems as Multilevel Interaction Systems

by Nathalie Goeders and Laurence Van Melderen

Toxins 2014, 6(1), 304-324; https://doi.org/10.3390/toxins6010304 - 10 Jan 2014

Cited by 183 | Viewed by 17213

Abstract

Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to [...] Read more.

Toxin-antitoxin (TA) systems are small genetic modules usually composed of a toxin and an antitoxin counteracting the activity of the toxic protein. These systems are widely spread in bacterial and archaeal genomes. TA systems have been assigned many functions, ranging from persistence to DNA stabilization or protection against mobile genetic elements. They are classified in five types, depending on the nature and mode of action of the antitoxin. In type I and III, antitoxins are RNAs that either inhibit the synthesis of the toxin or sequester it. In type II, IV and V, antitoxins are proteins that either sequester, counterbalance toxin activity or inhibit toxin synthesis. In addition to these interactions between the antitoxin and toxin components (RNA-RNA, protein-protein, RNA-protein), TA systems interact with a variety of cellular factors, e.g., toxins target essential cellular components, antitoxins are degraded by RNAses or ATP-dependent proteases. Hence, TA systems have the capacity to interact with each other at different levels. In this review, we will discuss the different interactions in which TA systems are involved and their implications in TA system functions and evolution. Full article

(This article belongs to the Special Issue Toxin-Antitoxin System)

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Open AccessArticle

Immunohistochemical Approach to Study Cylindrospermopsin Distribution in Tilapia (Oreochromis niloticus) under Different Exposure Conditions

by Remedios Guzmán-Guillén, Daniel Gutiérrez-Praena, María De los Ángeles Risalde, Rosario Moyano, Ana Isabel Prieto, Silvia Pichardo, Ángeles Jos, Vitor Vasconcelos and Ana María Cameán

Toxins 2014, 6(1), 283-303; https://doi.org/10.3390/toxins6010283 - 8 Jan 2014

Cited by 11 | Viewed by 8538

Abstract

Cylindrospermopsin (CYN) is a cytotoxic cyanotoxin produced by several species of freshwater cyanobacteria (i.e., Aphanizomenon ovalisporum). CYN is a tricyclic alkaloid combined with a guanidine moiety. It is well known that CYN inhibits both protein and glutathione synthesis, and also [...] Read more.

Cylindrospermopsin (CYN) is a cytotoxic cyanotoxin produced by several species of freshwater cyanobacteria (i.e., Aphanizomenon ovalisporum). CYN is a tricyclic alkaloid combined with a guanidine moiety. It is well known that CYN inhibits both protein and glutathione synthesis, and also induces genotoxicity and the alteration of different oxidative stress biomarkers. Although the liver and kidney appear to be the main target organs for this toxin based on previous studies, CYN also affects other organs. In the present study, we studied the distribution of CYN in fish (Oreochromis niloticus) under two different exposure scenarios using immunohistochemical (IHC) techniques. In the first method, fish were exposed acutely by intraperitoneal injection or by gavage to 200 µg pure CYN/Kg body weight (bw), and euthanized after 24 h or five days of exposure. In the second method, fish were exposed by immersion to lyophilized A. ovalisporum CYN-producing cells using two concentration levels (10 or 100 µg/L) for two different exposure times (7 or 14 days). The IHC was carried out in liver, kidney, intestine, and gills of fish. Results demonstrated a similar pattern of CYN distribution in both experimental methods. The organ that presented the most immunopositive results was the liver, followed by the kidney, intestine, and gills. Moreover, the immunolabeling signal intensified with increasing time in both assays, confirming the delayed toxicity of CYN, and also with the increment of the dose, as it is shown in the sub-chronic assay. Thus, IHC is shown to be a valuable technique to study CYN distribution in these organisms. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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Open AccessArticle

The E. coli CNF1 as a Pioneering Therapy for the Central Nervous System Diseases

by Sara Travaglione, Stefano Loizzo, Giulia Ballan, Carla Fiorentini and Alessia Fabbri

Toxins 2014, 6(1), 270-282; https://doi.org/10.3390/toxins6010270 - 7 Jan 2014

Cited by 11 | Viewed by 7145

Abstract

The Cytotoxic Necrotizing Factor 1 (CNF1), a protein toxin from pathogenic E. coli, modulates the Rho GTPases, thus, directing the organization of the actin cytoskeleton. In the nervous system, the Rho GTPases play a key role in several processes, controlling the morphogenesis [...] Read more.

