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Toxins
Volume 12
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Toxins, Volume 12, Issue 12 (December 2020) – 78 articles

Cover Story (view full-size image): Current anticancer therapy suffers from several limitations, including lack of selectivity and multidrug resistance. Natural products represent an excellent opportunity for the identification of new therapeutic options due to their safety, low toxicity, and general availability. Piper nigrum is one of the most popular species in the world, with growing fame as a source of bioactive molecules with pharmacological properties. The present review provides a comprehensive overview of the anticancer potential of Piper nigrum and its main bioactive component piperine, with particular emphasis on their anticancer mechanisms, chemosensitizing effects, and pharmacokinetic and toxicological profile. View this paper
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16 pages, 1341 KiB  
Review
Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins
by Chia-Ter Chao and Shih-Hua Lin
Toxins 2020, 12(12), 812; https://doi.org/10.3390/toxins12120812 - 21 Dec 2020
Cited by 20 | Viewed by 5052
Abstract
Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these [...] Read more.
Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC. Full article
(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)
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28 pages, 1799 KiB  
Review
Effects of Chronic Kidney Disease and Uremic Toxins on Extracellular Vesicle Biology
by Linda Yaker, Saïd Kamel, Jérôme Ausseil and Agnès Boullier
Toxins 2020, 12(12), 811; https://doi.org/10.3390/toxins12120811 - 21 Dec 2020
Cited by 14 | Viewed by 4196
Abstract
Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate, especially in patients with diabetes, atherosclerosis or chronic kidney disease (CKD). In CKD patients, VC is associated with the accumulation of uremic toxins, such as indoxyl sulphate or inorganic phosphate, [...] Read more.
Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate, especially in patients with diabetes, atherosclerosis or chronic kidney disease (CKD). In CKD patients, VC is associated with the accumulation of uremic toxins, such as indoxyl sulphate or inorganic phosphate, which can have a major impact in vascular remodeling. During VC, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch and secrete extracellular vesicles (EVs) that are heterogeneous in terms of their origin and composition. Under physiological conditions, EVs are involved in cell-cell communication and the maintenance of cellular homeostasis. They contain high levels of calcification inhibitors, such as fetuin-A and matrix Gla protein. Under pathological conditions (and particularly in the presence of uremic toxins), the secreted EVs acquire a pro-calcifying profile and thereby act as nucleating foci for the crystallization of hydroxyapatite and the propagation of calcification. Here, we review the most recent findings on the EVs’ pathophysiological role in VC, the impact of uremic toxins on EV biogenesis and functions, the use of EVs as diagnostic biomarkers and the EVs’ therapeutic potential in CKD. Full article
(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)
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18 pages, 4888 KiB  
Article
Kinetics of Microcystin-LR Removal in a Real Lake Water by UV/H2O2 Treatment and Analysis of Specific Energy Consumption
by Sabrina Sorlini, Carlo Collivignarelli, Marco Carnevale Miino, Francesca Maria Caccamo and Maria Cristina Collivignarelli
Toxins 2020, 12(12), 810; https://doi.org/10.3390/toxins12120810 - 21 Dec 2020
Cited by 10 | Viewed by 2640
Abstract
The hepatotoxin microcystin-LR (MC-LR) represents one of the most toxic cyanotoxins for human health. Considering its harmful effect, the World Health Organization recommended a limit in drinking water (DW) of 1 µg L−1. Due to the ineffectiveness of conventional treatments present [...] Read more.
The hepatotoxin microcystin-LR (MC-LR) represents one of the most toxic cyanotoxins for human health. Considering its harmful effect, the World Health Organization recommended a limit in drinking water (DW) of 1 µg L−1. Due to the ineffectiveness of conventional treatments present in DW treatment plants against MC-LR, advanced oxidation processes (AOPs) are gaining interest due to the high redox potential of the OH• radicals. In this work UV/H2O2 was applied to a real lake water to remove MC-LR. The kinetics of the UV/H2O2 were compared with those of UV and H2O2 showing the following result: UV/H2O2 > UV > H2O2. Within the range of H2O2 tested (0–0.9 mM), the results showed that H2O2 concentration and the removal kinetics followed an increasing quadratic relation. By increasing the initial concentration of H2O2, the consumption of oxidant also increased but, in terms of MC-LR degraded for H2O2 dosed, the removal efficiency decreased. As the initial MC-LR initial concentration increased, the removal kinetics increased up to a limit concentration (80 µg L−1) in which the presence of high amounts of the toxin slowed down the process. Operating with UV fluence lower than 950 mJ cm−2, UV alone minimized the specific energy consumption required. UV/H2O2 (0.3 mM) and UV/H2O2 (0.9 mM) were the most advantageous combination when operating with UV fluence of 950–1400 mJ cm−2 and higher than 1400 mJ cm−2, respectively. Full article
(This article belongs to the Special Issue Removal of Cyanobacteria and Cyanotoxins in Waters)
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11 pages, 1345 KiB  
Article
Effects of Modification of Light Parameters on the Production of Cryptophycin, Cyanotoxin with Potent Anticancer Activity, in Nostoc sp.
by Alexandros Polyzois, Diana Kirilovsky, Thi-hanh Dufat and Sylvie Michel
Toxins 2020, 12(12), 809; https://doi.org/10.3390/toxins12120809 - 21 Dec 2020
Cited by 11 | Viewed by 2902
Abstract
Cryptophycin-1 is a cyanotoxin produced by filamentous cyanobacteria. It has been evaluated as an anticancer agent with great potential. However, its synthesis provides insufficient yield for industrial use. An alternative solution for metabolite efficient production is to stress cyanobacteria by modifying the environmental [...] Read more.
Cryptophycin-1 is a cyanotoxin produced by filamentous cyanobacteria. It has been evaluated as an anticancer agent with great potential. However, its synthesis provides insufficient yield for industrial use. An alternative solution for metabolite efficient production is to stress cyanobacteria by modifying the environmental conditions of the culture (Nostoc sp. ATCC 53789). Here, we examined the effects of light photoperiod, wavelength, and intensity. In light photoperiod, photoperiods 24:0 and 16:8 (light:dark) were tested while in wavelength, orange-red light was compared with blue. Medium, high, and very high light intensity experiments were performed to test the effect of light stress. For a 10-day period, growth was measured, metabolite concentration was calculated through HPLC, and the related curves were drawn. The differentiation of light wavelength had a major effect on the culture, as orange-red filter contributed to noticeable increase in both growth and doubled the cyanotoxin concentration in comparison to blue light. Remarkably, constant light provides higher cryptophycin yield, but slightly lower growth rate. Lastly, the microorganism prefers medium light intensities for both growth and metabolite expression. The combination of these optimal conditions would contribute to the further exploitation of cryptophycin. Full article
(This article belongs to the Special Issue Selected Papers from the 26th Meeting of the French Society for Toxinology—Bioengineering of Toxins)
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15 pages, 323 KiB  
Review
Targeting Uremic Toxins to Prevent Peripheral Vascular Complications in Chronic Kidney Disease
by Chia-Lin Wu and Der-Cherng Tarng
Toxins 2020, 12(12), 808; https://doi.org/10.3390/toxins12120808 - 20 Dec 2020
Cited by 7 | Viewed by 2999
Abstract
Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer [...] Read more.
