Toxins

11 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Central Effects of Botulinum Neurotoxin—Evidence from Human Studies

by David Weise, Christopher M. Weise and Markus Naumann

Toxins 2019, 11(1), 21; https://doi.org/10.3390/toxins11010021 - 6 Jan 2019

Cited by 61 | Viewed by 6799

For more than three decades, Botulinum neurotoxin (BoNT) has been used to treat a variety of clinical conditions such as spastic or dystonic disorders by inducing a temporary paralysis of the injected muscle as the desired clinical effect. BoNT is known to primarily [...] Read more.

For more than three decades, Botulinum neurotoxin (BoNT) has been used to treat a variety of clinical conditions such as spastic or dystonic disorders by inducing a temporary paralysis of the injected muscle as the desired clinical effect. BoNT is known to primarily act at the neuromuscular junction resulting in a biochemical denervation of the treated muscle. However, recent evidence suggests that BoNT’s pharmacological properties may not only be limited to local muscular denervation at the injection site but may also include additional central effects. In this review, we report and discuss the current evidence for BoNT’s central effects based on clinical observations, neurophysiological investigations and neuroimaging studies in humans. Collectively, these data strongly point to indirect mechanisms via changes to sensory afferents that may be primarily responsible for the marked plastic effects of BoNT on the central nervous system. Importantly, BoNT-related central effects and consecutive modulation and/or reorganization of the brain may not solely be considered “side-effects” but rather an additional therapeutic impact responsible for a number of clinical observations that cannot be explained by merely peripheral actions. Full article

(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)

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23 pages, 2325 KiB

Open AccessEditor’s ChoiceArticle

Interannual Variability of Dinophysis acuminata and Protoceratium reticulatum in a Chilean Fjord: Insights from the Realized Niche Analysis

by Catharina Alves-de-Souza, José Luis Iriarte and Jorge I. Mardones

Toxins 2019, 11(1), 19; https://doi.org/10.3390/toxins11010019 - 5 Jan 2019

Cited by 29 | Viewed by 4526

Abstract

Here, we present the interannual distribution of Dinophysis acuminata and Protoceratium reticulatum over a 10-year period in the Reloncaví Fjord, a highly stratified fjord in southern Chile. A realized subniche approach based on the Within Outlying Mean Index (WitOMI) was used to decompose [...] Read more.

Here, we present the interannual distribution of Dinophysis acuminata and Protoceratium reticulatum over a 10-year period in the Reloncaví Fjord, a highly stratified fjord in southern Chile. A realized subniche approach based on the Within Outlying Mean Index (WitOMI) was used to decompose the species’ realized niche into realized subniches (found within subsets of environmental conditions). The interannual distribution of both D. acuminata and P. reticulatum summer blooms was strongly influenced by climatological regional events, i.e., El Niño Southern Oscillation (ENSO) and the Southern Annual Mode (SAM). The two species showed distinct niche preferences, with blooms of D. acuminata occurring under La Niña conditions (cold years) and low river streamflow whereas P. reticulatum blooms were observed in years of El Niño conditions and positive SAM phase. The biological constraint exerted on the species was further estimated based on the difference between the existing fundamental subniche and the realized subniche. The observed patterns suggested that D. acuminata was subject to strong biological constraint during the studied period, probably as a result of low cell densities of its putative prey (the mixotrophic ciliate Mesodinium cf. rubrum) usually observed in the studied area. Full article

(This article belongs to the Special Issue Dinophysis Toxins: Distribution, Fate in Shellfish and Impacts)

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11 pages, 573 KiB

Open AccessEditor’s ChoiceReview

Pseudomonas Exotoxin Immunotoxins and Anti-Tumor Immunity: From Observations at the Patient’s Bedside to Evaluation in Preclinical Models

by Yasmin Leshem and Ira Pastan

Toxins 2019, 11(1), 20; https://doi.org/10.3390/toxins11010020 - 5 Jan 2019

Cited by 38 | Viewed by 4866

Abstract

Immunotoxins are protein drugs composed of a targeting domain genetically fused to a protein toxin. One killing domain being explored is a truncated Pseudomonas exotoxin A (PE). PE based immunotoxins are designed to kill cells directly by inhibiting their ability to synthesize proteins. [...] Read more.

