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Toxins
Volume 7
Issue 9
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Toxins, Volume 7, Issue 9 (September 2015) – 29 articles , Pages 3372-3844

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333 KiB  
Review
Botulinum Toxin Type A as a Therapeutic Agent against Headache and Related Disorders
by Siro Luvisetto, Parisa Gazerani, Carlo Cianchetti and Flaminia Pavone
Toxins 2015, 7(9), 3818-3844; https://doi.org/10.3390/toxins7093818 - 23 Sep 2015
Cited by 54 | Viewed by 9580
Abstract
Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a [...] Read more.
Botulinum neurotoxin A (BoNT/A) is a toxin produced by the naturally-occurring Clostridium botulinum that causes botulism. The potential of BoNT/A as a useful medical intervention was discovered by scientists developing a vaccine to protect against botulism. They found that, when injected into a muscle, BoNT/A causes a flaccid paralysis. Following this discovery, BoNT/A has been used for many years in the treatment of conditions of pathological muscle hyperactivity, like dystonias and spasticities. In parallel, the toxin has become a “glamour” drug due to its power to ward off facial wrinkles, particularly frontal, due to the activity of the mimic muscles. After the discovery that the drug also appeared to have a preventive effect on headache, scientists spent many efforts to study the potentially-therapeutic action of BoNT/A against pain. BoNT/A is effective at reducing pain in a number of disease states, including cervical dystonia, neuropathic pain, lower back pain, spasticity, myofascial pain and bladder pain. In 2010, regulatory approval for the treatment of chronic migraine with BoNT/A was given, notwithstanding the fact that the mechanism of action is still not completely elucidated. In the present review, we summarize experimental evidence that may help to clarify the mechanisms of action of BoNT/A in relation to the alleviation of headache pain, with particular emphasis on preclinical studies, both in animals and humans. Moreover, we summarize the latest clinical trials that show evidence on headache conditions that may obtain benefits from therapy with BoNT/A. Full article
(This article belongs to the Collection Botulinum Toxins on Human Pain)
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Article
Impact of Gastrointestinal Bacillus anthracis Infection on Hepatic B Cells
by Natacha Colliou, Bikash Sahay, Mojgan Zadeh, Jennifer L. Owen and Mansour Mohamadzadeh
Toxins 2015, 7(9), 3805-3817; https://doi.org/10.3390/toxins7093805 - 22 Sep 2015
Cited by 1 | Viewed by 5137
Abstract
Ingestion of Bacillus anthracis results in rapid gastrointestinal (GI) infection, known as GI anthrax. We previously showed that during GI anthrax, there is swift deterioration of intestinal barrier function leading to translocation of gut-associated bacteria into systemic circulation. Additionally, we described dysfunction in [...] Read more.
Ingestion of Bacillus anthracis results in rapid gastrointestinal (GI) infection, known as GI anthrax. We previously showed that during GI anthrax, there is swift deterioration of intestinal barrier function leading to translocation of gut-associated bacteria into systemic circulation. Additionally, we described dysfunction in colonic B cells. In concordance with our previous studies, here, we report early migration of the Sterne strain of B. anthracis along with other gut-resident bacteria into the infected murine liver. Additionally, despite a global decrease in the B cell population, we observed an increase in both B-1a and marginal zone (MZ)-like B cells. Both of these cell types are capable of producing immunoglobulins against common pathogens and commensals, which act as a general antibody barrier before an antigen-specific antibody response. Accumulation of these cells in the liver was associated with an increase in chemokine expression. These data suggest that the presence of Sterne and other commensals in the liver trigger migration of MZ-like B cells from the spleen to the liver to neutralize systemic spread. Further research is required to evaluate the possible cause of their failure to clear the infection within the liver, including the potential role of dysfunctional mitogen-activated protein kinase (MAPK) signaling. Full article
(This article belongs to the Collection Anthrax Toxins)
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Review
Are Some Fungal Volatile Organic Compounds (VOCs) Mycotoxins?
by Joan W. Bennett and Arati A. Inamdar
Toxins 2015, 7(9), 3785-3804; https://doi.org/10.3390/toxins7093785 - 22 Sep 2015
Cited by 114 | Viewed by 12192
Abstract
Volatile organic compounds (VOCs) are carbon-compounds that easily evaporate at room temperature. Toxins are biologically produced poisons; mycotoxins are those toxins produced by microscopic fungi. All fungi emit blends of VOCs; the qualitative and quantitative composition of these volatile blends varies with the [...] Read more.
Volatile organic compounds (VOCs) are carbon-compounds that easily evaporate at room temperature. Toxins are biologically produced poisons; mycotoxins are those toxins produced by microscopic fungi. All fungi emit blends of VOCs; the qualitative and quantitative composition of these volatile blends varies with the species of fungus and the environmental situation in which the fungus is grown. These fungal VOCs, produced as mixtures of alcohols, aldehydes, acids, ethers, esters, ketones, terpenes, thiols and their derivatives, are responsible for the characteristic moldy odors associated with damp indoor spaces. There is increasing experimental evidence that some of these VOCs have toxic properties. Laboratory tests in mammalian tissue culture and Drosophila melanogaster have shown that many single VOCs, as well as mixtures of VOCs emitted by growing fungi, have toxic effects. This paper describes the pros and cons of categorizing toxigenic fungal VOCs as mycotoxins, uses genomic data to expand on the definition of mycotoxin, and summarizes some of the linguistic and other conventions that can create barriers to communication between the scientists who study VOCs and those who study toxins. We propose that “volatoxin” might be a useful term to describe biogenic volatile compounds with toxigenic properties. Full article
(This article belongs to the Collection Evolutionary/Phylogenetic Studies of Mycotoxin Biosynthetic Pathways)
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Article
Titanium Dioxide Nanoparticles (TiO2) Quenching Based Aptasensing Platform: Application to Ochratoxin A Detection
by Atul Sharma, Akhtar Hayat, Rupesh K. Mishra, Gaëlle Catanante, Sunil Bhand and Jean Louis Marty
Toxins 2015, 7(9), 3771-3784; https://doi.org/10.3390/toxins7093771 - 22 Sep 2015
Cited by 30 | Viewed by 8411
Abstract
We demonstrate for the first time, the development of titanium dioxide nanoparticles (TiO2) quenching based aptasensing platform for detection of target molecules. TiO2 quench the fluorescence of FAM-labeled aptamer (fluorescein labeled aptamer) upon the non-covalent adsorption of fluorescent labeled aptamer [...] Read more.