Chronic kidney disease (CKD) exhibits progressive kidney dysfunction and leads to disturbed homeostasis, including accumulation of uremic toxins, activated renin-angiotensin system, and increased oxidative stress and proinflammatory cytokines. Patients with CKD are prone to developing the peripheral vascular disease (PVD), leading to poorer outcomes than those without CKD. Cumulative evidence has showed that the synergy of uremic milieu and PVD could exaggerate vascular complications such as limb ischemia, amputation, stenosis, or thrombosis of a dialysis vascular access, and increase mortality risk. The role of uremic toxins in the pathogenesis of vascular dysfunction in CKD has been investigated. Moreover, growing evidence has shown the promising role of uremic toxins as a therapeutic target for PVD in CKD. This review focused on uremic toxins in the pathophysiology, in vitro and animal models, and current novel clinical approaches in reducing the uremic toxin to prevent peripheral vascular complications in CKD patients. Full article
(This article belongs to the Special Issue New Strategies for the Reduction of Uremic Toxins)
15 pages, 2357 KiB  
Article
Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized, Double-Blind, Placebo-Controlled Study
by Mandar Jog, Jack Lee, Astrid Scheschonka, Robert Chen, Farooq Ismail, Chris Boulias, Douglas Hobson, David King, Michael Althaus, Olivier Simon, Hanna Dersch, Steven Frucht and David M. Simpson
Toxins 2020, 12(12), 807; https://doi.org/10.3390/toxins12120807 - 20 Dec 2020
Cited by 11 | Viewed by 2971
Abstract
In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical [...] Read more.
In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p= 0.003) and Week 8 (p= 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p= 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites. Full article
(This article belongs to the Special Issue Botulinum Toxin for the Treatment of Neurological Disorders—Where We Are and Where We Need to Go)
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13 pages, 3180 KiB  
Article
A Monoclonal Antibody against the C-Terminal Domain of Bacillus cereus Hemolysin II Inhibits HlyII Cytolytic Activity
by Natalia Rudenko, Alexey Nagel, Anna Zamyatina, Anna Karatovskaya, Vadim Salyamov, Zhanna Andreeva-Kovalevskaya, Alexander Siunov, Alexander Kolesnikov, Anna Shepelyakovskaya, Khanafiy Boziev, Bogdan Melnik, Fedor Brovko and Alexander Solonin
Toxins 2020, 12(12), 806; https://doi.org/10.3390/toxins12120806 - 19 Dec 2020
Cited by 10 | Viewed by 2498
Abstract
Bacillus cereus is the fourth most common cause of foodborne illnesses that produces a variety of pore-forming proteins as the main pathogenic factors. B. cereus hemolysin II (HlyII), belonging to pore-forming β-barrel toxins, has a C-terminal extension of 94 amino acid residues designated [...] Read more.
Bacillus cereus is the fourth most common cause of foodborne illnesses that produces a variety of pore-forming proteins as the main pathogenic factors. B. cereus hemolysin II (HlyII), belonging to pore-forming β-barrel toxins, has a C-terminal extension of 94 amino acid residues designated as HlyIICTD. An analysis of a panel of monoclonal antibodies to the recombinant HlyIICTD protein revealed the ability of the antibody HlyIIC-20 to inhibit HlyII hemolysis. A conformational epitope recognized by HlyIIC-20 was found. by the method of peptide phage display and found that it is localized in the N-terminal part of HlyIICTD. The HlyIIC-20 interacted with a monomeric form of HlyII, thus suppressing maturation of the HlyII toxin. Protection efficiencies of various B. cereus strains against HlyII were different and depended on the epitope amino acid composition, as well as, insignificantly, on downstream amino acids. Substitution of L324P and P324L in the hemolysins ATCC14579T and B771, respectively, determined the role of leucine localized to the epitope in suppressing the hemolysis by the antibody. Pre-incubation of HlyIIC-20 with HlyII prevented the death of mice up to an equimolar ratio. A strategy of detecting and neutralizing the toxic activity of HlyII could provide a tool for monitoring and reducing B. cereus pathogenicity. Full article
(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)
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17 pages, 671 KiB  
Review
Industrial Applications of Dinoflagellate Phycotoxins Based on Their Modes of Action: A Review
by Kichul Cho, Jina Heo, Jinwook Han, Hyun Dae Hong, Hancheol Jeon, Hyun-Ju Hwang, Chang-Yu Hong, Daekyung Kim, Jong Won Han and Kyunghwa Baek
Toxins 2020, 12(12), 805; https://doi.org/10.3390/toxins12120805 - 18 Dec 2020
Cited by 7 | Viewed by 3473
Abstract
Dinoflagellates are an important group of phytoplanktons, characterized by two dissimilar flagella and distinctive features of both plants and animals. Dinoflagellate-generated harmful algal blooms (HABs) and associated damage frequently occur in coastal areas, which are concomitant with increasing eutrophication and climate change derived [...] Read more.
Dinoflagellates are an important group of phytoplanktons, characterized by two dissimilar flagella and distinctive features of both plants and animals. Dinoflagellate-generated harmful algal blooms (HABs) and associated damage frequently occur in coastal areas, which are concomitant with increasing eutrophication and climate change derived from anthropogenic waste and atmospheric carbon dioxide, respectively. The severe damage and harmful effects of dinoflagellate phycotoxins in the fishing industry have been recognized over the past few decades, and the management and monitoring of HABs have attracted much attention, leaving aside the industrial application of their valuable toxins. Specific modes of action of the organisms’ toxins can effectively be utilized for producing beneficial materials, such as Botox and other therapeutic agents. This review aims to explore the potential industrial applications of marine dinoflagellate phycotoxins; furthermore, this review focuses on their modes of action and summarizes the available knowledge on them. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
17 pages, 1584 KiB  
Article
Engineering an Effective Human SNAP-23 Cleaving Botulinum Neurotoxin A Variant
by Stefan Sikorra, Sarah Donald, Mark Elliott, Susan Schwede, Shu-Fen Coker, Adam P. Kupinski, Vineeta Tripathi, Keith Foster, Matthew Beard and Thomas Binz
Toxins 2020, 12(12), 804; https://doi.org/10.3390/toxins12120804 - 18 Dec 2020
Cited by 4 | Viewed by 3222
Abstract
Botulinum neurotoxin (BoNT) serotype A inhibits neurotransmitter release by cleaving SNAP-25 and represents an established pharmaceutical for treating medical conditions caused by hyperactivity of cholinergic nerves. Oversecretion from non-neuronal cells is often also the cause of diseases. Notably, excessive release of inflammatory messengers [...] Read more.