The Cytotoxic Necrotizing Factor 1 (CNF1), a protein toxin from pathogenic E. coli, modulates the Rho GTPases, thus, directing the organization of the actin cytoskeleton. In the nervous system, the Rho GTPases play a key role in several processes, controlling the morphogenesis of dendritic spines and synaptic plasticity in brain tissues. This review is focused on the peculiar property of CNF1 to enhance brain plasticity in in vivo animal models of central nervous system (CNS) diseases, and on its possible application in therapy. Full article

(This article belongs to the Special Issue Cytotoxic Necrotizing Factors)

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Open AccessArticle

Methylglyoxal (MG) and Cerebro-Renal Interaction: Does Long-Term Orally Administered MG Cause Cognitive Impairment in Normal Sprague-Dawley Rats?

by Kimio Watanabe, Kana Okada, Ryoji Fukabori, Yoshimitsu Hayashi, Koichi Asahi, Hiroyuki Terawaki, Kazuto Kobayashi, Tsuyoshi Watanabe and Masaaki Nakayama

Toxins 2014, 6(1), 254-269; https://doi.org/10.3390/toxins6010254 - 7 Jan 2014

Cited by 23 | Viewed by 7721

Abstract

Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG [...] Read more.

Methylglyoxal (MG), one of the uremic toxins, is a highly reactive alpha-dicarbonyl compound. Recent clinical studies have demonstrated the close associations of cognitive impairment (CI) with plasma MG levels and presence of kidney dysfunction. Therefore, the present study aims to examine whether MG is a direct causative substance for CI development. Eight-week-old male Sprague-Dawley (SD) rats were divided into two groups: control (n = 9) and MG group (n = 10; 0.5% MG in drinking water), and fed a normal diet for 12 months. Cognitive function was evaluated by two behavioral tests (object exploration test and radial-arm maze test) in early (4–6 months of age) and late phase (7–12 months of age). Serum MG was significantly elevated in the MG group (495.8 ± 38.1 vs. 244.8 ± 28.2 nM; p < 0.001) at the end of study. The groups did not differ in cognitive function during the course of study. No time-course differences were found in oxidative stress markers between the two groups, while, antioxidants such as glutathione peroxidase and superoxide dismutase activities were significantly increased in the MG group compared to the control. Long-term MG administration to rats with normal kidney function did not cause CI. A counter-balanced activation of the systemic anti-oxidant system may offset the toxicity of MG in this model. Pathogenetic significance of MG for CI requires further investigation. Full article

(This article belongs to the Special Issue Uremic Toxins)

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Open AccessArticle

Simultaneous Effect of Temperature and Irradiance on Growth and Okadaic Acid Production from the Marine Dinoflagellate Prorocentrum belizeanum

by Lorenzo López-Rosales, Juan Jose Gallardo-Rodríguez, Asterio Sánchez-Mirón, María Del Carmen Cerón-García, El Hassan Belarbi, Francisco García-Camacho and Emilio Molina-Grima

Toxins 2014, 6(1), 229-253; https://doi.org/10.3390/toxins6010229 - 3 Jan 2014

Cited by 40 | Viewed by 8693

Abstract

Benthic marine dioflagellate microalgae belonging to the genus Prorocentrum are a major source of okadaic acid (OA), OA analogues and polyketides. However, dinoflagellates produce these valuable toxins and bioactives in tiny quantities, and they grow slowly compared to other commercially used microalgae. This [...] Read more.