We demonstrate for the first time, the development of titanium dioxide nanoparticles (TiO2) quenching based aptasensing platform for detection of target molecules. TiO2 quench the fluorescence of FAM-labeled aptamer (fluorescein labeled aptamer) upon the non-covalent adsorption of fluorescent labeled aptamer on TiO2 surface. When OTA interacts with the aptamer, it induced aptamer G-quadruplex complex formation, weakens the interaction between FAM-labeled aptamer and TiO2, resulting in fluorescence recovery. As a proof of concept, an assay was employed for detection of Ochratoxin A (OTA). At optimized experimental condition, the obtained limit of detection (LOD) was 1.5 nM with a good linearity in the range 1.5 nM to 1.0 µM for OTA. The obtained results showed the high selectivity of assay towards OTA without interference to structurally similar analogue Ochratoxin B (OTB). The developed aptamer assay was evaluated for detection of OTA in beer sample and recoveries were recorded in the range from 94.30%–99.20%. Analytical figures of the merits of the developed aptasensing platform confirmed its applicability to real samples analysis. However, this is a generic aptasensing platform and can be extended for detection of other toxins or target analyte. Full article
(This article belongs to the Collection Biorecognition Assays for Mycotoxins)
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Article
A Double-Blind Randomized Controlled Trial Investigating the Most Efficacious Dose of Botulinum Toxin-A for Sialorrhea Treatment in Asian Adults with Neurological Diseases
by Mazlina Mazlan, Shivani Rajasegaran, Julia Patrick Engkasan, Ouzreiah Nawawi, Khean-Jin Goh and Saini Jeffery Freddy
Toxins 2015, 7(9), 3758-3770; https://doi.org/10.3390/toxins7093758 - 22 Sep 2015
Cited by 34 | Viewed by 6453
Abstract
This study aims to determine the most efficacious dose of Botulinum neurotoxin type A (BoNT-A) in reducing sialorrhea in Asian adults with neurological diseases. A prospective, double-blind randomized controlled trial was conducted over 24 weeks. Thirty patients with significant sialorrhea were randomly assigned [...] Read more.
This study aims to determine the most efficacious dose of Botulinum neurotoxin type A (BoNT-A) in reducing sialorrhea in Asian adults with neurological diseases. A prospective, double-blind randomized controlled trial was conducted over 24 weeks. Thirty patients with significant sialorrhea were randomly assigned to receive a BoNT-A (Dysport®) injection into the submandibular and the parotid glands bilaterally via an ultrasound guidance. The total dose given per patient was either BoNT-A injection of (i) 50 U; (ii) 100 U; or (iii) 200 U. The primary outcome was the amount of saliva reduction, measured by the differential weight (wet versus dry) of intraoral dental gauze at baseline and at 2, 6, 12, and 24 weeks after injection. The secondary outcome was the subjective report of drooling using the Drooling Frequency and Severity Scale (DFS). Saliva reduction was observed in response to all BoNT-A doses in 17 patients who completed the assessments. Although no statistically significant difference among the doses was found, the measured reduction was greater in groups that received higher doses (100 U and 200 U). The group receiving 200 U of Dysport® showed the greatest reduction of saliva until 24 weeks and reported the most significant improvement in the DFS score. Full article
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Article
First Report of Ciguatoxins in Two Starfish Species: Ophidiaster ophidianus and Marthasterias glacialis
by Marisa Silva, Inés Rodriguez, Aldo Barreiro, Manfred Kaufmann, Ana Isabel Neto, Meryem Hassouani, Brahim Sabour, Amparo Alfonso, Luis M. Botana and Vitor Vasconcelos
Toxins 2015, 7(9), 3740-3757; https://doi.org/10.3390/toxins7093740 - 21 Sep 2015
Cited by 55 | Viewed by 7712
Abstract
Ciguatera fish poisoning (CFP) is a syndrome caused by the ingestion of fish contaminated with Ciguatoxins (CTXs). These phycotoxins are produced mainly by dinoflagellates that belong to the genus Gambierdiscus that are transformed in more toxic forms in predatory fish guts, and are [...] Read more.
Ciguatera fish poisoning (CFP) is a syndrome caused by the ingestion of fish contaminated with Ciguatoxins (CTXs). These phycotoxins are produced mainly by dinoflagellates that belong to the genus Gambierdiscus that are transformed in more toxic forms in predatory fish guts, and are more present in the Indo-Pacific and Caribbean areas. It is estimated that CFP causes per year more than 10,000 intoxications worldwide. With the rise of water temperature and anthropogenic intervention, it is important to study the prevalence of CFP in more temperate waters. Through inter- and subtidal sampling, 22 species of organisms were collected, in Madeira and Azores archipelagos and in the northwestern Moroccan coast, during September of 2012 and June and July of 2013. A total of 94 samples of 22 different species of bivalves, gastropods, echinoderms and crustaceans where analyzed by Ultra Performance Liquid Chromatography-Mass Spectometry-Ion Trap-Time of Flight (UPLC-MS-IT-TOF) and Ultra Performance Chromatography- Mass Spectrometry (UPLC-MS). Our main aim was to detect new vectors and ascertain if there were some geographical differences. We detected for the first time putative CTXs in echinoderms, in two starfish species—M. glacialis and O. ophidianus. We detected differences regarding uptake values by organisms and geographical location. Toxin amounts were significant, showing the importance and the need for continuity of these studies to gain more knowledge about the prevalence of these toxins, in order to better access human health risk. In addition, we suggest monitoring of these toxins should be extended to other vectors, starfish being a good alternative for protecting and accessing human health risk. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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Article
UV-Sensitivity of Shiga Toxin-Converting Bacteriophage Virions Φ24B, 933W, P22, P27 and P32
by Sylwia Bloch, Bożena Nejman-Faleńczyk, Gracja Topka, Aleksandra Dydecka, Katarzyna Licznerska, Magdalena Narajczyk, Agnieszka Necel, Alicja Węgrzyn and Grzegorz Węgrzyn
Toxins 2015, 7(9), 3727-3739; https://doi.org/10.3390/toxins7093727 - 21 Sep 2015
Cited by 12 | Viewed by 5448
Abstract
Shiga toxin-converting bacteriophages (Stx phages) are present as prophages in Shiga toxin-producing Escherichia coli (STEC) strains. Theses phages can be transmitted to previously non-pathogenic E. coli cells making them potential producers of Shiga toxins, as they bear genes for these toxins in their [...] Read more.