Botulinum neurotoxin (BoNT) serotype A inhibits neurotransmitter release by cleaving SNAP-25 and represents an established pharmaceutical for treating medical conditions caused by hyperactivity of cholinergic nerves. Oversecretion from non-neuronal cells is often also the cause of diseases. Notably, excessive release of inflammatory messengers is thought to contribute to diseases such as chronic obstructive pulmonary disease, asthma, diabetes etc. The expansion of its application to these medical conditions is prevented because the major non-neuronal SNAP-25 isoform responsible for exocytosis, SNAP-23, is, in humans, virtually resistant to BoNT/A. Based on previous structural data and mutagenesis studies of SNAP-23 we optimized substrate binding pockets of the enzymatic domain for interaction with SNAP-23. Systematic mutagenesis and rational design yielded the mutations E148Y, K166F, S254A, and G305D, each of which individually increased the activity of LC/A against SNAP-23 between 3- to 23-fold. The assembled quadruple mutant showed approximately 2000-fold increased catalytic activity against human SNAP-23 in in vitro cleavage assays. A comparable increase in activity was recorded for the full-length BoNT/A quadruple mutant tested in cultivated primary neurons transduced with a fluorescently tagged-SNAP-23 encoding gene. Equipped with a suitable targeting domain this quadruple mutant promises to complete successfully tests in cells of the immune system. Full article
(This article belongs to the Section Bacterial Toxins)
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11 pages, 287 KiB  
Review
Botulinum Toxin in the Treatment of Headache
by Werner J. Becker
Toxins 2020, 12(12), 803; https://doi.org/10.3390/toxins12120803 - 17 Dec 2020
Cited by 32 | Viewed by 8450
Abstract
Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action [...] Read more.
Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action in migraine prevention. Given that its mechanism of action is quite different from that of the new monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) or its receptor, it is unlikely to be displaced to any major extent by them. Both will likely remain as important tools for patients with chronic migraine and the clinicians assisting them. New types of botulinum toxin selective for sensory pain neurons may well be discovered or produced by recombinant DNA techniques in the coming decade, and this may greatly enhance its therapeutic usefulness. This review summarizes the evolution of botulinum toxin use in headache management over the past several decades and its role in the preventive treatment of chronic migraine and other headache disorders. Full article
(This article belongs to the Special Issue Botulinum Toxin for the Treatment of Neurological Disorders—Where We Are and Where We Need to Go)
19 pages, 3621 KiB  
Article
N-Terminal Tagging with GFP Enhances Selectivity of Agitoxin 2 to Kv1.3-Channel Binding Site
by Oksana V. Nekrasova, Alexandra L. Primak, Anastasia A. Ignatova, Valery N. Novoseletsky, Olga V. Geras’kina, Ksenia S. Kudryashova, Sergey A. Yakimov, Mikhail P. Kirpichnikov, Alexander S. Arseniev and Alexey V. Feofanov
Toxins 2020, 12(12), 802; https://doi.org/10.3390/toxins12120802 - 16 Dec 2020
Cited by 10 | Viewed by 3680
Abstract
Recently developed fluorescent protein-scorpion toxin chimeras (FP-Tx) show blocking activities for potassium voltage-gated channels of Kv1 family and retain almost fully pharmacological profiles of the parental peptide toxins (Kuzmenkov et al., Sci Rep. 2016, 6, 33314). Here we report on N-terminally green fluorescent [...] Read more.
Recently developed fluorescent protein-scorpion toxin chimeras (FP-Tx) show blocking activities for potassium voltage-gated channels of Kv1 family and retain almost fully pharmacological profiles of the parental peptide toxins (Kuzmenkov et al., Sci Rep. 2016, 6, 33314). Here we report on N-terminally green fluorescent protein (GFP)-tagged agitoxin 2 (GFP-L2-AgTx2) with high affinity and selectivity for the binding site of Kv1.3 channel involved in the pathogenesis of various (primarily of autoimmune origin) diseases. The basis for this selectivity relates to N-terminal location of GFP, since transposition of GFP to the C-terminus of AgTx2 recovered specific interactions with the Kv1.1 and Kv1.6 binding sites. Competitive binding experiments revealed that the binding site of GFP-L2-AgTx2 overlaps that of charybdotoxin, kaliotoxin 1, and agitoxin 2, the known Kv1.3-channel pore blockers. GFP-L2-AgTx2 was demonstrated to be applicable as a fluorescent probe to search for Kv1.3 pore blockers among individual compounds and in complex mixtures, to measure blocker affinities, and to visualize Kv1.3 distribution at the plasma membrane of Kv1.3-expressing HEK293 cells. Our studies show that definite combinations of fluorescent proteins and peptide blockers can result in considerable modulation of the natural blocker-channel binding profile yielding selective fluorescent ligands of certain channels. Full article
(This article belongs to the Section Animal Venoms)
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17 pages, 1016 KiB  
Article
Antitoxin ε Reverses Toxin ζ-Facilitated Ampicillin Dormants
by María Moreno-del Álamo, Chiara Marchisone and Juan C. Alonso
Toxins 2020, 12(12), 801; https://doi.org/10.3390/toxins12120801 - 15 Dec 2020
Cited by 6 | Viewed by 2448
Abstract
Toxin-antitoxin (TA) modules are ubiquitous in bacteria, but their biological importance in stress adaptation remains a matter of debate. The inactive ζ-ε2-ζ TA complex is composed of one labile ε2 antitoxin dimer flanked by two stable ζ toxin monomers. Free [...] Read more.
Toxin-antitoxin (TA) modules are ubiquitous in bacteria, but their biological importance in stress adaptation remains a matter of debate. The inactive ζ-ε2-ζ TA complex is composed of one labile ε2 antitoxin dimer flanked by two stable ζ toxin monomers. Free toxin ζ reduces the ATP and GTP levels, increases the (p)ppGpp and c-di-AMP pool, inactivates a fraction of uridine diphosphate-N-acetylglucosamine, and induces reversible dormancy. A small subpopulation, however, survives toxin action. Here, employing a genetic orthogonal control of ζ and ε levels, the fate of bacteriophage SPP1 infection was analyzed. Toxin ζ induces an active slow-growth state that halts SPP1 amplification, but it re-starts after antitoxin expression rather than promoting abortive infection. Toxin ζ-induced and toxin-facilitated ampicillin (Amp) dormants have been revisited. Transient toxin ζ expression causes a metabolic heterogeneity that induces toxin and Amp dormancy over a long window of time rather than cell persistence. Antitoxin ε expression, by reversing ζ activities, facilitates the exit of Amp-induced dormancy both in rec+ and recA cells. Our findings argue that an unexploited target to fight against antibiotic persistence is to disrupt toxin-antitoxin interactions. Full article
(This article belongs to the Special Issue Toxin-Antitoxin Systems in Pathogenic Bacteria)
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14 pages, 1884 KiB  
Article
Grape Seed Waste Counteracts Aflatoxin B1 Toxicity in Piglet Mesenteric Lymph Nodes
by Daniela Eliza Marin, Cristina Valeria Bulgaru, Cristian Andrei Anghel, Gina Cecilia Pistol, Madalina Ioana Dore, Mihai Laurentiu Palade and Ionelia Taranu
Toxins 2020, 12(12), 800; https://doi.org/10.3390/toxins12120800 - 15 Dec 2020
Cited by 29 | Viewed by 3222
Abstract
Aflatoxin B1 (AFB1) is a mycotoxin that frequently contaminates cereals and cereal byproducts. This study investigates the effect of AFB1 on the mesenteric lymph nodes (MLNs) of piglets and evaluates if a diet containing grape seed meal (GSM) can counteract the negative effect [...] Read more.