Immunotoxins are protein drugs composed of a targeting domain genetically fused to a protein toxin. One killing domain being explored is a truncated Pseudomonas exotoxin A (PE). PE based immunotoxins are designed to kill cells directly by inhibiting their ability to synthesize proteins. However, observations from clinical trials suggest that this alone cannot explain their anti-tumor activity. Here we discuss patterns of clinical responses suggesting that PE immunotoxins can provoke anti-tumor immunity, and review murine models that further support this ability. In addition, we describe our preclinical effort to develop a combination therapy of local PE immunotoxins with a systemic anti-CTLA-4 immune check point blocking antibody. The combination eradicated murine tumors and prolonged the survival of mice. Clinical trials that test the ability of immunotoxins to augment immunotherapy have been recently opened. Full article

(This article belongs to the Special Issue Toxins and Immunology)

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14 pages, 13578 KiB

Open AccessEditor’s ChoiceArticle

Phytic Acid Decreases Oxidative Stress and Intestinal Lesions Induced by Fumonisin B₁ and Deoxynivalenol in Intestinal Explants of Pigs

by Elisângela O. Da Silva, Juliana R. Gerez, Miriam S. N. Hohmann, Waldiceu A. Verri, Jr. and Ana Paula F. R. L. Bracarense

Toxins 2019, 11(1), 18; https://doi.org/10.3390/toxins11010018 - 4 Jan 2019

Cited by 49 | Viewed by 4541

Abstract

The purpose of the present study was to investigate the effects of phytic acid (IP6) on morphological and immunohistochemical parameters and oxidative stress response in intestinal explants of pigs exposed to fumonisin B₁ (FB₁) and/or deoxynivalenol (DON). The jejunal explants [...] Read more.

The purpose of the present study was to investigate the effects of phytic acid (IP6) on morphological and immunohistochemical parameters and oxidative stress response in intestinal explants of pigs exposed to fumonisin B₁ (FB₁) and/or deoxynivalenol (DON). The jejunal explants were exposed to the following treatments: vehicle, IP6 5 mM, DON 10 µM, FB₁ 70 µM, DON 10 µM + FB₁ 70 µM, DON 10 µM + IP6 5 mM, FB₁ 70 µM + IP6 5 mM, and DON 10 µM + FB₁ 70 µM + IP6 5 mM. The decrease in villus height and goblet cell density was more evident in DON and DON + FB₁ treatments. In addition, a significant increase in cell apoptosis and cell proliferation and a decrease in E-cadherin expression were observed in the same groups. DON and FB₁ exposure increased cyclooxygenase-2 expression and decreased the cellular antioxidant capacity. An increase in lipid peroxidation was observed in DON- and FB₁-treated groups. IP6 showed beneficial effects, such as a reduction in intestinal morphological changes, cell apoptosis, cell proliferation, and cyclooxygenase-2 expression, and an increase in E-cadherin expression when compared with DON, FB₁ alone, or DON and FB₁ in association. IP6 inhibited oxidative stress and increased the antioxidant capacity in the explants exposed to mycotoxins. Full article

(This article belongs to the Section Mycotoxins)

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15 pages, 3785 KiB

Open AccessEditor’s ChoiceArticle

Lactobacillus bulgaricus or Lactobacillus rhamnosus Suppresses NF-κB Signaling Pathway and Protects against AFB₁-Induced Hepatitis: A Novel Potential Preventive Strategy for Aflatoxicosis?

by Yuanyuan Chen, Ruirui Li, Qiaocheng Chang, Zhihao Dong, Huanmin Yang and Chuang Xu

Toxins 2019, 11(1), 17; https://doi.org/10.3390/toxins11010017 - 4 Jan 2019

Cited by 35 | Viewed by 4628

Abstract

Aflatoxin B₁ (AFB₁), a mycotoxin found in food and feed, is immunotoxic to animals and poses significant threat to the food industry and animal production. The primary target of AFB₁ is the liver. To overcome aflatoxin toxicity, probiotic-mediated detoxification [...] Read more.

Aflatoxin B₁ (AFB₁), a mycotoxin found in food and feed, is immunotoxic to animals and poses significant threat to the food industry and animal production. The primary target of AFB₁ is the liver. To overcome aflatoxin toxicity, probiotic-mediated detoxification has been proposed. In the present study, to investigate the protective effects and molecular mechanisms of Lactobacillus bulgaricus or Lactobacillus rhamnosus against liver inflammatory responses to AFB₁, mice were administered with AFB₁ (300 μg/kg) and/or Lactobacillus intragastrically for 8 weeks. AML12 cells were cultured and treated with AFB₁, BAY 11-7082 (an NF-κB inhibitor), and different concentrations of L. bulgaricus or L. rhamnosus. The body weight, liver index, histopathological changes, biochemical indices, cytokines, cytotoxicity, and activation of the NF-κB signaling pathway were measured. AFB₁ exposure caused changes in liver histopathology and biochemical functions, altered inflammatory response, and activated the NF-κB pathway. Supplementation of L. bulgaricus or L. rhamnosus significantly prevented AFB₁-induced liver injury and alleviated histopathological changes and inflammatory response by decreasing NF-κB p65 expression. The results of in vitro experiments revealed that L. rhamnosus evidently protected against AFB₁-induced inflammatory response and decreased NF-κB p65 expression when compared with L. bulgaricus. These findings indicated that AFB₁ exposure can cause inflammatory response by inducing hepatic injury, and supplementation of L. bulgaricus or L. rhamnosus can produce significant protective effect against AFB₁-induced liver damage and inflammatory response by regulating the activation of the NF-κB signaling pathway. Full article