Shiga toxin-converting bacteriophages (Stx phages) are present as prophages in Shiga toxin-producing Escherichia coli (STEC) strains. Theses phages can be transmitted to previously non-pathogenic E. coli cells making them potential producers of Shiga toxins, as they bear genes for these toxins in their genomes. Therefore, sensitivity of Stx phage virions to various conditions is important in both natural processes of spreading of these viruses and potential prophylactic control of appearance of novel pathogenic E. coli strains. In this report we provide evidence that virions of Stx phages are significantly more sensitive to UV irradiation than bacteriophage λ. Following UV irradiation of Stx virions at the dose of 50 J/m2, their infectivity dropped by 1–3 log10, depending on the kind of phage. Under these conditions, a considerable release of phage DNA from virions was observed, and electron microscopy analyses indicated a large proportion of partially damaged virions. Infection of E. coli cells with UV-irradiated Stx phages resulted in significantly decreased levels of expression of N and cro genes, crucial for lytic development. We conclude that inactivation of Stx virions caused by relatively low dose of UV light is due to damage of capsids that prevents effective infection of the host cells. Full article
(This article belongs to the Special Issue Shiga Toxin)
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Article
Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells
by So Young Jung, Kang-Woo Lee, Sun-Mi Choi and Eun Jin Yang
Toxins 2015, 7(9), 3715-3726; https://doi.org/10.3390/toxins7093715 - 21 Sep 2015
Cited by 23 | Viewed by 6914
Abstract
Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine [...] Read more.
Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A2. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death. Full article
(This article belongs to the Special Issue Bee and Wasp Venoms: Biological Characteristics and Therapeutic Application)
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Article
Detection of N-(1-deoxy-d-fructos-1-yl) Fumonisins B2 and B3 in Corn by High-Resolution LC-Orbitrap MS
by Yosuke Matsuo, Kentaro Takahara, Yuki Sago, Masayo Kushiro, Hitoshi Nagashima and Hiroyuki Nakagawa
Toxins 2015, 7(9), 3700-3714; https://doi.org/10.3390/toxins7093700 - 16 Sep 2015
Cited by 12 | Viewed by 5733
Abstract
The existence of glucose conjugates of fumonisin B2 (FB2) and fumonisin B3 (FB3) in corn powder was confirmed for the first time. These “bound-fumonisins” (FB2 and FB3 bound to glucose) were identified as N-(1-deoxy-d-fructos-1-yl) [...] Read more.
The existence of glucose conjugates of fumonisin B2 (FB2) and fumonisin B3 (FB3) in corn powder was confirmed for the first time. These “bound-fumonisins” (FB2 and FB3 bound to glucose) were identified as N-(1-deoxy-d-fructos-1-yl) fumonisin B2 (NDfrc-FB2) and N-(1-deoxy-d-fructos-1-yl) fumonisin B3 (NDfrc-FB3) respectively, based on the accurate mass measurements of characteristic ions and fragmentation patterns using high-resolution liquid chromatography-Orbitrap mass spectrometry (LC-Orbitrap MS) analysis. Treatment on NDfrc-FB2 and NDfrc-FB3 with the o-phthalaldehyde (OPA) reagent also supported that d-glucose binding to FB2 and FB3 molecules occurred to their primary amine residues. Full article
(This article belongs to the Collection Fusarium Toxins – Relevance for Human and Animal Health)
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Article
Staphylococcus epidermidis and Staphylococcus haemolyticus: Molecular Detection of Cytotoxin and Enterotoxin Genes
by Luiza Pinheiro, Carla Ivo Brito, Adilson De Oliveira, Patrícia Yoshida Faccioli Martins, Valéria Cataneli Pereira and Maria De Lourdes Ribeiro de Souza Da Cunha
Toxins 2015, 7(9), 3688-3699; https://doi.org/10.3390/toxins7093688 - 14 Sep 2015
Cited by 44 | Viewed by 9443
Abstract
Although opportunistic pathogens, coagulase-negative staphylococci (CoNS), including Staphylococcus epidermidis and Staphylococcus haemolyticus, have long been regarded as avirulent organisms. The role of toxins in the development of infections caused by CoNS is still controversial. The objective of this study was to characterize [...] Read more.
Although opportunistic pathogens, coagulase-negative staphylococci (CoNS), including Staphylococcus epidermidis and Staphylococcus haemolyticus, have long been regarded as avirulent organisms. The role of toxins in the development of infections caused by CoNS is still controversial. The objective of this study was to characterize the presence of enterotoxin and cytotoxin genes in S. epidermidis and S. haemolyticus isolates obtained from blood cultures. Cytotoxin genes were detected by PCR using novel species-specific primers. Among the 85 S. epidermidis and 84 S. haemolyticus isolates, 95.3% and 79.8%, respectively, carried at least one enterotoxin gene. The most frequent enterotoxin genes were sea (53.3%), seg (64.5%) and sei (67.5%). The seg gene was positively associated with S. epidermidis (p = 0.02), and this species was more toxigenic than S. haemolyticus. The hla/yidD gene was detected in 92.9% of S. epidermidis and the hla gene in 91.7% of S. haemolyticus isolates; hlb was detected in 92.9% of the S. epidermidis isolates and hld in 95.3%. Nosocomial Staphylococcus epidermidis and S. haemolyticus isolates exhibited a high toxigenic potential, mainly producing the non-classical enterotoxins seg and sei. The previously unreported detection of hla/yidD and hlb in S. epidermidis and S. haemolyticus using species-specific primers showed that these hemolysin genes differ between CoNS species and that they are highly frequent in blood culture isolates. Full article
(This article belongs to the Section Bacterial Toxins)
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Article
Scorpion Toxin, BmP01, Induces Pain by Targeting TRPV1 Channel
by Md Abdul Hakim, Wenbin Jiang, Lei Luo, Bowen Li, Shilong Yang, Yuzhu Song and Ren Lai
Toxins 2015, 7(9), 3671-3687; https://doi.org/10.3390/toxins7093671 - 14 Sep 2015
Cited by 50 | Viewed by 7374
Abstract
The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from [...] Read more.
The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from scorpion venoms is available. Here, a pain-inducing peptide (BmP01) has been identified and characterized from the venoms of scorpion (Mesobuthus martensii). In an animal model, intraplantar injection of BmP01 in mouse hind paw showed significant acute pain in wild type (WT) mice but not in TRPV1 knock-out (TRPV1 KO) mice during 30 min recording. BmP01 evoked currents in WT dorsal root ganglion (DRG) neurons but had no effect on DRG neurons of TRPV1 KO mice. Furthermore, OPEN ACCESS Toxins 2015, 7 3672 BmP01 evoked currents on TRPV1-expressed HEK293T cells, but not on HEK293T cells without TRPV1. These results suggest that (1) BmP01 is one of the pain-inducing agents in scorpion venoms; and (2) BmP01 induces pain by acting on TRPV1. To our knowledge, this is the first report about a scorpion toxin that produces pain by targeting TRPV1. Identification of a pain-inducing compound may facilitate treating pain induced by scorpion envenomation. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Article
Open Field Study of Some Zea mays Hybrids, Lipid Compounds and Fumonisins Accumulation
by Paola Giorni, Chiara Dall'Asta, Massimo Reverberi, Valeria Scala, Matteo Ludovici, Martina Cirlini, Gianni Galaverna, Corrado Fanelli and Paola Battilani
Toxins 2015, 7(9), 3657-3670; https://doi.org/10.3390/toxins7093657 - 11 Sep 2015
Cited by 9 | Viewed by 5144
Abstract
Lipid molecules are increasingly recognized as signals exchanged by organisms interacting in pathogenic and/or symbiotic ways. Some classes of lipids actively determine the fate of the interactions. Host cuticle/cell wall/membrane components such as sphingolipids and oxylipins may contribute to determining the fate of [...] Read more.