Aflatoxin B1 (AFB1) is a mycotoxin that frequently contaminates cereals and cereal byproducts. This study investigates the effect of AFB1 on the mesenteric lymph nodes (MLNs) of piglets and evaluates if a diet containing grape seed meal (GSM) can counteract the negative effect of AFB1 on inflammation and oxidative stress. Twenty-four weaned piglets were fed the following diets: Control, AFB1 group (320 μg AFB1/kg feed), GSM group (8% GSM), and AFB1 + GSM group (8% GSM + 320 μg AFB1/kg feed) for 30 days. AFB1 has an important antioxidative effect by decreasing the activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and total antioxidant status. As a result of the exposure to AFB1, an increase of MAP kinases, metalloproteinases, and cytokines, as effectors of an inflammatory response, were observed in the MLNs of intoxicated piglets. GSM induced a reduction of AFB1-induced oxidative stress by increasing the activity of GPx and SOD and by decreasing lipid peroxidation. GSM decreased the inflammatory markers increased by AFB1. These results represent an important and promising way to valorize this waste, which is rich in bioactive compounds, for decreasing AFB1 toxic effects in mesenteric lymph nodes. Full article
(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)
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12 pages, 3427 KiB  
Article
Aflatoxin B1 and Sterigmatocystin Binding Potential of Non-Lactobacillus LAB Strains
by Ildikó Bata-Vidács, Judit Kosztik, Mária Mörtl, András Székács and József Kukolya
Toxins 2020, 12(12), 799; https://doi.org/10.3390/toxins12120799 - 14 Dec 2020
Cited by 12 | Viewed by 2755
Abstract
Research on the ability of lactic acid bacteria (LAB) to bind aflatoxin B1 (AFB1) has mostly been focusing on lactobacilli and bifidobacteria. In this study, the AFB1 binding capacities of 20 Enterococcus strains belonging to E. casseliflavus, E. faecalis, E. faecium [...] Read more.
Research on the ability of lactic acid bacteria (LAB) to bind aflatoxin B1 (AFB1) has mostly been focusing on lactobacilli and bifidobacteria. In this study, the AFB1 binding capacities of 20 Enterococcus strains belonging to E. casseliflavus, E. faecalis, E. faecium, E. hirae, E. lactis, and E. mundtii, 24 Pediococcus strains belonging to species P. acidilactici, P. lolii, P. pentosaceus, and P. stilesii, one strain of Lactococcus formosensis and L.garviae, and 3 strains of Weissella soli were investigated in MRS broth at 37 °C at 0.2 µg/mL mycotoxin concentration. According to our results, among non-lactobacilli LAB, the genera with the best AFB1 binding abilities were genus Pediococcus, with a maximum binding percentage of 7.6% by P. acidilactici OR83, followed by genus Lactococcus. For AFB1 bio-detoxification purposes, beside lactobacilli, pediococci can also be chosen, but it is important to select a strain with better binding properties than the average value of its genus. Five Pediococcus strains have been selected to compare their sterigmatocystin (ST) binding abilities to AFB1 binding, and a 2–3-fold difference was obtained similar to previous findings for lactobacilli. The best strain was P. acidilactici OR83 with 18% ST binding capacity. This is the first report on ST binding capabilities of non-Lactobacillus LAB strains. Full article
(This article belongs to the Special Issue Rapid Detection of Mycotoxin Contamination)
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19 pages, 1935 KiB  
Article
Quality-Related Properties of Equine Immunoglobulins Purified by Different Approaches
by Sanja Mateljak Lukačević, Tihana Kurtović, Maja Lang Balija, Marija Brgles, Stephanie Steinberger, Martina Marchetti-Deschmann and Beata Halassy
Toxins 2020, 12(12), 798; https://doi.org/10.3390/toxins12120798 - 14 Dec 2020
Cited by 8 | Viewed by 3463
Abstract
Whole IgG antivenoms are prepared from hyperimmune animal plasma by various refinement strategies. The ones most commonly used at industrial scale are precipitation by sodium or ammonium sulphate (ASP), and caprylic acid precipitation (CAP) of non-immunoglobulin proteins. The additional procedures, which have so [...] Read more.
Whole IgG antivenoms are prepared from hyperimmune animal plasma by various refinement strategies. The ones most commonly used at industrial scale are precipitation by sodium or ammonium sulphate (ASP), and caprylic acid precipitation (CAP) of non-immunoglobulin proteins. The additional procedures, which have so far been used for experimental purposes only, are anion-exchange (AEX) and cation-exchange chromatography (CEX), as well as affinity chromatography (AC) using IgG’s Fc-binding ligands. These protocols extract the whole IgG fraction from plasma, which contains both venom-specific and therapeutically irrelevant antibodies. Such preparations represent a complex mixture of various IgG subclasses whose functional and/or structural properties, as well as relative distribution, might be affected differently, depending on employed purification procedure. The aim of this work was to compare the influence of aforementioned refinement strategies on the IgG subclass distribution, venom-specific protective efficacy, thermal stability, aggregate formation and retained impurity profile of the final products. A unique sample of Vipera ammodytes ammodytes specific hyperimmune horse plasma was used as a starting material, enabling direct comparison of five purification approaches. The highest purity was achieved by CAP and AC (above 90% in a single step), while the lowest aggregate content was present in samples from AEX processing. Albumin was the main contaminant in IgG preparations obtained by ASP and CEX, while transferrin dominantly contaminated IgG sample from AEX processing. Alpha-1B-glycoprotein was present in CAP IgG fraction, as well as in those from ASP- and AEX-based procedures. AC approach induced the highest loss of IgG(T) subclass. CEX and AEX showed the same tendency, while CAP and ASP had almost no impact on subclass distribution. The shift in IgG subclass composition influenced the specific protective efficacy of the respective final preparation as measured in vivo. AC and CEX remarkably affected drug’s venom-neutralization activity, in contrary to the CAP procedure, that preserved protective efficacy of the IgG fraction. Presented data might improve the process of designing and establishing novel downstream processing strategies and give guidance for optimization of the current ones by providing information on potency-protecting and purity-increasing properties of each purification principle. Full article
(This article belongs to the Special Issue Novel Strategies for the Diagnosis and Treatment of Snakebites)
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7 pages, 473 KiB  
Communication
Does Botulinum Toxin Treatment Affect the Ultrasonographic Characteristics of Post-Stroke Spastic Equinus? A Retrospective Pilot Study
by Alessandro Picelli, Mirko Filippetti, Camilla Melotti, Flavio Guerrazzi, Angela Modenese and Nicola Smania
Toxins 2020, 12(12), 797; https://doi.org/10.3390/toxins12120797 - 14 Dec 2020
Cited by 9 | Viewed by 2394
Abstract
Equinovarus/equinus foot is a pattern most commonly treated with botulinum toxin type A in patients with post-stroke spasticity involving the lower limbs; the gastrocnemius is the muscle most frequently injected. Spastic equinovarus/equinus can present a mixture of conditions, including spasticity, muscle/tendon shortening, muscle [...] Read more.