Benthic marine dioflagellate microalgae belonging to the genus Prorocentrum are a major source of okadaic acid (OA), OA analogues and polyketides. However, dinoflagellates produce these valuable toxins and bioactives in tiny quantities, and they grow slowly compared to other commercially used microalgae. This hinders evaluation in possible large-scale applications. The careful selection of producer species is therefore crucial for success in a hypothetical scale-up of culture, as are appropriate environmental conditions for optimal growth. A clone of the marine toxic dinoflagellate P. belizeanum was studied in vitro to evaluate its capacities to grow and produce OA as an indicator of general polyketide toxin production under the simultaneous influence of temperature (T) and irradiance (I₀). Three temperatures and four irradiance levels were tested (18, 25 and 28 °C; 20, 40, 80 and 120 µE·m⁻²·s⁻¹), and the response variables measured were concentration of cells, maximum photochemical yield of photosystem II (PSII), pigments and OA. Experiments were conducted in T-flasks, since their parallelepipedal geometry proved ideal to ensure optically thin cultures, which are essential for reliable modeling of growth-irradiance curves. The net maximum specific growth rate (µ_m) was 0.204 day⁻¹ at 25 °C and 40 µE·m⁻²·s⁻¹. Photo-inhibition was observed at I₀ > 40 μEm⁻²s⁻¹, leading to culture death at 120 µE·m⁻²·s⁻¹and 28 °C. Cells at I₀ ≥ 80 µE·m⁻²·s⁻¹were photoinhibited irrespective of the temperature assayed. A mechanistic model for µ_m-I₀ curves and another empirical model for relating µ_m-T satisfactorily interpreted the growth kinetics obtained. ANOVA for responses of PSII maximum photochemical yield and pigment profile has demonstrated that P. belizeanum is extremely light sensitive. The pool of photoprotective pigments (diadinoxanthin and dinoxanthin) and peridinin was not able to regulate the excessive light-absorption at high I₀-T. OA synthesis in cells was decoupled from optimal growth conditions, as OA overproduction was observed at high temperatures and when both temperature and irradiance were low. T-flask culture observations were consistent with preliminary assays outdoors. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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Open AccessArticle

Experimental Basis for the High Oral Toxicity of Dinophysistoxin 1: A Comparative Study of DSP

by Diego A. Fernández, M. Carmen Louzao, María Fraga, Natalia Vilariño, Mercedes R. Vieytes and Luis M. Botana

Toxins 2014, 6(1), 211-228; https://doi.org/10.3390/toxins6010211 - 3 Jan 2014

Cited by 32 | Viewed by 8374

Abstract

Okadaic acid (OA) and its analogues, dinophysistoxin 1 (DTX1) and dinophysistoxin 2 (DTX2), are lipophilic and heat-stable marine toxins produced by dinoflagellates, which can accumulate in filter-feeding bivalves. These toxins cause diarrheic shellfish poisoning (DSP) in humans shortly after the ingestion of contaminated [...] Read more.

Okadaic acid (OA) and its analogues, dinophysistoxin 1 (DTX1) and dinophysistoxin 2 (DTX2), are lipophilic and heat-stable marine toxins produced by dinoflagellates, which can accumulate in filter-feeding bivalves. These toxins cause diarrheic shellfish poisoning (DSP) in humans shortly after the ingestion of contaminated seafood. Studies carried out in mice indicated that DSP poisonous are toxic towards experimental animals with a lethal oral dose 2–10 times higher than the intraperitoneal (i.p.) lethal dose. The focus of this work was to study the absorption of OA, DTX1 and DTX2 through the human gut barrier using differentiated Caco-2 cells. Furthermore, we compared cytotoxicity parameters. Our data revealed that cellular viability was not compromised by toxin concentrations up to 1 μM for 72 h. Okadaic acid and DTX2 induced no significant damage; nevertheless, DTX1 was able to disrupt the integrity of Caco-2 monolayers at concentrations above 50 nM. In addition, confocal microscopy imaging confirmed that the tight-junction protein, occludin, was affected by DTX1. Permeability assays revealed that only DTX1 was able to significantly cross the intestinal epithelium at concentrations above 100 nM. These data suggest a higher oral toxicity of DTX1 compared to OA and DTX2. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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Open AccessReview

Cytotoxic Proteins and Therapeutic Targets in Severe Cutaneous Adverse Reactions

by Shih-Chi Su and Wen-Hung Chung

Toxins 2014, 6(1), 194-210; https://doi.org/10.3390/toxins6010194 - 3 Jan 2014

Cited by 45 | Viewed by 11943

Abstract

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are rare but life-threatening conditions induced mainly by a variety of drugs. Until now, an effective treatment for SJS/TEN still remains unavailable. Current studies have suggested that the [...] Read more.