Lipid molecules are increasingly recognized as signals exchanged by organisms interacting in pathogenic and/or symbiotic ways. Some classes of lipids actively determine the fate of the interactions. Host cuticle/cell wall/membrane components such as sphingolipids and oxylipins may contribute to determining the fate of host–pathogen interactions. In the present field study, we considered the relationship between specific sphingolipids and oxylipins of different hybrids of Zea mays and fumonisin by F. verticillioides, sampling ears at different growth stages from early dough to fully ripe. The amount of total and free fumonisin differed significantly between hybrids and increased significantly with maize ripening. Oxylipins and phytoceramides changed significantly within the hybrids and decreased with kernel maturation, starting from physiological maturity. Although the correlation between fumonisin accumulation and plant lipid profile is certain, the data collected so far cannot define a cause-effect relationship but open up new perspectives. Therefore, the question—“Does fumonisin alter plant lipidome or does plant lipidome modulate fumonisin accumulation?”—is still open. Full article
(This article belongs to the Special Issue Mycotoxins and Human Diseases 2015)
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Article
Quantitative Analysis of Staphylococcal Enterotoxins A and B in Food Matrices Using Ultra High-Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS)
by Aida Zuberovic Muratovic, Thomas Hagström, Johan Rosén, Kristina Granelli and Karl-Erik Hellenäs
Toxins 2015, 7(9), 3637-3656; https://doi.org/10.3390/toxins7093637 - 11 Sep 2015
Cited by 36 | Viewed by 6913
Abstract
A method that uses mass spectrometry (MS) for identification and quantification of protein toxins, staphylococcal enterotoxins A and B (SEA and SEB), in milk and shrimp is described. The analysis was performed using a tryptic peptide, from each of the toxins, as the [...] Read more.
A method that uses mass spectrometry (MS) for identification and quantification of protein toxins, staphylococcal enterotoxins A and B (SEA and SEB), in milk and shrimp is described. The analysis was performed using a tryptic peptide, from each of the toxins, as the target analyte together with the corresponding 13C-labeled synthetic internal standard peptide. The performance of the method was evaluated by analyzing spiked samples in the quantification range 2.5–30 ng/g (R2 = 0.92–0.99). The limit of quantification (LOQ) in milk and the limit of detection (LOD) in shrimp was 2.5 ng/g, for both SEA and SEB toxins. The in-house reproducibility (RSD) was 8%–30% and 5%–41% at different concentrations for milk and shrimp, respectively. The method was compared to the ELISA method, used at the EU-RL (France), for milk samples spiked with SEA at low levels, in the quantification range of 2.5 to 5 ng/g. The comparison showed good coherence for the two methods: 2.9 (MS)/1.8 (ELISA) and 3.6 (MS)/3.8 (ELISA) ng/g. The major advantage of the developed method is that it allows direct confirmation of the molecular identity and quantitative analysis of SEA and SEB at low nanogram levels using a label and antibody free approach. Therefore, this method is an important step in the development of alternatives to the immune-assay tests currently used for staphylococcal enterotoxin analysis. Full article
(This article belongs to the Collection Rapid Detection of Bacterial Toxins)
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Addendum
Addendum: Qian, C.; Fang, Q.; Wang, L.; Ye, G.Y. Molecular Cloning and Functional Studies of Two Kazal-Type Serine Protease Inhibitors Specifically Expressed by Nasonia vitripennis Venom Apparatus. Toxins 2015, 7, 2888–2905
by Cen Qian, Qi Fang, Lei Wang and Gong-Yin Ye
Toxins 2015, 7(9), 3636; https://doi.org/10.3390/toxins7093636 - 11 Sep 2015
Viewed by 3274
Abstract
This research was supported by grants from the National Program on Key Basic Research Projects (973 Program, 2013CB127600), the National Natural Science Foundation of China (Grant Nos. 31272098, 31472038, 31402018), the Research Fund for the Doctoral Program of Higher Education of China (Grant [...] Read more.
This research was supported by grants from the National Program on Key Basic Research Projects (973 Program, 2013CB127600), the National Natural Science Foundation of China (Grant Nos. 31272098, 31472038, 31402018), the Research Fund for the Doctoral Program of Higher Education of China (Grant Number 2012010113004), the National Science Fund for Innovative Research Groups of Biological Control (Grant No. 31321063), the Zhejiang Provincial Natural Science Foundation of China (Grant Number Y14C140006) and the Fundamental Research Funds for the Central Universities (Grant Number 2014FZA6014). [...] Full article
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Article
Ochratoxin A Dietary Exposure of Ten Population Groups in the Czech Republic: Comparison with Data over the World
by Vladimir Ostry, Frantisek Malir, Marcela Dofkova, Jarmila Skarkova, Annie Pfohl-Leszkowicz and Jiri Ruprich
Toxins 2015, 7(9), 3608-3635; https://doi.org/10.3390/toxins7093608 - 10 Sep 2015
Cited by 51 | Viewed by 6561
Abstract
Ochratoxin A is a nephrotoxic and renal carcinogenic mycotoxin and is a common contaminant of various food commodities. Eighty six kinds of foodstuffs (1032 food samples) were collected in 2011–2013. High-performance liquid chromatography with fluorescence detection was used for ochratoxin A determination. Limit [...] Read more.