Equinovarus/equinus foot is a pattern most commonly treated with botulinum toxin type A in patients with post-stroke spasticity involving the lower limbs; the gastrocnemius is the muscle most frequently injected. Spastic equinovarus/equinus can present a mixture of conditions, including spasticity, muscle/tendon shortening, muscle weakness and imbalance. In this study, we wanted to determine whether botulinum toxin treatment affects the ultrasonographic characteristics of post-stroke spastic equinus. The same dose of AbobotulinumtoxinA was injected into the gastrocnemius medialis and lateralis of 21 chronic stroke patients with spastic equinus. Clinical (Ashworth scale and ankle range of motion) and ultrasound (conventional and sonoelastography) evaluation of the treated leg was carried out before and 4 weeks after injection. No significant effects of botulinum toxin treatment on the ultrasonographic characteristics of spastic equinus were observed. As expected, there were significant improvements in ankle passive dorsiflexion range of motion and calf muscle spasticity at 1 month after treatment. There was a direct association between Achilles tendon elasticity and calf muscle spasticity at baseline evaluation. Larger studies with a long-term timeline of serial evaluations are needed to further investigate the possible effects of botulinum toxin injection on spastic muscle characteristics in patients with post-stroke spasticity. Full article
(This article belongs to the Special Issue Spastic Muscle Features: Evaluation and Implications for Botulinum Toxin Treatment)
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21 pages, 2073 KiB  
Article
Evaluation of Resistance to Fescue Toxicosis in Purebred Angus Cattle Utilizing Animal Performance and Cytokine Response
by Daniel H. Poole, Kyle J. Mayberry, McKayla Newsome, Rebecca K. Poole, Justine M Galliou, Piush Khanal, Matthew H. Poore and Nick V. L. Serão
Toxins 2020, 12(12), 796; https://doi.org/10.3390/toxins12120796 - 14 Dec 2020
Cited by 8 | Viewed by 2880
Abstract
Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue; however, varying symptomatic responses potentially imply genetic tolerance to the syndrome. It was hypothesized that a subpopulation of animals within a herd would develop tolerance to ergot alkaloid toxicity. Therefore, [...] Read more.
Fescue toxicosis is a multifaceted syndrome common in cattle grazing endophyte-infected tall fescue; however, varying symptomatic responses potentially imply genetic tolerance to the syndrome. It was hypothesized that a subpopulation of animals within a herd would develop tolerance to ergot alkaloid toxicity. Therefore, the goals of this study were to develop selection criteria to identify tolerant and susceptible animals within a herd based on animal performance, and then examine responsive phenotypic and cytokine profiles to fescue toxicosis. Angus cows grazed endophyte-infected tall fescue at two locations for 13 weeks starting in mid-April 2016. Forage measurements were collected to evaluate ergot alkaloid exposure during the study. A post hoc analysis of animal performance was utilized to designate cattle into either tolerant or susceptible groups, and weekly physiological measurements and blood samples were collected to evaluate responses to chronic exposure to endophyte-infected tall fescue. Findings from this study support the proposed fescue toxicosis selection method formulated herein, could accurately distinguish between tolerant and susceptible animals based on the performance parameters in cattle chronically exposed to ergot alkaloids, and provides evidence to warrant additional analysis to examine the impact of ergot alkaloids on immune responsiveness in cattle experiencing fescue toxicosis. Full article
(This article belongs to the Special Issue Global Impact of Ergot Alkaloids)
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44 pages, 1244 KiB  
Review
Immunoaffinity Extraction and Alternative Approaches for the Analysis of Toxins in Environmental, Food or Biological Matrices
by Nathalie Delaunay, Audrey Combès and Valérie Pichon
Toxins 2020, 12(12), 795; https://doi.org/10.3390/toxins12120795 - 13 Dec 2020
Cited by 26 | Viewed by 3603
Abstract
The evolution of instrumentation in terms of separation and detection allowed a real improvement of the sensitivity and analysis time. However, the analysis of ultra-traces of toxins in complex samples requires often a step of purification and even preconcentration before their chromatographic analysis. [...] Read more.
The evolution of instrumentation in terms of separation and detection allowed a real improvement of the sensitivity and analysis time. However, the analysis of ultra-traces of toxins in complex samples requires often a step of purification and even preconcentration before their chromatographic analysis. Therefore, immunoaffinity sorbents based on specific antibodies thus providing a molecular recognition mechanism appear as powerful tools for the selective extraction of a target molecule and its structural analogs to obtain more reliable and sensitive quantitative analysis in environmental, food or biological matrices. This review focuses on immunosorbents that have proven their efficiency in selectively extracting various types of toxins of various sizes (from small mycotoxins to large proteins) and physicochemical properties. Immunosorbents are now commercially available, and their use has been validated for numerous applications. The wide variety of samples to be analyzed, as well as extraction conditions and their impact on extraction yields, is discussed. In addition, their potential for purification and thus suppression of matrix effects, responsible for quantification problems especially in mass spectrometry, is presented. Due to their similar properties, molecularly imprinted polymers and aptamer-based sorbents that appear to be an interesting alternative to antibodies are also briefly addressed by comparing their potential with that of immunosorbents. Full article
(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)
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15 pages, 3530 KiB  
Article
Betulinic Acid Ameliorates the T-2 Toxin-Triggered Intestinal Impairment in Mice by Inhibiting Inflammation and Mucosal Barrier Dysfunction through the NF-κB Signaling Pathway
by Chenxi Luo, Chenglong Huang, Lijuan Zhu, Li Kong, Zhihang Yuan, Lixin Wen, Rongfang Li, Jing Wu and Jine Yi
Toxins 2020, 12(12), 794; https://doi.org/10.3390/toxins12120794 - 13 Dec 2020
Cited by 28 | Viewed by 2986
Abstract
T-2 toxin, a trichothecene mycotoxin produced by Fusarium, is widely distributed in crops and animal feed and frequently induces intestinal damage. Betulinic acid (BA), a plant-derived pentacyclic lupane-type triterpene, possesses potential immunomodulatory, antioxidant and anti-inflammatory biological properties. The current study aimed to [...] Read more.
T-2 toxin, a trichothecene mycotoxin produced by Fusarium, is widely distributed in crops and animal feed and frequently induces intestinal damage. Betulinic acid (BA), a plant-derived pentacyclic lupane-type triterpene, possesses potential immunomodulatory, antioxidant and anti-inflammatory biological properties. The current study aimed to explore the protective effect and molecular mechanisms of BA on intestinal mucosal impairment provoked by acute exposure to T-2 toxin. Mice were intragastrically administered BA (0.25, 0.5, or 1 mg/kg) daily for 2 weeks and then injected intraperitoneally with T-2 toxin (4 mg/kg) once to induce an intestinal impairment. BA pretreatment inhibited the loss of antioxidant capacity in the intestine of T-2 toxin-treated mice by elevating the levels of CAT, GSH-PX and GSH and reducing the accumulation of MDA. In addition, BA pretreatment alleviated the T-2 toxin-triggered intestinal immune barrier dysregulation by increasing the SIgA level in the intestine at dosages of 0.5 and 1 mg/kg, increasing IgG and IgM levels in serum at dosages of 0.5 and 1 mg/kg and restoring the intestinal C3 and C4 levels at a dosage of 1 mg/kg. BA administration at a dosage of 1 mg/kg also improved the intestinal chemical barrier by decreasing the serum level of DAO. Moreover, BA pretreatment improved the intestinal physical barrier via boosting the expression of ZO-1 and Occludin mRNAs and restoring the morphology of intestinal villi that was altered by T-2 toxin. Furthermore, treatment with 1 mg/kg BA downregulated the expression of p-NF-κB and p-IκB-α proteins in the intestine, while all doses of BA suppressed the pro-inflammatory cytokines expression of IL-1β, IL-6 and TNF-α mRNAs and increased the anti-inflammatory cytokine expression of IL-10 mRNA in the intestine of T-2 toxin-exposed mice. BA was proposed to exert a protective effect on intestinal mucosal disruption in T-2 toxin-stimulated mice by enhancing the intestinal antioxidant capacity, inhibiting the secretion of inflammatory cytokines and repairing intestinal mucosal barrier functions, which may be associated with BA-mediated inhibition of the NF-κB signaling pathway activation. Full article
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18 pages, 2623 KiB  
Article
Boronic Acids of Pharmaceutical Importance Affect the Growth and Photosynthetic Apparatus of Cyanobacteria in a Dose-Dependent Manner
by Emilia Niemczyk, Jerzy Pogrzeba, Agnieszka Adamczyk-Woźniak and Jacek Lipok
Toxins 2020, 12(12), 793; https://doi.org/10.3390/toxins12120793 - 13 Dec 2020
Cited by 2 | Viewed by 2639
Abstract
The dynamic increase in the commercial application of antimicrobial derivatives of boronic acids, and potential impact of their presence in aquatic systems, supports the necessity to study the toxicity of these substances towards microorganisms of crucial meaning in the environment. One example of [...] Read more.