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN), are rare but life-threatening conditions induced mainly by a variety of drugs. Until now, an effective treatment for SJS/TEN still remains unavailable. Current studies have suggested that the pathobiology of drug-mediated SJS and TEN involves major histocompatibility class (MHC) I-restricted activation of cytotoxic T lymphocytes (CTLs) response. This CTLs response requires several cytotoxic signals or mediators, including granulysin, perforin/granzyme B, and Fas/Fas ligand, to trigger extensive keratinocyte death. In this article, we will discuss the cytotoxic mechanisms of severe cutaneous adverse reactions and their potential applications on therapeutics for this disease. Full article

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Open AccessArticle

Neurological Disorders in a Murine Model of Chronic Renal Failure

by Jean-Marc Chillon, François Brazier, Philippe Bouquet and Ziad A. Massy

Toxins 2014, 6(1), 180-193; https://doi.org/10.3390/toxins6010180 - 3 Jan 2014

Cited by 9 | Viewed by 6365

Abstract

Cardiovascular disease is highly prevalent in patients with chronic renal failure (CRF). However, data on the impact of CRF on the cerebral circulatory system are scarce—despite the fact that stroke is the third most common cause of cardiovascular death in people with CRF. [...] Read more.

Cardiovascular disease is highly prevalent in patients with chronic renal failure (CRF). However, data on the impact of CRF on the cerebral circulatory system are scarce—despite the fact that stroke is the third most common cause of cardiovascular death in people with CRF. In the present study, we examined the impact of CRF on behavior (anxiety), recognition and ischemic stroke severity in a well-defined murine model of CRF. We did not observe any significant increases between CRF mice and non-CRF mice in terms of anxiety. In contrast, CRF mice showed lower levels of anxiety in some tests. Recognition was not impaired (vs. controls) after 6 weeks of CRF but was impaired after 10 weeks of CRF. Chronic renal failure enhances the severity of ischemic stroke, as evaluated by the infarct volume size in CRF mice after 34 weeks of CRF. Furthermore, neurological test results in non-CRF mice tended to improve in the days following ischemic stroke, whereas the results in CRF mice tended to worsen. In conclusion, we showed that a murine model of CRF is suitable for evaluating uremic toxicity and the associated neurological disorders. Our data confirm the role of uremic toxicity in the genesis of neurological abnormalities (other than anxiety). Full article

(This article belongs to the Special Issue Uremic Toxins)

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Open AccessArticle

Effects of the Amino Acid Constituents of Microcystin Variants on Cytotoxicity to Primary Cultured Rat Hepatocytes

by Kumiko Shimizu, Tomoharu Sano, Reiji Kubota, Norihiro Kobayashi, Maiko Tahara, Tomoko Obama, Naoki Sugimoto, Tetsuji Nishimura and Yoshiaki Ikarashi

Toxins 2014, 6(1), 168-179; https://doi.org/10.3390/toxins6010168 - 30 Dec 2013

Cited by 33 | Viewed by 6892

Abstract

Microcystins, which are cyclic heptapeptides produced by some cyanobacterial species from algal blooms, strongly inhibit serine/threonine protein phosphatase and are known as hepatotoxins. Microcystins have many structural variations, yet insufficient information is available on the differences in the cytotoxic potentials among the structural [...] Read more.

Microcystins, which are cyclic heptapeptides produced by some cyanobacterial species from algal blooms, strongly inhibit serine/threonine protein phosphatase and are known as hepatotoxins. Microcystins have many structural variations, yet insufficient information is available on the differences in the cytotoxic potentials among the structural variants. In this study, the cytotoxicities of 16 microcystin variants at concentrations of 0.03–10 μg/mL to primary cultured rat hepatocytes were determined by measuring cellular ATP content, and subsequently determined by their 50% inhibitory concentration (IC₅₀). Differences in the amino acid constituents were associated with differences in cytotoxic potential. [d-Asp³, Z-Dhb⁷] microcystin-LR exhibited the strongest cytotoxicity at IC₅₀ of 0.053 μg/mL among the microcystin variants tested. Furthermore, [d-Asp³, Z-Dhb⁷] microcystin-HtyR was also highly cytotoxic. These results suggest that both d-Asp and Z-Dhb residues are important in determining the cytotoxic potential of microcystin variants. Full article