Ochratoxin A is a nephrotoxic and renal carcinogenic mycotoxin and is a common contaminant of various food commodities. Eighty six kinds of foodstuffs (1032 food samples) were collected in 2011–2013. High-performance liquid chromatography with fluorescence detection was used for ochratoxin A determination. Limit of quantification of the method varied between 0.01–0.2 μg/kg depending on the food matrices. The most exposed population is children aged 4–6 years old. Globally for this group, the maximum ochratoxin A dietary exposure for “average consumer” was estimated at 3.3 ng/kg bw/day (lower bound, considering the analytical values below the limit of quantification as 0) and 3.9 ng/kg bw/day (middle bound, considering the analytical values below the limit of quantification as 1/2 limit of quantification). Important sources of exposure for this latter group include grain-based products, confectionery, meat products and fruit juice. The dietary intake for “high consumers” in the group 4–6 years old was estimated from grains and grain-based products at 19.8 ng/kg bw/day (middle bound), from tea at 12.0 ng/kg bw/day (middle bound) and from confectionery at 6.5 ng/kg bw/day (middle bound). For men aged 18–59 years old beer was the main contributor with an intake of 2.60 ng/kg bw/day (“high consumers”, middle bound). Tea and grain-based products were identified to be the main contributors for dietary exposure in women aged 18–59 years old. Coffee and wine were identified as a higher contributor of the OTA intake in the population group of women aged 18–59 years old compared to the other population groups. Full article
(This article belongs to the Collection Ochratoxins-Collection)
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Article
Evolution of Chemical Diversity in a Group of Non-Reduced Polyketide Gene Clusters: Using Phylogenetics to Inform the Search for Novel Fungal Natural Products
by Kurt Throckmorton, Philipp Wiemann and Nancy P. Keller
Toxins 2015, 7(9), 3572-3607; https://doi.org/10.3390/toxins7093572 - 10 Sep 2015
Cited by 27 | Viewed by 9036
Abstract
Fungal polyketides are a diverse class of natural products, or secondary metabolites (SMs), with a wide range of bioactivities often associated with toxicity. Here, we focus on a group of non-reducing polyketide synthases (NR-PKSs) in the fungal phylum Ascomycota that lack a thioesterase [...] Read more.
Fungal polyketides are a diverse class of natural products, or secondary metabolites (SMs), with a wide range of bioactivities often associated with toxicity. Here, we focus on a group of non-reducing polyketide synthases (NR-PKSs) in the fungal phylum Ascomycota that lack a thioesterase domain for product release, group V. Although widespread in ascomycete taxa, this group of NR-PKSs is notably absent in the mycotoxigenic genus Fusarium and, surprisingly, found in genera not known for their secondary metabolite production (e.g., the mycorrhizal genus Oidiodendron, the powdery mildew genus Blumeria, and the causative agent of white-nose syndrome in bats, Pseudogymnoascus destructans). This group of NR-PKSs, in association with the other enzymes encoded by their gene clusters, produces a variety of different chemical classes including naphthacenediones, anthraquinones, benzophenones, grisandienes, and diphenyl ethers. We discuss the modification of and transitions between these chemical classes, the requisite enzymes, and the evolution of the SM gene clusters that encode them. Integrating this information, we predict the likely products of related but uncharacterized SM clusters, and we speculate upon the utility of these classes of SMs as virulence factors or chemical defenses to various plant, animal, and insect pathogens, as well as mutualistic fungi. Full article
(This article belongs to the Collection Evolutionary/Phylogenetic Studies of Mycotoxin Biosynthetic Pathways)
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827 KiB  
Article
Development of a Rapid LC-MS/MS Method for the Determination of Emerging Fusarium mycotoxins Enniatins and Beauvericin in Human Biological Fluids
by Ana Belén Serrano, Anna Laura Capriotti, Chiara Cavaliere, Susy Piovesana, Roberto Samperi, Salvatore Ventura and Aldo Laganà
Toxins 2015, 7(9), 3554-3571; https://doi.org/10.3390/toxins7093554 - 9 Sep 2015
Cited by 47 | Viewed by 5864
Abstract
A novel method for the simultaneous determination of enniatins A, A1, B and B1 and beauvericin, both in human urine and plasma samples, was developed and validated. The method consisted of a simple and easy pretreatment, specific for each matrix, followed by solid [...] Read more.
A novel method for the simultaneous determination of enniatins A, A1, B and B1 and beauvericin, both in human urine and plasma samples, was developed and validated. The method consisted of a simple and easy pretreatment, specific for each matrix, followed by solid phase extraction (SPE) and detection by high performance liquid chromatography-tandem mass spectrometry with an electrospray ion source. The optimized SPE method was performed on graphitized carbon black cartridges after suitable dilution of the extracts, which allowed high mycotoxin absolute recoveries (76%–103%) and the removal of the major interferences from the matrix. The method was extensively evaluated for plasma and urine samples separately, providing satisfactory results in terms of linearity (R2 of 0.991–0.999), process efficiency (>81%), trueness (recoveries between 85% and 120%), intra-day precision (relative standard deviation, RSD < 18%), inter-day precision (RSD < 21%) and method quantification limits (ranging between 20 ng·L−1 and 40 ng·L−1 in plasma and between 5 ng·L−1 and 20 ng·L−1 in urine). Finally, the highly sensitive validated method was applied to some urine and plasma samples from different donors. Full article
(This article belongs to the Section Mycotoxins)
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1923 KiB  
Article
Aflatoxin B1 Detection Using a Highly-Sensitive Molecularly-Imprinted Electrochemical Sensor Based on an Electropolymerized Metal Organic Framework
by Mengjuan Jiang, Mohamed Braiek, Anca Florea, Amani Chrouda, Carole Farre, Anne Bonhomme, Francois Bessueille, Francis Vocanson, Aidong Zhang and Nicole Jaffrezic-Renault
Toxins 2015, 7(9), 3540-3553; https://doi.org/10.3390/toxins7093540 - 7 Sep 2015
Cited by 67 | Viewed by 8978
Abstract
A sensitive electrochemical molecularly-imprinted sensor was developed for the detection of aflatoxin B1 (AFB1), by electropolymerization of p-aminothiophenol-functionalized gold nanoparticles in the presence of AFB1 as a template molecule. The extraction of the template leads to the formation of cavities that are [...] Read more.