The dynamic increase in the commercial application of antimicrobial derivatives of boronic acids, and potential impact of their presence in aquatic systems, supports the necessity to study the toxicity of these substances towards microorganisms of crucial meaning in the environment. One example of the mentioned derivatives is tavaborole (5-fluoro-substituted benzoxaborole), a pharmaceutical agent with antifungal activity. Cyanobacteria were used as model organisms, which are photoautotrophic prokaryotes, as representative aquatic bacteria and photoautotrophs associated with the plant kingdom. To the best of our knowledge, we investigated this issue for the first time. In order to recognize the under-stress response of those microorganisms, the concentration of photopigments—a key factor in the activity of photosynthetic apparatus—was measured spectrophotometrically. We found that the 3-piperazine bis(benzoxaborole) significantly suppressed the growth of halophilic and freshwater cyanobacteria, at a concentration 3.0 mM and 0.3 mM, respectively. Our results also showed that the tested substances at micromolar concentrations stimulated the growth of cyanobacteria, particularly in the freshwater strain Chroococcidiopsis thermalis. The tested substances acted with various strengths, depending on their structure and concentration; nevertheless, they had a greater influence on the synthesis of phycobiliproteins (e.g., lowered their concentration) than on the formation of chlorophyll and carotenoids. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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30 pages, 3184 KiB  
Article
Several New Putative Bacterial ADP-Ribosyltransferase Toxins Are Revealed from In Silico Data Mining, Including the Novel Toxin Vorin, Encoded by the Fire Blight Pathogen Erwinia amylovora
by Olivier Tremblay, Zachary Thow, Jennifer Geddes-McAlister and A. Rod Merrill
Toxins 2020, 12(12), 792; https://doi.org/10.3390/toxins12120792 - 11 Dec 2020
Cited by 4 | Viewed by 4369
Abstract
Mono-ADP-ribosyltransferase (mART) toxins are secreted by several pathogenic bacteria that disrupt vital host cell processes in deadly diseases like cholera and whooping cough. In the last two decades, the discovery of mART toxins has helped uncover the mechanisms of disease employed by pathogens [...] Read more.
Mono-ADP-ribosyltransferase (mART) toxins are secreted by several pathogenic bacteria that disrupt vital host cell processes in deadly diseases like cholera and whooping cough. In the last two decades, the discovery of mART toxins has helped uncover the mechanisms of disease employed by pathogens impacting agriculture, aquaculture, and human health. Due to the current abundance of mARTs in bacterial genomes, and an unprecedented availability of genomic sequence data, mART toxins are amenable to discovery using an in silico strategy involving a series of sequence pattern filters and structural predictions. In this work, a bioinformatics approach was used to discover six bacterial mART sequences, one of which was a functional mART toxin encoded by the plant pathogen, Erwinia amylovora, called Vorin. Using a yeast growth-deficiency assay, we show that wild-type Vorin inhibited yeast cell growth, while catalytic variants reversed the growth-defective phenotype. Quantitative mass spectrometry analysis revealed that Vorin may cause eukaryotic host cell death by suppressing the initiation of autophagic processes. The genomic neighbourhood of Vorin indicated that it is a Type-VI-secreted effector, and co-expression experiments showed that Vorin is neutralized by binding of a cognate immunity protein, VorinI. We demonstrate that Vorin may also act as an antibacterial effector, since bacterial expression of Vorin was not achieved in the absence of VorinI. Vorin is the newest member of the mART family; further characterization of the Vorin/VorinI complex may help refine inhibitor design for mART toxins from other deadly pathogens. Full article
(This article belongs to the Special Issue Structure and Function of Bacterial ADP-Ribosylation Toxins)
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25 pages, 3265 KiB  
Article
Size Matters: An Evaluation of the Molecular Basis of Ontogenetic Modifications in the Composition of Bothrops jararacussu Snake Venom
by Luciana A. Freitas-de-Sousa, Pedro G. Nachtigall, José A. Portes-Junior, Matthew L. Holding, Gunnar S. Nystrom, Schyler A. Ellsworth, Noranathan C. Guimarães, Emilly Tioyama, Flora Ortiz, Bruno R. Silva, Tobias S. Kunz, Inácio L. M. Junqueira-de-Azevedo, Felipe G. Grazziotin, Darin R. Rokyta and Ana M. Moura-da-Silva
Toxins 2020, 12(12), 791; https://doi.org/10.3390/toxins12120791 - 11 Dec 2020
Cited by 24 | Viewed by 4813
Abstract
Ontogenetic changes in venom composition have been described in Bothrops snakes, but only a few studies have attempted to identify the targeted paralogues or the molecular mechanisms involved in modifications of gene expression during ontogeny. In this study, we decoded B. jararacussu venom [...] Read more.
Ontogenetic changes in venom composition have been described in Bothrops snakes, but only a few studies have attempted to identify the targeted paralogues or the molecular mechanisms involved in modifications of gene expression during ontogeny. In this study, we decoded B. jararacussu venom gland transcripts from six specimens of varying sizes and analyzed the variability in the composition of independent venom proteomes from 19 individuals. We identified 125 distinct putative toxin transcripts, and of these, 73 were detected in venom proteomes and only 10 were involved in the ontogenetic changes. Ontogenetic variability was linearly related to snake size and did not correspond to the maturation of the reproductive stage. Changes in the transcriptome were highly predictive of changes in the venom proteome. The basic myotoxic phospholipases A2 (PLA2s) were the most abundant components in larger snakes, while in venoms from smaller snakes, PIII-class SVMPs were the major components. The snake venom metalloproteinases (SVMPs) identified corresponded to novel sequences and conferred higher pro-coagulant and hemorrhagic functions to the venom of small snakes. The mechanisms modulating venom variability are predominantly related to transcriptional events and may consist of an advantage of higher hematotoxicity and more efficient predatory function in the venom from small snakes. Full article
(This article belongs to the Collection Evolution of Venom Systems)
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14 pages, 2554 KiB  
Article
Regulation Efficacy and Mechanism of the Toxicity of Microcystin-LR Targeting Protein Phosphatase 1 via the Biodegradation Pathway
by Luyao Ren, Zhengxin Hu, Qian Wang, Yonggang Du and Wansong Zong
Toxins 2020, 12(12), 790; https://doi.org/10.3390/toxins12120790 - 11 Dec 2020
Cited by 5 | Viewed by 2135
Abstract
Biodegradation is important to regulate the toxicity and environmental risk of microcystins (MCs). To explore their regulation effectiveness and mechanism, typical biodegradation products originating from microcystin-LR (MCLR) were prepared and purified. The protein phosphatase 1 (PP1) inhibition experiment showed the biodegradation pathway was [...] Read more.