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Open AccessArticle

Fates of Microcystis aeruginosa Cells and Associated Microcystins in Sediment and the Effect of Coagulation Process on Them

by Xiaoguo Chen, Huiyi Xiang, Yue Hu, Yang Zhang, Liao Ouyang and Meiying Gao

Toxins 2014, 6(1), 152-167; https://doi.org/10.3390/toxins6010152 - 30 Dec 2013

Cited by 13 | Viewed by 7404

Abstract

During toxic Microcystis aeruginosa blooms, large amounts of cells can enter sediment through natural settlement, and coagulation treatment used to control water blooms can enhance the accumulation of cells. However, the current understanding of the fates of these cells and associated microcystins (MCs), [...] Read more.

During toxic Microcystis aeruginosa blooms, large amounts of cells can enter sediment through natural settlement, and coagulation treatment used to control water blooms can enhance the accumulation of cells. However, the current understanding of the fates of these cells and associated microcystins (MCs), as well as the effect of coagulation treatment on these factors, is limited. The results of the present study show that Microcystis aeruginosa cells in sediment were steadily decomposed under experimental conditions, and that they completely disappeared within 28 days. The major MCs released from settled cells were immediately degraded in sediment, and microbial degradation may be the main mechanism involved in this process. Coagulation treatment with PAC (polyaluminium chloride) + sepiolite can efficiently remove Microcystis aeruginosa cells from the water column and prevent their re-invasion. Furthermore, coagulation treatment with PAC + sepiolite had no significant effect on the release and decomposition of MCs and, thus, will not enhance the MCs pollution. However, coagulation treatment can accelerate the nutrient cycle by enhancing the settlement of cells. More attention should be paid to the effect on nutrient cycle when coagulation treatment is used for restoration of aquatic ecosystems. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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Open AccessReview

Cytotoxic and Cytolytic Cnidarian Venoms. A Review on Health Implications and Possible Therapeutic Applications

by Gian Luigi Mariottini and Luigi Pane

Toxins 2014, 6(1), 108-151; https://doi.org/10.3390/toxins6010108 - 27 Dec 2013

Cited by 73 | Viewed by 10992

Abstract

The toxicity of Cnidaria is a subject of concern for its influence on human activities and public health. During the last decades, the mechanisms of cell injury caused by cnidarian venoms have been studied utilizing extracts from several Cnidaria that have been tested [...] Read more.

The toxicity of Cnidaria is a subject of concern for its influence on human activities and public health. During the last decades, the mechanisms of cell injury caused by cnidarian venoms have been studied utilizing extracts from several Cnidaria that have been tested in order to evaluate some fundamental parameters, such as the activity on cell survival, functioning and metabolism, and to improve the knowledge about the mechanisms of action of these compounds. In agreement with the modern tendency aimed to avoid the utilization of living animals in the experiments and to substitute them with in vitro systems, established cell lines or primary cultures have been employed to test cnidarian extracts or derivatives. Several cnidarian venoms have been found to have cytotoxic properties and have been also shown to cause hemolytic effects. Some studied substances have been shown to affect tumour cells and microorganisms, so making cnidarian extracts particularly interesting for their possible therapeutic employment. The review aims to emphasize the up-to-date knowledge about this subject taking in consideration the importance of such venoms in human pathology, the health implications and the possible therapeutic application of these natural compounds. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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Open AccessArticle

Surface Plasmon Resonance Biosensor Method for Palytoxin Detection Based on Na⁺,K⁺-ATPase Affinity

by Amparo Alfonso, María-José Pazos, Andrea Fernández-Araujo, Araceli Tobio, Carmen Alfonso, Mercedes R. Vieytes and Luis M. Botana

Toxins 2014, 6(1), 96-107; https://doi.org/10.3390/toxins6010096 - 27 Dec 2013

Cited by 17 | Viewed by 7367

Abstract

Palytoxin (PLTX), produced by dinoflagellates from the genus Ostreopsis was first discovered, isolated, and purified from zoanthids belonging to the genus Palythoa. The detection of this toxin in contaminated shellfish is essential for human health preservation. A broad range of studies indicate [...] Read more.