A sensitive electrochemical molecularly-imprinted sensor was developed for the detection of aflatoxin B1 (AFB1), by electropolymerization of p-aminothiophenol-functionalized gold nanoparticles in the presence of AFB1 as a template molecule. The extraction of the template leads to the formation of cavities that are able to specifically recognize and bind AFB1 through π-π interactions between AFB1 molecules and aniline moities. The performance of the developed sensor for the detection of AFB1 was investigated by linear sweep voltammetry using a hexacyanoferrate/hexacyanoferrite solution as a redox probe, the electron transfer rate increasing when the concentration of AFB1 increases, due to a p-doping effect. The molecularly-imprinted sensor exhibits a broad linear range, between 3.2 fM and 3.2 µM, and a quantification limit of 3 fM. Compared to the non-imprinted sensor, the imprinting factor was found to be 10. Selectivity studies were also performed towards the binding of other aflatoxins and ochratoxin A, proving good selectivity. Full article
(This article belongs to the Collection Biorecognition Assays for Mycotoxins)
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293 KiB  
Correction
Correction: Sangare, L., et al. Aflatoxin B1 Degradation by a Pseudomonas Strain. Toxins 2014, 6, 3028–3040
by Lancine Sangare, Yueju Zhao, Yawa Minnie Elodie Folly, Jinghua Chang, Jinhan Li, Jonathan Nimal Selvaraj, Fuguo Xing, Lu Zhou, Yan Wang and Yang Liu
Toxins 2015, 7(9), 3538-3539; https://doi.org/10.3390/toxins7093538 - 2 Sep 2015
Cited by 5 | Viewed by 3707
Abstract
The authors are sorry to report that the legend of Figure 5 in their published paper [1] was incorrect. [...] Full article
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Article
Taxonomic Characterization and Secondary Metabolite Profiling of Aspergillus Section Aspergillus Contaminating Feeds and Feedstuffs
by Mariana Greco, Minna Kemppainen, Graciela Pose and Alejandro Pardo
Toxins 2015, 7(9), 3512-3537; https://doi.org/10.3390/toxins7093512 - 2 Sep 2015
Cited by 27 | Viewed by 7620
Abstract
Xerophilic fungal species of the genus Aspergillus are economically highly relevant due to their ability to grow on low water activity substrates causing spoilage of stored goods and animal feeds. These fungi can synthesize a variety of secondary metabolites, many of which show [...] Read more.
Xerophilic fungal species of the genus Aspergillus are economically highly relevant due to their ability to grow on low water activity substrates causing spoilage of stored goods and animal feeds. These fungi can synthesize a variety of secondary metabolites, many of which show animal toxicity, creating a health risk for food production animals and to humans as final consumers, respectively. Animal feeds used for rabbit, chinchilla and rainbow trout production in Argentina were analysed for the presence of xerophilic Aspergillus section Aspergillus species. High isolation frequencies (>60%) were detected in all the studied rabbit and chinchilla feeds, while the rainbow trout feeds showed lower fungal charge (25%). These section Aspergillus contaminations comprised predominantly five taxa. Twenty isolates were subjected to taxonomic characterization using both ascospore SEM micromorphology and two independent DNA loci sequencing. The secondary metabolite profiles of the isolates were determined qualitatively by HPLC-MS. All the isolates produced neoechinulin A, 17 isolates were positive for cladosporin and echinulin, and 18 were positive for neoechinulin B. Physcion and preechinulin were detected in a minor proportion of the isolates. This is the first report describing the detailed species composition and the secondary metabolite profiles of Aspergillus section Aspergillus contaminating animal feeds. Full article
(This article belongs to the Section Mycotoxins)
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Article
Mass Spectrometric Detection of Bacterial Protein Toxins and Their Enzymatic Activity
by Suzanne R. Kalb, Anne E. Boyer and John R. Barr
Toxins 2015, 7(9), 3497-3511; https://doi.org/10.3390/toxins7093497 - 31 Aug 2015
Cited by 28 | Viewed by 6896
Abstract
Mass spectrometry has recently become a powerful technique for bacterial identification. Mass spectrometry approaches generally rely upon introduction of the bacteria into a matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometer with mass spectrometric recognition of proteins specific to that organism that form a reliable [...] Read more.
Mass spectrometry has recently become a powerful technique for bacterial identification. Mass spectrometry approaches generally rely upon introduction of the bacteria into a matrix-assisted laser-desorption time-of-flight (MALDI-TOF) mass spectrometer with mass spectrometric recognition of proteins specific to that organism that form a reliable fingerprint. With some bacteria, such as Bacillus anthracis and Clostridium botulinum, the health threat posed by these organisms is not the organism itself, but rather the protein toxins produced by the organisms. One such example is botulinum neurotoxin (BoNT), a potent neurotoxin produced by C. botulinum. There are seven known serotypes of BoNT, A–G, and many of the serotypes can be further differentiated into toxin variants, which are up to 99.9% identical in some cases. Mass spectrometric proteomic techniques have been established to differentiate the serotype or toxin variant of BoNT produced by varied strains of C. botulinum. Detection of potent biological toxins requires high analytical sensitivity and mass spectrometry based methods have been developed to determine the enzymatic activity of BoNT and the anthrax lethal toxins produced by B. anthracis. This enzymatic activity, unique for each toxin, is assessed with detection of the toxin-induced cleavage of strategically designed peptide substrates by MALDI-TOF mass spectrometry offering unparalleled specificity. Furthermore, activity assays allow for the assessment of the biological activity of a toxin and its potential health risk. Such methods have become important diagnostics for botulism and anthrax. Here, we review mass spectrometry based methods for the enzymatic activity of BoNT and the anthrax lethal factor toxin. Full article
(This article belongs to the Collection Rapid Detection of Bacterial Toxins)
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Article
Development of a Monoclonal Antibody-Based icELISA for the Detection of Ustiloxin B in Rice False Smut Balls and Rice Grains
by Xiaoxiang Fu, Ali Wang, Xiaohan Wang, Fengke Lin, Lishan He, Daowan Lai, Yang Liu, Qing X. Li, Ligang Zhou and Baoming Wang
Toxins 2015, 7(9), 3481-3496; https://doi.org/10.3390/toxins7093481 - 28 Aug 2015
Cited by 21 | Viewed by 6313
Abstract
Rice false smut is an emerging and economically-important rice disease caused by infection by the fungal pathogen Villosiclava virens. Ustiloxin B is an antimitotic cyclopeptide mycotoxin isolated from the rice false smut balls that formed in the pathogen-infected rice spikelets. A monoclonal [...] Read more.
Rice false smut is an emerging and economically-important rice disease caused by infection by the fungal pathogen Villosiclava virens. Ustiloxin B is an antimitotic cyclopeptide mycotoxin isolated from the rice false smut balls that formed in the pathogen-infected rice spikelets. A monoclonal antibody (mAb) designated as mAb 1B5A10 was generated with ustiloxin B—ovalbumin conjugate. A highly-sensitive and specific indirect competitive enzyme-linked immunosorbent assay (icELISA) was then developed. The median inhibitory concentration (IC50) of the icELISA was 18.0 ng/mL for the detection of ustiloxin B; the limit of detection was 0.6 ng/mL, and the calibration range was from 2.5 to 107.4 ng/mL. The LOD/LOQ values of the developed ELISA used for the determination of ustiloxin B in rice false smut balls and rice grains were 12/50 μg/g and 30/125 ng/g, respectively. The mAb 1B5A10 cross-reacted with ustiloxin A at 13.9% relative to ustiloxin B. Average recoveries of ustiloxin B ranged from 91.3% to 105.1% for rice false smut balls at spiking levels of 0.2 to 3.2 mg/g and from 92.6% to 103.5% for rice grains at spiking levels of 100 to 5000 ng/g. Comparison of ustiloxin B content in rice false smut balls and rice grains detected by both icELISA and high performance liquid chromatography (HPLC) demonstrated that the developed icELISA can be employed as an effective and accurate method for the detection of ustiloxin B in rice false smut balls, as well as rice food and feed samples. Full article
(This article belongs to the Collection Biorecognition Assays for Mycotoxins)
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Article
Effects of Dietary Exposure to Zearalenone (ZEN) on Carp (Cyprinus carpio L.)