Biodegradation is important to regulate the toxicity and environmental risk of microcystins (MCs). To explore their regulation effectiveness and mechanism, typical biodegradation products originating from microcystin-LR (MCLR) were prepared and purified. The protein phosphatase 1 (PP1) inhibition experiment showed the biodegradation pathway was effective in regulating the toxicity of the biodegradation products by extending the biodegradation. With the assistance of molecular docking, the specific interaction between the toxins and PP1 was explored. The MCLR/MCLR biodegradation products combined with PP1 mainly by the aid of interactions related to the active sites Adda5, Glu6, Mdha7, and the ionic bonds/hydrogen bonds between the integral toxin and PP1. As a consequence, the interactions between Mn22+ and Asp64/Asp92 in the catalytic center were inhibited to varying degrees, resulting in the reduced toxicity of the biodegradation products. During the biodegradation process, the relevant key interactions might be weakened or even disappear, and thus the toxicity was regulated. It is worth noting that the secondary pollution of the partial products (especially for Adda5-Glu6-Mdha7-Ala1 and the linearized MCLR), which still possessed the major active sites, is of deep concern. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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33 pages, 3583 KiB  
Review
A Review on Mycotoxins and Microfungi in Spices in the Light of the Last Five Years
by Darina Pickova, Vladimir Ostry, Jan Malir, Jakub Toman and Frantisek Malir
Toxins 2020, 12(12), 789; https://doi.org/10.3390/toxins12120789 - 11 Dec 2020
Cited by 46 | Viewed by 5457
Abstract
Spices are imported worldwide mainly from developing countries with tropical and/or subtropical climate. Local conditions, such as high temperature, heavy rainfall, and humidity, promote fungal growth leading to increased occurrence of mycotoxins in spices. Moreover, the lack of good agricultural practice (GAP), good [...] Read more.
Spices are imported worldwide mainly from developing countries with tropical and/or subtropical climate. Local conditions, such as high temperature, heavy rainfall, and humidity, promote fungal growth leading to increased occurrence of mycotoxins in spices. Moreover, the lack of good agricultural practice (GAP), good manufacturing practice (GMP), and good hygienic practice (GHP) in developing countries are of great concern. This review summarizes recent data from a total of 56 original papers dealing with mycotoxins and microfungi in various spices in the last five years. A total of 38 kinds of spices, 17 mycotoxins, and 14 microfungi are discussed in the review. Worldwide, spices are rather overlooked in terms of mycotoxin regulations, which usually only cover aflatoxins (AFs) and ochratoxin A (OTA). In this paper, an extensive attention is devoted to the limits on mycotoxins in spices in the context of the European Union (EU) as well as other countries. As proven in this review, the incidence of AFs and OTA, as well as other mycotoxins, is relatively high in many spices; thus, the preparation of new regulation limits is advisable. Full article
(This article belongs to the Special Issue Exposure to Mycotoxins via Food Chain)
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12 pages, 1181 KiB  
Article
The Links between Microbiome and Uremic Toxins in Acute Kidney Injury: Beyond Gut Feeling—A Systematic Review
by Alicja Rydzewska-Rosołowska, Natalia Sroka, Katarzyna Kakareko, Mariusz Rosołowski, Edyta Zbroch and Tomasz Hryszko
Toxins 2020, 12(12), 788; https://doi.org/10.3390/toxins12120788 - 11 Dec 2020
Cited by 21 | Viewed by 3222
Abstract
The last years have brought an abundance of data on the existence of a gut-kidney axis and the importance of microbiome in kidney injury. Data on kidney-gut crosstalk suggest the possibility that microbiota alter renal inflammation; we therefore aimed to answer questions about [...] Read more.
The last years have brought an abundance of data on the existence of a gut-kidney axis and the importance of microbiome in kidney injury. Data on kidney-gut crosstalk suggest the possibility that microbiota alter renal inflammation; we therefore aimed to answer questions about the role of microbiome and gut-derived toxins in acute kidney injury. PubMed and Cochrane Library were searched from inception to October 10, 2020 for relevant studies with an additional search performed on ClinicalTrials.gov. We identified 33 eligible articles and one ongoing trial (21 original studies and 12 reviews/commentaries), which were included in this systematic review. Experimental studies prove the existence of a kidney-gut axis, focusing on the role of gut-derived uremic toxins and providing concepts that modification of the microbiota composition may result in better AKI outcomes. Small interventional studies in animal models and in humans show promising results, therefore, microbiome-targeted therapy for AKI treatment might be a promising possibility. Full article
(This article belongs to the Special Issue Study on the Uremic Toxin Targeting Mechanism)
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15 pages, 3158 KiB  
Article
Exposure to Aerosolized Algal Toxins in South Florida Increases Short- and Long-Term Health Risk in Drosophila Model of Aging
by Jiaming Hu, Jiaqi Liu, Yi Zhu, Zoraida Diaz-Perez, Michael Sheridan, Haley Royer, Raymond Leibensperger III, Daniela Maizel, Larry Brand, Kimberly J. Popendorf, Cassandra J. Gaston and R. Grace Zhai
Toxins 2020, 12(12), 787; https://doi.org/10.3390/toxins12120787 - 11 Dec 2020
Cited by 14 | Viewed by 5493
Abstract
Harmful algal blooms (HABs) are a rising health and environmental concern in the United States, particularly in South Florida. Skin contact and the ingestion of contaminated water or fish and other seafood have been proven to have severe toxicity to humans in some [...] Read more.
Harmful algal blooms (HABs) are a rising health and environmental concern in the United States, particularly in South Florida. Skin contact and the ingestion of contaminated water or fish and other seafood have been proven to have severe toxicity to humans in some cases. However, the impact of aerosolized HAB toxins is poorly understood. In particular, knowledge regarding either the immediate or long-term effects of exposure to aerosolized cyanotoxins produced by freshwater blue-green algae does not exist. The aim of this study was to probe the toxicity of aerosolized cyanobacterial blooms using Drosophila melanogaster as an animal model. The exposure of aerosolized HABs at an early age leads to the most severe long-term impact on health and longevity among all age groups. Young groups and old males showed a strong acute response to HAB exposure. In addition, brain morphological analysis using fluorescence imaging reveals significant indications of brain degeneration in females exposed to aerosolized HABs in early or late stages. These results indicate that one-time exposure to aerosolized HAB particles causes a significant health risk, both immediately and in the long-term. Interestingly, age at the time of exposure plays an important role in the specific nature of the impact of aerosol HABs. As BMAA and microcystin have been found to be the significant toxins in cyanobacteria, the concentration of both toxins in the water and aerosols was examined. BMAA and microcystin are consistently detected in HAB waters, although their concentrations do not always correlate with the severity of the health impact, suggesting the potential contribution from additional toxins present in the aerosolized HAB. This study demonstrates, for the first time, the health risk of exposure to aerosolized HAB, and further highlights the critical need and importance of understanding the toxicity of aerosolized cyanobacteria HAB particles and determining the immediate and long-term health impacts of HAB exposure. Full article
(This article belongs to the Special Issue Emerging Health Impacts of Harmful Algal Blooms (HABs) on Human Health)
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16 pages, 871 KiB  
Article
Determination of Zearalenone and Trichothecenes, Including Deoxynivalenol and Its Acetylated Derivatives, Nivalenol, T-2 and HT-2 Toxins, in Wheat and Wheat Products by LC-MS/MS: A Collaborative Study
by Annalisa De Girolamo, Biancamaria Ciasca, Michelangelo Pascale and Veronica M.T. Lattanzio
Toxins 2020, 12(12), 786; https://doi.org/10.3390/toxins12120786 - 10 Dec 2020
Cited by 25 | Viewed by 3429
Abstract
An analytical method for the simultaneous determination of trichothecenes—namely, nivalenol (NIV), deoxynivalenol (DON) and its acetylated derivatives (3- and 15-acetyl-DON), T-2 and HT-2 toxins—and zearalenone (ZEN) in wheat, wheat flour, and wheat crackers was validated through a collaborative study involving 15 participants from [...] Read more.