Palytoxin (PLTX), produced by dinoflagellates from the genus Ostreopsis was first discovered, isolated, and purified from zoanthids belonging to the genus Palythoa. The detection of this toxin in contaminated shellfish is essential for human health preservation. A broad range of studies indicate that mammalian Na⁺,K⁺-ATPase is a high affinity cellular receptor for PLTX. The toxin converts the pump into an open channel that stimulates sodium influx and potassium efflux. In this work we develop a detection method for PLTX based on its binding to the Na⁺,K⁺-ATPase. The method was developed by using the phenomenon of surface plasmon resonance (SPR) to monitor biomolecular reactions. This technique does not require any labeling of components. The interaction of PLTX over immobilized Na⁺,K⁺-ATPase is quantified by injecting different concentrations of toxin in the biosensor and checking the binding rate constant (k_obs). From the representation of k_obs versus PLTX concentration, the kinetic equilibrium dissociation constant (K_D) for the PLTX-Na⁺,K⁺-ATPase association can be calculated. The value of this constant is K_D = 6.38 × 10⁻⁷ ± 6.67 × 10⁻⁸ M PLTX. In this way the PLTX-Na⁺,K⁺-ATPase association was used as a suitable method for determination of the toxin concentration in a sample. This method represents a new and useful approach to easily detect the presence of PLTX-like compounds in marine products using the mechanism of action of these toxins and in this way reduce the use of other more expensive and animal based methods. Full article

(This article belongs to the Collection Marine and Freshwater Toxins)

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286 KiB

Open AccessArticle

Durum Wheat (Triticum Durum Desf.) Lines Show Different Abilities to Form Masked Mycotoxins under Greenhouse Conditions

by Martina Cirlini, Silvia Generotti, Andrea Dall'Erta, Pietro Lancioni, Gianluca Ferrazzano, Andrea Massi, Gianni Galaverna and Chiara Dall'Asta

Toxins 2014, 6(1), 81-95; https://doi.org/10.3390/toxins6010081 - 24 Dec 2013

Cited by 28 | Viewed by 7829

Abstract

Deoxynivalenol (DON) is the most prevalent trichothecene in Europe and its occurrence is associated with infections of Fusarium graminearum and F. culmorum, causal agents of Fusarium head blight (FHB) on wheat. Resistance to FHB is a complex character and high variability occurs [...] Read more.

Deoxynivalenol (DON) is the most prevalent trichothecene in Europe and its occurrence is associated with infections of Fusarium graminearum and F. culmorum, causal agents of Fusarium head blight (FHB) on wheat. Resistance to FHB is a complex character and high variability occurs in the relationship between DON content and FHB incidence. DON conjugation to glucose (DON-3-glucoside, D3G) is the primary plant mechanism for resistance towards DON accumulation. Although this mechanism has been already described in bread wheat and barley, no data are reported so far about durum wheat, a key cereal in the pasta production chain. To address this issue, the ability of durum wheat to detoxify and convert deoxynivalenol into D3G was studied under greenhouse controlled conditions. Four durum wheat varieties (Svevo, Claudio, Kofa and Neodur) were assessed for DON-D3G conversion; Sumai 3, a bread wheat variety carrying a major QTL for FHB resistance (QFhs.ndsu-3B), was used as a positive control. Data reported hereby clearly demonstrate the ability of durum wheat to convert deoxynivalenol into its conjugated form, D3G. Full article

(This article belongs to the Special Issue Recent Advances and Perspectives in Deoxynivalenol Research)

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506 KiB

Open AccessArticle

Chronic Illness Associated with Mold and Mycotoxins: Is Naso-Sinus Fungal Biofilm the Culprit?

by Joseph H. Brewer, Jack D. Thrasher and Dennis Hooper

Toxins 2014, 6(1), 66-80; https://doi.org/10.3390/toxins6010066 - 24 Dec 2013

Cited by 19 | Viewed by 28675

Abstract

It has recently been demonstrated that patients who develop chronic illness after prior exposure to water damaged buildings (WDB) and mold have the presence of mycotoxins, which can be detected in the urine. We hypothesized that the mold may be harbored internally and [...] Read more.