(This article belongs to the Collection Aflatoxins)

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11 pages, 1133 KiB

Open AccessEditor’s ChoiceArticle

Toxic Indole Diterpenes from Endophyte-Infected Perennial Ryegrass Lolium perenne L.: Isolation and Stability

by Priyanka Reddy, Myrna A. Deseo, Vilnis Ezernieks, Kathryn Guthridge, German Spangenberg and Simone Rochfort

Toxins 2019, 11(1), 16; https://doi.org/10.3390/toxins11010016 - 3 Jan 2019

Cited by 15 | Viewed by 4505

Abstract

The most potent of the indole diterpenes, lolitrem B, is found in perennial ryegrass (Lolium perenne L.) infected with the endophyte Epichloë festucae var. lolii (also termed LpTG-1). Ingestion causes a neurological syndrome in grazing livestock called ryegrass staggers disease. To [...] Read more.

The most potent of the indole diterpenes, lolitrem B, is found in perennial ryegrass (Lolium perenne L.) infected with the endophyte Epichloë festucae var. lolii (also termed LpTG-1). Ingestion causes a neurological syndrome in grazing livestock called ryegrass staggers disease. To enable the rapid development of new forage varieties, the toxicity of lolitrem B and its biosynthetic intermediates needs to be established. However, most of these indole diterpenes are not commercially available; thus, isolation of these compounds is paramount. A concentrated endophyte-infected perennial ryegrass seed extract was subjected to silica flash chromatography followed by preparative HPLC and purification by crystallization resulting in lolitrem B and the intermediate compounds lolitrem E, paspaline and terpendole B. The four-step isolation and purification method resulted in a 25% yield of lolitrem B. After isolation, lolitrem B readily degraded to its biosynthetic intermediate, lolitriol. We also found that lolitrem B can readily degrade depending on the solvent and storage conditions. The facile method which takes into consideration the associated instability of lolitrem B, led to the purification of indole diterpenes in quantities sufficient for use as analytical standards for identification in pastures, and/or for toxicity testing in pasture development programs. Full article

(This article belongs to the Special Issue Fungal Infestations in Humans, Animals, Crops)

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12 pages, 9389 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Cytotoxicity Induced by the Bufadienolides 1α,2α-Epoxyscillirosidine and Lanceotoxin B on Rat Myocardial and Mouse Neuroblastoma Cell Lines

by Danielle Henn, Annette Venter and Christo Botha

Toxins 2019, 11(1), 14; https://doi.org/10.3390/toxins11010014 - 2 Jan 2019

Cited by 7 | Viewed by 2845

Abstract

Consumption of bufadienolide-containing plants are responsible for many livestock mortalities annually. Bufadienolides are divided into two groups; non-cumulative bufadienolides and cumulative bufadienolides. Cumulative bufadienolides are referred to as neurotoxic, as the chronic intoxication with this type of bufadienolide results in a paretic/paralytic syndrome [...] Read more.

Consumption of bufadienolide-containing plants are responsible for many livestock mortalities annually. Bufadienolides are divided into two groups; non-cumulative bufadienolides and cumulative bufadienolides. Cumulative bufadienolides are referred to as neurotoxic, as the chronic intoxication with this type of bufadienolide results in a paretic/paralytic syndrome known as ‘krimpsiekte’. The in vitro cytotoxicity of a non-cumulative bufadienolide, 1α,2α-epoxyscillirosidine, and a cumulative bufadienolide, lanceotoxin B, were compared using the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction) assay after exposing rat myocardial (H9c2) and mouse neuroblastoma (Neuro-2a) cell lines. The effect of these two bufadienolides on cell ultrastructure was also investigated using transmission electron microscopy (TEM). H9c2 cells exhibited greater cytotoxicity when exposed to 1α,2α-epoxyscillirosidine, compared to lanceotoxin B. In contrast, Neuro-2a cells were more susceptible to lanceotoxin B. The EC₅₀ (half maximal effective concentration) of lanceotoxin B exposure of Neuro-2a cells for 24–72 h ranged from 4.4–5.5 µM compared to EC₅₀s of 35.7–37.6 µM for 1α,2α-epoxyscillirosidine exposure of Neuro-2a cells over the same period. 1α,2α-Epoxyscillirosidine induced extensive vacuolization in both cell types, with swollen RER (rough endoplasmic reticulum) and perinuclear spaces. Lanceotoxin B caused swelling of the mitochondria and sequestration of cytoplasmic material within autophagic vesicles. These results corroborate the notion that cumulative bufadienolides are neurotoxic. Full article