by Constanze Pietsch, Susanne Kersten, Hana Valenta, Sven Dänicke, Carsten Schulz, Patricia Burkhardt-Holm and Ranka Junge
Toxins 2015, 7(9), 3465-3480; https://doi.org/10.3390/toxins7093465 - 26 Aug 2015
Cited by 30 | Viewed by 7310
Abstract
The mycotoxin zearalenone (ZEN) is frequently contaminating animal feeds including feed used in aquaculture. In the present study, the effects of dietary exposure to ZEN on carp (Cyprinus carpio L.) were investigated. ZEN at three different concentrations (low dose: 332 µg kg [...] Read more.
The mycotoxin zearalenone (ZEN) is frequently contaminating animal feeds including feed used in aquaculture. In the present study, the effects of dietary exposure to ZEN on carp (Cyprinus carpio L.) were investigated. ZEN at three different concentrations (low dose: 332 µg kg−1, medium dose: 621 µg kg−1 and high dose: 797 µg kg−1 final feed, respectively) was administered to juvenile carp for four weeks. Additional groups received the mycotoxin for the same time period but were fed with the uncontaminated diet for two more weeks to examine the reversibility of the ZEN effects. No effects on growth were observed during the feeding trial, but effects on haematological parameters occurred. In addition, an influence on white blood cell counts was noted whereby granulocytes and monocytes were affected in fish treated with the medium and high dose ZEN diet. In muscle samples, marginal ZEN and α-zearalenol (α-ZEL) concentrations were detected. Furthermore, the genotoxic potential of ZEN was confirmed by analysing formation of micronuclei in erythrocytes. In contrast to previous reports on other fish species, estrogenic effects measured as vitellogenin concentrations in serum samples were not increased by dietary exposure to ZEN. This is probably due to the fact that ZEN is rapidly metabolized in carp. Full article
(This article belongs to the Collection Understanding Mycotoxin Occurrence in Food and Feed Chains)
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Article
Effects of a Calcium Bentonite Clay in Diets Containing Aflatoxin when Measuring Liver Residues of Aflatoxin B1 in Starter Broiler Chicks
by Justin Fowler, Wei Li and Christopher Bailey
Toxins 2015, 7(9), 3455-3464; https://doi.org/10.3390/toxins7093455 - 26 Aug 2015
Cited by 40 | Viewed by 6505
Abstract
Research has shown success using clay-based binders to adsorb aflatoxin in animal feeds; however, no adsorbent has been approved for the prevention or treatment of aflatoxicosis. In this study, growth and relative organ weights were evaluated along with a residue analysis for aflatoxin [...] Read more.
Research has shown success using clay-based binders to adsorb aflatoxin in animal feeds; however, no adsorbent has been approved for the prevention or treatment of aflatoxicosis. In this study, growth and relative organ weights were evaluated along with a residue analysis for aflatoxin B1 in liver tissue collected from broiler chickens consuming dietary aflatoxin (0, 600, 1200, and 1800 µg/kg) both with and without 0.2% of a calcium bentonite clay additive (TX4). After one week, only the combined measure of a broiler productivity index was significantly affected by 1800 µg/kg aflatoxin. However, once birds had consumed treatment diets for two weeks, body weights and relative kidney weights were affected by the lowest concentration. Then, during the third week, body weights, feed conversion, and the productivity index were affected by the 600 µg/kg level. Results also showed that 0.2% TX4 was effective at reducing the accumulation of aflatoxin B1 residues in the liver and improving livability in birds fed aflatoxin. The time required to clear all residues from the liver was less than one week. With evidence that the liver’s ability to process aflatoxin becomes relatively efficient within three weeks, this would imply that an alternative strategy for handling aflatoxin contamination in feed could be to allow a short, punctuated exposure to a higher level, so long as that exposure is followed by at least a week of a withdrawal period on a clean diet free of aflatoxin. Full article
(This article belongs to the Section Mycotoxins)
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Article
Tetrodotoxin and Its Analogues in the Pufferfish Arothron hispidus and A. nigropunctatus from the Solomon Islands: A Comparison of Their Toxin Profiles with the Same Species from Okinawa, Japan
by Clyde Gorapava Puilingi, Yuta Kudo, Yuko Cho, Keiichi Konoki and Mari Yotsu-Yamashita
Toxins 2015, 7(9), 3436-3454; https://doi.org/10.3390/toxins7093436 - 26 Aug 2015
Cited by 25 | Viewed by 7625
Abstract
Pufferfish poisoning has not been well documented in the South Pacific, although fish and other seafood are sources of protein in these island nations. In this study, tetrodotoxin (TTX) and its analogues in each organ of the pufferfish Arothron hispidus and A. nigropunctatus [...] Read more.
Pufferfish poisoning has not been well documented in the South Pacific, although fish and other seafood are sources of protein in these island nations. In this study, tetrodotoxin (TTX) and its analogues in each organ of the pufferfish Arothron hispidus and A. nigropunctatus collected in the Solomon Islands were investigated using high resolution LC-MS. The toxin profiles of the same two species of pufferfish from Okinawa, Japan were also examined for comparison. TTXs concentrations were higher in the skin of both species from both regions, and relatively lower in the liver, ovary, testis, stomach, intestine, and flesh. Due to higher TTX concentrations (51.0 and 28.7 µg/g at highest) detected in the skin of the two species from the Solomon Islands (saxitoxin was <0.02 µg/g), these species should be banned from consumption. Similar results were obtained from fish collected in Okinawa, Japan: TTX in the skin of A. hispidus and A. nigropunctatus were 12.7 and 255 µg/g, respectively, at highest, and saxitoxin was also detected in the skin (2.80 µg/g at highest) and ovary of A. hispidus. TTX, 5,6,11-trideoxyTTX (with its 4-epi form), and its anhydro forms were the most abundant, and 11-oxoTTX was commonly detected in the skin. Full article
(This article belongs to the Collection Marine and Freshwater Toxins)
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Article
Intradetrusorial Botulinum Toxin in Patients with Multiple Sclerosis: A Neurophysiological Study
by Antonella Conte, Antonella Giannantoni, Marilena Gubbiotti, Simona Pontecorvo, Enrico Millefiorini, Ada Francia, Massimo Porena and Alfredo Berardelli
Toxins 2015, 7(9), 3424-3435; https://doi.org/10.3390/toxins7093424 - 26 Aug 2015
Cited by 5 | Viewed by 4831
Abstract
Patients with multiple sclerosis (MS) often complain of urinary disturbances characterized by overactive bladder syndrome and difficulties in bladder emptying. The aim of the study was to investigate the pathophysiology of bladder dysfunction and the neurophysiological effects of intradetrusorial incobotulinum toxin A (BoNT/A) [...] Read more.