It has recently been demonstrated that patients who develop chronic illness after prior exposure to water damaged buildings (WDB) and mold have the presence of mycotoxins, which can be detected in the urine. We hypothesized that the mold may be harbored internally and continue to release and/or produce mycotoxins which contribute to ongoing chronic illness. The sinuses are the most likely candidate as a site for the internal mold and mycotoxin production. In this paper, we review the literature supporting this concept. Full article

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315 KiB

Open AccessArticle

Triggering of Suicidal Erythrocyte Death by Penta-O-galloyl-β-d-glucose

by Kousi Alzoubi, Sabina Honisch, Majed Abed and Florian Lang

Toxins 2014, 6(1), 54-65; https://doi.org/10.3390/toxins6010054 - 24 Dec 2013

Cited by 53 | Viewed by 6344

Abstract

The polyphenolic 1,2,3,4,6-penta-O-galloyl-beta-d-glucose from several medicinal herbs triggers apoptosis and has, thus, been proposed for treatment of malignancy. The substance is at least partially effective through caspase activation. In analogy to apoptosis of nucleated cells, erythrocytes may enter suicidal death or [...] Read more.

The polyphenolic 1,2,3,4,6-penta-O-galloyl-beta-d-glucose from several medicinal herbs triggers apoptosis and has, thus, been proposed for treatment of malignancy. The substance is at least partially effective through caspase activation. In analogy to apoptosis of nucleated cells, erythrocytes may enter suicidal death or eryptosis, which is characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Eryptosis is triggered by increase of cytosolic Ca²⁺-activity ([Ca²⁺]i). The sensitivity to [Ca²⁺]i is enhanced by ceramide. The present study explored whether penta-O-galloyl-β-d-glucose stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin V binding, hemolysis from hemoglobin-release, [Ca²⁺]i from Fluo3-fluorescence and ceramide abundance from fluorescent antibodies. A 48-h exposure of human erythrocytes to penta-O-galloyl-β-d-glucose significantly decreased forward scatter (50 µM) and significantly increased annexin V binding (10 µM). Up to 50 µM penta-O-galloyl-β-d-glucose did not significantly modify [Ca²⁺]i. However, the effect of penta-O-galloyl-β-d-glucose (25 µM) induced annexin V binding was slightly, but significantly, blunted by removal of extracellular Ca²⁺, pointing to sensitization of erythrocytes to the scrambling effect of Ca²⁺. Penta-O-galloyl-β-d-glucose (25 µM) further increased ceramide formation. In conclusion, penta-O-galloyl-β-d-glucose stimulates suicidal erythrocyte death or eryptosis, an effect partially due to stimulation of ceramide formation with subsequent sensitization of erythrocytes to Ca²⁺. Full article

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Open AccessArticle

Novel Class of Potential Therapeutics that Target Ricin Retrograde Translocation

by Veronika Redmann, Thomas Gardner, Zerlina Lau, Keita Morohashi, Dan Felsenfeld and Domenico Tortorella

Toxins 2014, 6(1), 33-53; https://doi.org/10.3390/toxins6010033 - 23 Dec 2013

Cited by 8 | Viewed by 5877

Abstract

Ricin toxin, an A-B toxin from Ricinus communis, induces cell death through the inhibition of protein synthesis. The toxin binds to the cell surface via its B chain (RTB) followed by its retrograde trafficking through intracellular compartments to the ER where the [...] Read more.