(This article belongs to the Collection Toxic and Pharmacological Effect of Plant Toxins)

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18 pages, 1522 KiB

Open AccessEditor’s ChoiceArticle

In Vitro and in Field Response of Different Fungicides against Aspergillus flavus and Fusarium Species Causing Ear Rot Disease of Maize

by Mario Masiello, Stefania Somma, Veronica Ghionna, Antonio Francesco Logrieco and Antonio Moretti

Toxins 2019, 11(1), 11; https://doi.org/10.3390/toxins11010011 - 1 Jan 2019

Cited by 59 | Viewed by 6238

Abstract

Aspergillus flavus, the main aflatoxin B₁ producing fungal species, Fusarium graminearum, a deoxynivalenol producer, and the fumonisin-producing species F. proliferatum and F. verticillioides are the main toxigenic fungi (TF) that colonize maize. Several strategies are available to control TF and [...] Read more.

Aspergillus flavus, the main aflatoxin B₁ producing fungal species, Fusarium graminearum, a deoxynivalenol producer, and the fumonisin-producing species F. proliferatum and F. verticillioides are the main toxigenic fungi (TF) that colonize maize. Several strategies are available to control TF and related mycotoxins, such as chemical control. However, there is poor knowledge on the efficacy of fungicides on maize plants since few molecules are registered. The sensitivity of F. graminearum, F. proliferatum, F. verticillioides, and A. flavus to eleven fungicides, selected based on their different modes of action, was evaluated in both in vitro assays and, after selection, in the field. In vitro, demethylation inhibitors (DMI) showed excellent performances, followed by thiophanate-methyl and folpet. Among the succinate dehydrogenase inhibitors (SDHI), isopyrazam showed a higher effectiveness against Fusarium species than boscalid, which was ineffective against Fusarium, like the phenyl-pyrrole fludioxonil. Furthermore, both SDHIs and fludioxonil were more active against A. flavus than Fusarium species. In field trials, prothioconazole and thiophanate-methyl were confirmed to be effective to reduce F. graminearum (52% and 48%) and F. proliferatum contamination (44% and 27%). On the other hand, prothioconazole and boscalid could reduce A. flavus contamination at values of 75% and 56%, respectively. Full article

(This article belongs to the Special Issue 2^nd MycoKey International Conference - Integrated Solutions for Mycotoxin Management)

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16 pages, 1903 KiB

Open AccessEditor’s ChoiceArticle

Comparative Analysis of Microcystin Prevalence in Michigan Lakes by Online Concentration LC/MS/MS and ELISA

by Johnna A. Birbeck, Judy A. Westrick, Grace M. O’Neill, Brian Spies and David C. Szlag

Toxins 2019, 11(1), 13; https://doi.org/10.3390/toxins11010013 - 1 Jan 2019

Cited by 51 | Viewed by 5928

Abstract

Fast and reliable workflows are needed to quantitate microcystins (MCs), a ubiquitous class of hepatotoxic cyanotoxins, so that the impact of human and environmental exposure is assessed quickly and minimized. Our goal was to develop a high-throughput online concentration liquid chromatography tandem mass [...] Read more.

Fast and reliable workflows are needed to quantitate microcystins (MCs), a ubiquitous class of hepatotoxic cyanotoxins, so that the impact of human and environmental exposure is assessed quickly and minimized. Our goal was to develop a high-throughput online concentration liquid chromatography tandem mass spectrometry (LC/MS/MS) workflow to quantitate the 12 commercially available MCs and nodularin in surface and drinking waters. The method run time was 8.5 min with detection limits in the low ng/L range and minimum reporting levels between 5 and 10 ng/L. This workflow was benchmarked by determining the prevalence of MCs and comparing the Adda-ELISA quantitation to our new workflow from 122 samples representing 31 waterbodies throughout Michigan. The frequency of MC occurrence was MC-LA > LR > RR > D-Asp³-LR > YR > HilR > WR > D-Asp³-RR > HtyR > LY = LW = LF, while MC-RR had the highest concentrations. MCs were detected in 33 samples and 13 of these samples had more than 20% of their total MC concentration from MCs not present in US Environmental Protection Agency (US EPA) Method 544. Furthermore, seasonal deviations between the LC/MS/MS and Adda-ELISA data suggest Adda-ELISA cross-reacts with MC degradation products. This workflow provides less than 24-h turnaround for quantification and also identified key differences between LC/MS/MS and ELISA quantitation that should be investigated further. Full article

(This article belongs to the Collection Freshwater HABs and Health in a Changing World)

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