An analytical method for the simultaneous determination of trichothecenes—namely, nivalenol (NIV), deoxynivalenol (DON) and its acetylated derivatives (3- and 15-acetyl-DON), T-2 and HT-2 toxins—and zearalenone (ZEN) in wheat, wheat flour, and wheat crackers was validated through a collaborative study involving 15 participants from 10 countries. The validation study, performed within the M/520 standardization mandate of the European Commission, was carried out according to the IUPAC (International Union of Pure and Applied Chemistry) International Harmonized Protocol. The method was based on mycotoxin extraction from the homogenized sample material with a mixture of acetonitrile-water followed by purification and concentration on a solid phase extraction column. High-performance liquid chromatography coupled with tandem mass spectrometry was used for mycotoxin detection, using isotopically labelled mycotoxins as internal standards. The tested contamination ranges were from 27.7 to 378 μg/kg for NIV, from 234 to 2420 μg/kg for DON, from 18.5 to 137 μg/kg for 3-acetyl-DON, from 11.4 to 142 μg/kg for 15-acetyl-DON, from 2.1 to 37.6 μg/kg for T-2 toxin, from 6.6 to 134 μg/kg for HT-2 toxin, and from 31.6 to 230 μg/kg for ZEN. Recoveries were in the range 71–97% with the lowest values for NIV, the most polar mycotoxin. The relative standard deviation for repeatability (RSDr) was in the range of 2.2–34%, while the relative standard deviation for reproducibility (RSDR) was between 6.4% and 45%. The HorRat values ranged from 0.4 to 2.0. The results of the collaborative study showed that the candidate method is fit for the purpose of enforcing the legislative limits of the major Fusarium toxins in wheat and wheat-based products. Full article
(This article belongs to the Special Issue Application of Novel Methods for Mycotoxins Analysis)
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3 pages, 226 KiB  
Editorial
Bacillus thuringiensis Toxins: Functional Characterization and Mechanism of Action
by Yolanda Bel, Juan Ferré and Patricia Hernández-Martínez
Toxins 2020, 12(12), 785; https://doi.org/10.3390/toxins12120785 - 10 Dec 2020
Cited by 22 | Viewed by 5101
Abstract
Bacillus thuringiensis (Bt)-based products are the most successful microbial insecticides to date [...] Full article
(This article belongs to the Special Issue Bacillus thuringiensis Toxins: Functional Characterization and Mechanism of Action)
14 pages, 2904 KiB  
Article
Establishment of a Novel Oral Murine Model of Ricin Intoxication and Efficacy Assessment of Ovine Ricin Antitoxins
by Sarah J. Whitfield, Debbie B. Padgen, Simon Knight, Robert J. Gwyther, Jane L. Holley, Graeme C. Clark and A. Christopher Green
Toxins 2020, 12(12), 784; https://doi.org/10.3390/toxins12120784 - 8 Dec 2020
Cited by 4 | Viewed by 2626
Abstract
Ricin, produced from the castor beans of Ricinus communis, is a cytotoxin that exerts its action by inactivating ribosomes and causing cell death. Accidental (e.g., ingestion of castor beans) and/or intentional (e.g., suicide) exposure to ricin through the oral route is an [...] Read more.
Ricin, produced from the castor beans of Ricinus communis, is a cytotoxin that exerts its action by inactivating ribosomes and causing cell death. Accidental (e.g., ingestion of castor beans) and/or intentional (e.g., suicide) exposure to ricin through the oral route is an area of concern from a public health perspective and no current licensed medical interventions exist to protect from the action of the toxin. Therefore, we examined the oral toxicity of ricin in Balb/C mice and developed a robust food deprivation model of ricin oral intoxication that has enabled the assessment of potential antitoxin treatments. A lethal oral dose was identified and mice were found to succumb to the toxin within 48 h of exposure. We then examined whether a despeciated ovine F(ab′)2 antibody fragment, that had previously been demonstrated to protect mice from exposure to aerosolised ricin, could also protect against oral intoxication. Mice were challenged orally with an LD99 of ricin, and 89 and 44% of mice exposed to this otherwise lethal exposure survived after receiving either the parent anti-ricin IgG or F(ab′)2, respectively. Combined with our previous work, these results further highlight the benefit of ovine-derived polyclonal antibody antitoxin in providing post-exposure protection against ricin intoxication. Full article
(This article belongs to the Special Issue Antibodies for Toxins: From Detection to Therapeutics)
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14 pages, 1153 KiB  
Article
Differences in Toxic Response Induced by Three Variants of the Diarrheic Shellfish Poisoning Phycotoxins in Human Intestinal Epithelial Caco-2 Cells
by Antoine Huguet, Olivia Drapeau, Fanny Rousselet, Hélène Quenault and Valérie Fessard
Toxins 2020, 12(12), 783; https://doi.org/10.3390/toxins12120783 - 8 Dec 2020
Cited by 9 | Viewed by 2792
Abstract
Diarrheic shellfish poisoning (DSP) is caused by the consumption of shellfish contaminated with a group of phycotoxins that includes okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2). These toxins are inhibitors of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A), but show distinct [...] Read more.
Diarrheic shellfish poisoning (DSP) is caused by the consumption of shellfish contaminated with a group of phycotoxins that includes okadaic acid (OA), dinophysistoxin-1 (DTX-1), and dinophysistoxin-2 (DTX-2). These toxins are inhibitors of serine/threonine protein phosphatases 1 (PP1) and 2A (PP2A), but show distinct levels of toxicity. Aside from a difference in protein phosphatases (PP) inhibition potency that would explain these differences in toxicity, others mechanisms of action are thought to be involved. Therefore, we investigated and compared which mechanisms are involved in the toxicity of these three analogues. As the intestine is one of the target organs, we studied the transcriptomic profiles of human intestinal epithelial Caco-2 cells exposed to OA, DTX-1, and DTX-2. The pathways specifically affected by each toxin treatment were further confirmed through the expression of key genes and markers of toxicity. Our results did not identify any distinct biological mechanism for OA and DTX-2. However, only DTX-1 induced up-regulation of the MAPK transduction signalling pathway, and down-regulation of gene products involved in the regulation of DNA repair. As a consequence, based on transcriptomic results, we demonstrated that the higher toxicity of DTX-1 compared to OA and DTX-2 was consistent with certain specific pathways involved in intestinal cell response. Full article
(This article belongs to the Special Issue Omic Technologies Applied to the Study of Marine Shellfish Toxins)
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