Ricin toxin, an A-B toxin from Ricinus communis, induces cell death through the inhibition of protein synthesis. The toxin binds to the cell surface via its B chain (RTB) followed by its retrograde trafficking through intracellular compartments to the ER where the A chain (RTA) is transported across the membrane and into the cytosol. Ricin A chain is transported across the ER membrane utilizing cellular proteins involved in the disposal of aberrant ER proteins by a process referred to as retrograde translocation. Given the current lack of therapeutics against ricin intoxication, we developed a high-content screen using an enzymatically attenuated RTA chimera engineered with a carboxy-terminal enhanced green fluorescent protein (RTA_E177Qegfp) to identify compounds that target RTA retrograde translocation. Stabilizing RTA_E177Qegfp through the inclusion of proteasome inhibitor produced fluorescent peri-nuclear granules. Quantitative analysis of the fluorescent granules provided the basis to discover compounds from a small chemical library (2080 compounds) with known bioactive properties. Strikingly, the screen found compounds that stabilized RTA molecules within the cell and several compounds limited the ability of wild type RTA to suppress protein synthesis. Collectively, a robust high-content screen was developed to discover novel compounds that stabilize intracellular ricin and limit ricin intoxication. Full article

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206 KiB

Open AccessArticle

Incidence and Levels of Deoxynivalenol, Fumonisins and Zearalenone Contaminants in Animal Feeds Used in Korea in 2012

by Dong-Ho Kim, In-Hye Lee, Woo-Hyun Do, Woo-Seon Nam, Hua Li, Han-Sub Jang and Chan Lee

Toxins 2014, 6(1), 20-32; https://doi.org/10.3390/toxins6010020 - 23 Dec 2013

Cited by 25 | Viewed by 6273

Abstract

The objective of this study was to evaluate the occurrence and levels of deoxynivalenol (DON), fumonisins B₁ and B₂(FBs), and zearalenone (ZEN) contaminants in animal feeds used in Korea in 2012. Contamination with DON was observed in 91.33% and 53.33% [...] Read more.

The objective of this study was to evaluate the occurrence and levels of deoxynivalenol (DON), fumonisins B₁ and B₂(FBs), and zearalenone (ZEN) contaminants in animal feeds used in Korea in 2012. Contamination with DON was observed in 91.33% and 53.33% in compound feeds and feed ingredients, respectively. Among compound feeds, poultry layer feed (laying) exhibited the highest contaminant level of 1.492 mg/kg. FBscontaminants were present in compound feeds and feed ingredients at 93.33% and 83.33%, respectively. Most poultry broiler (early) feeds were highly contaminated with FBs, and one of these feeds detected the level as 12.823 mg/kg as the highest level. The levels of ZEN in compound feeds and feed ingredients were 71.33% and 47%, respectively. Ninety-eight percent of compound feeds for cattle were contaminated with ZEN, and the highest contamination level of 0.405 mg/kg was observed in cattle fatting feeds. Full article

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Open AccessReview

Deoxynivalenol: A Major Player in the Multifaceted Response of Fusarium to Its Environment

by Kris Audenaert, Adriaan Vanheule, Monica Höfte and Geert Haesaert

Toxins 2014, 6(1), 1-19; https://doi.org/10.3390/toxins6010001 - 19 Dec 2013

Cited by 199 | Viewed by 12209

Abstract

The mycotoxin deoxynivalenol (DON), produced by several Fusarium spp., acts as a virulence factor and is essential for symptom development after initial wheat infection. Accumulating evidence shows that the production of this secondary metabolite can be triggered by diverse environmental and cellular signals, [...] Read more.

The mycotoxin deoxynivalenol (DON), produced by several Fusarium spp., acts as a virulence factor and is essential for symptom development after initial wheat infection. Accumulating evidence shows that the production of this secondary metabolite can be triggered by diverse environmental and cellular signals, implying that it might have additional roles during the life cycle of the fungus. Here, we review data that position DON in the saprophytic fitness of Fusarium, in defense and in the primary C and N metabolism of the plant and the fungus. We combine the available information in speculative models on the role of DON throughout the interaction with the host, providing working hypotheses that await experimental validation. We also highlight the possible impact of control measures in the field on DON production and summarize the influence of abiotic factors during processing and storage of food and feed matrices. Altogether, we can conclude that DON is a very important compound for Fusarium to cope with a changing environment and to assure its growth, survival, and production of toxic metabolites in diverse situations. Full article

(This article belongs to the Special Issue Recent Advances and Perspectives in Deoxynivalenol Research)

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Toxins, Volume 6, Issue 1 (January 2014) – 24 articles , Pages 1-401

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