Patients with multiple sclerosis (MS) often complain of urinary disturbances characterized by overactive bladder syndrome and difficulties in bladder emptying. The aim of the study was to investigate the pathophysiology of bladder dysfunction and the neurophysiological effects of intradetrusorial incobotulinum toxin A (BoNT/A) in patients with MS having both brain and spinal MS-related lesions. Twenty-five MS patients with neurogenic detrusor overactivity (NDO) underwent clinical evaluation and soleus Hoffmann reflex (H reflex) study during urodynamics. Of the 25 patients, 14 underwent a further session one month after intradetrusorial BoNT/A injection. Eighteen healthy subjects acted as the control. In healthy subjects, the H reflex size significantly decreased at maximum cystometric capacity (MCC), whereas in MS patients with NDO, the H reflex remained unchanged. In the patients who received intradetrusorial BoNT/A, clinical and urodynamic investigations showed that NDO improved significantly. Volumes at the first, normal and strong desire to void and MCC increased significantly. Despite its efficacy in improving bladder symptoms and in increasing volumes for first desire, normal and strong desire to void, BoNT/A left the H reflex modulation during bladder filling unchanged. In the MS patients we studied having both brain and spinal MS-related lesions, the H reflex size remained unchanged at maximum bladder filling. Since this neurophysiological pattern has been previously found in patients with spinal cord injury, we suggest that bladder dysfunction arises from the MS-related spinal lesions. BoNT/A improves bladder dysfunction by changing bladder afferent input, as shown by urodynamic findings on bladder filling sensations, but its effects on H reflex modulation remain undetectable. Full article
(This article belongs to the Section Bacterial Toxins)
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Article
Monoclonal Antibodies that Inhibit the Proteolytic Activity of Botulinum Neurotoxin Serotype/B
by Yongfeng Fan, Jianbo Dong, Jianlong Lou, Weihua Wen, Fraser Conrad, Isin N. Geren, Consuelo Garcia-Rodriguez, Theresa J. Smith, Leonard A. Smith, Mengfei Ho, Melissa Pires-Alves, Brenda A. Wilson and James D. Marks
Toxins 2015, 7(9), 3405-3423; https://doi.org/10.3390/toxins7093405 - 26 Aug 2015
Cited by 19 | Viewed by 5808
Abstract
Existing antibodies (Abs) used to treat botulism cannot enter the cytosol of neurons and bind to botulinum neurotoxin (BoNT) at its site of action, and thus cannot reverse paralysis. However, Abs targeting the proteolytic domain of the toxin could inhibit the proteolytic activity [...] Read more.
Existing antibodies (Abs) used to treat botulism cannot enter the cytosol of neurons and bind to botulinum neurotoxin (BoNT) at its site of action, and thus cannot reverse paralysis. However, Abs targeting the proteolytic domain of the toxin could inhibit the proteolytic activity of the toxin intracellularly and potentially reverse intoxication, if they could be delivered intracellularly. As such, antibodies that neutralize toxin activity could serve as potent inhibitory cargos for therapeutic antitoxins against botulism. BoNT serotype B (BoNT/B) contains a zinc endopeptidase light chain (LC) domain that cleaves synaoptobrevin-2, a SNARE protein responsible for vesicle fusion and acetylcholine vesicle release. To generate monoclonal Abs (mAbs) that could reverse paralysis, we targeted the protease domain for Ab generation. Single-chain variable fragment (scFv) libraries from immunized mice or humans were displayed on yeast, and 19 unique BoNT/B LC-specific mAbs isolated by fluorescence-activated cell sorting (FACS). The equilibrium dissociation constants (KD) of these mAbs for BoNT/B LC ranged from 0.24 nM to 14.3 nM (mean KD 3.27 nM). Eleven mAbs inhibited BoNT/B LC proteolytic activity. The fine epitopes of selected mAbs were identified by alanine-scanning mutagenesis, revealing that inhibitory mAbs bound near the active site, substrate-binding site or the extended substrate-binding site. The results provide mAbs that could prove useful for intracellular reversal of paralysis and identify epitopes that could be targeted by small molecules inhibitors. Full article
(This article belongs to the Section Bacterial Toxins)
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Review
The Role of Botulinum Toxin Type A in the Clinical Management of Refractory Anterior Knee Pain
by Barbara J. Singer, Benjamin I. Silbert, Peter L. Silbert and Kevin P. Singer
Toxins 2015, 7(9), 3388-3404; https://doi.org/10.3390/toxins7093388 - 25 Aug 2015
Cited by 8 | Viewed by 8054
Abstract
Anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults. Symptoms can recur in more than two thirds of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits. Persistent anterior knee pain is [...] Read more.
Anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults. Symptoms can recur in more than two thirds of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits. Persistent anterior knee pain is difficult to treat and many individuals eventually consider a surgical intervention. Evidence for long term benefit of most conservative treatments or surgical approaches is currently lacking. Injection of Botulinum toxin type A to the distal region of vastus lateralis muscle causes a short term functional “denervation” which moderates the influence of vastus lateralis muscle on the knee extensor mechanism and increases the relative contribution of the vastus medialis muscle. Initial data suggest that, compared with other interventions for anterior knee pain, Botulinum toxin type A injection, in combination with an active exercise programme, can lead to sustained relief of symptoms, reduced health care utilisation and increased activity participation. The procedure is less invasive than surgical intervention, relatively easy to perform, and is time- and cost-effective. Further studies, including larger randomized placebo-controlled trials, are required to confirm the effectiveness of Botulinum toxin type A injection for anterior knee pain and to elaborate the possible mechanisms underpinning pain and symptom relief. Full article
(This article belongs to the Collection Botulinum Toxins on Human Pain)
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Article
Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice
by Kyung-Hyun Kim, Hyun-Jung Sung, Woo-Ram Lee, Hyun-Jin An, Jung-Yeon Kim, Sok Cheon Pak, Sang-Mi Han and Kwan-Kyu Park
Toxins 2015, 7(9), 3372-3387; https://doi.org/10.3390/toxins7093372 - 25 Aug 2015
Cited by 18 | Viewed by 6778
Abstract
Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic [...] Read more.
Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy. Full article
(This article belongs to the Special Issue Bee and Wasp Venoms: Biological Characteristics and Therapeutic Application)
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