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Toxins, Volume 7, Issue 10 (October 2015) – 35 articles , Pages 3845-4389

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Brief Report
Quantitative Detection of Shiga Toxins Directly from Stool Specimens of Patients Associated with an Outbreak of Enterohemorrhagic Escherichia coli in Japan—Quantitative Shiga toxin detection from stool during EHEC outbreak
Toxins 2015, 7(10), 4381-4389; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104381 - 27 Oct 2015
Cited by 9 | Viewed by 2461
Abstract
Detection of Shiga toxins (Stx) is important for accurate diagnosis of Enterohemorrhagic Escherichia coli infection. In this study, we quantitatively analyzed Stx protein in nine patients’ stool during an outbreak that occurred in Japan. Highly sensitive immunoassay (bead enzyme-linked immunosorbent assay (bead-ELISA)) revealed [...] Read more.
Detection of Shiga toxins (Stx) is important for accurate diagnosis of Enterohemorrhagic Escherichia coli infection. In this study, we quantitatively analyzed Stx protein in nine patients’ stool during an outbreak that occurred in Japan. Highly sensitive immunoassay (bead enzyme-linked immunosorbent assay (bead-ELISA)) revealed that the concentrations of toxins in stool of patients ranged from 0.71 to 10.44 ng/mL for Stx1 and 2.75 to 51.61 ng/mL for Stx2. To our knowledge, this is the first report that reveals the range of Stx protein concentrations in human stools. Full article
(This article belongs to the Collection Rapid Detection of Bacterial Toxins)
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Article
The Cystine Knot Is Responsible for the Exceptional Stability of the Insecticidal Spider Toxin ω-Hexatoxin-Hv1a
Toxins 2015, 7(10), 4366-4380; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104366 - 26 Oct 2015
Cited by 63 | Viewed by 3704
Abstract
The inhibitor cystine knot (ICK) is an unusual three-disulfide architecture in which one of the disulfide bonds bisects a loop formed by the two other disulfide bridges and the intervening sections of the protein backbone. Peptides containing an ICK motif are frequently considered [...] Read more.
The inhibitor cystine knot (ICK) is an unusual three-disulfide architecture in which one of the disulfide bonds bisects a loop formed by the two other disulfide bridges and the intervening sections of the protein backbone. Peptides containing an ICK motif are frequently considered to have high levels of thermal, chemical and enzymatic stability due to cross-bracing provided by the disulfide bonds. Experimental studies supporting this contention are rare, in particular for spider-venom toxins, which represent the largest diversity of ICK peptides. We used ω-hexatoxin-Hv1a (Hv1a), an insecticidal toxin from the deadly Australian funnel-web spider, as a model system to examine the contribution of the cystine knot to the stability of ICK peptides. We show that Hv1a is highly stable when subjected to temperatures up to 75 °C, pH values as low as 1, and various organic solvents. Moreover, Hv1a was highly resistant to digestion by proteinase K and when incubated in insect hemolymph and human plasma. We demonstrate that the ICK motif is essential for the remarkable stability of Hv1a, with the peptide’s stability being dramatically reduced when the disulfide bonds are eliminated. Thus, this study demonstrates that the ICK motif significantly enhances the chemical and thermal stability of spider-venom peptides and provides them with a high level of protease resistance. This study also provides guidance to the conditions under which Hv1a could be stored and deployed as a bioinsecticide. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Article
Differential Adsorption of Ochratoxin A and Anthocyanins by Inactivated Yeasts and Yeast Cell Walls during Simulation of Wine Aging
Toxins 2015, 7(10), 4350-4365; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104350 - 26 Oct 2015
Cited by 22 | Viewed by 3045
Abstract
The adsorption of ochratoxin A (OTA) by yeasts is a promising approach for the decontamination of musts and wines, but some potential competitive or interactive phenomena between mycotoxin, yeast cells, and anthocyanins might modify the intensity of the phenomenon. The aim of this [...] Read more.
The adsorption of ochratoxin A (OTA) by yeasts is a promising approach for the decontamination of musts and wines, but some potential competitive or interactive phenomena between mycotoxin, yeast cells, and anthocyanins might modify the intensity of the phenomenon. The aim of this study was to examine OTA adsorption by two strains of Saccharomyces cerevisiae (the wild strain W13, and the commercial isolate BM45), previously inactivated by heat, and a yeast cell wall preparation. Experiments were conducted using Nero di Troia red wine contaminated with 2 μg/L OTA and supplemented with yeast biomass (20 g/L). The samples were analyzed periodically to assess mycotoxin concentration, chromatic characteristics, and total anthocyanins over 84 days of aging. Yeast cell walls revealed the highest OTA-adsorption in comparison to thermally-inactivated cells (50% vs. 43% toxin reduction), whilst no significant differences were found for the amount of adsorbed anthocyanins in OTA-contaminated and control wines. OTA and anthocyanins adsorption were not competitive phenomena. Unfortunately, the addition of yeast cells to wine could cause color loss; therefore, yeast selection should also focus on this trait to select the best strain. Full article
(This article belongs to the Collection Understanding Mycotoxin Occurrence in Food and Feed Chains)
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Review
AFM1 in Milk: Physical, Biological, and Prophylactic Methods to Mitigate Contamination
Toxins 2015, 7(10), 4330-4349; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104330 - 23 Oct 2015
Cited by 54 | Viewed by 4437
Abstract
Aflatoxins (AFs) are toxic, carcinogenic, immunosuppressive secondary metabolites produced by some Aspergillus species which colonize crops, including many dietary staple foods and feed components. AFB1 is the prevalent and most toxic among AFs. In the liver, it is biotransformed into AFM1 [...] Read more.
Aflatoxins (AFs) are toxic, carcinogenic, immunosuppressive secondary metabolites produced by some Aspergillus species which colonize crops, including many dietary staple foods and feed components. AFB1 is the prevalent and most toxic among AFs. In the liver, it is biotransformed into AFM1, which is then excreted into the milk of lactating mammals, including dairy animals. AFM1 has been shown to be cause of both acute and chronic toxicoses. The presence of AFM1 in milk and dairy products represents a worldwide concern since even small amounts of this metabolite may be of importance as long-term exposure is concerned. Contamination of milk may be mitigated either directly, decreasing the AFM1 content in contaminated milk, or indirectly, decreasing AFB1 contamination in the feed of dairy animals. Current strategies for AFM1 mitigation include good agricultural practices in pre-harvest and post-harvest management of feed crops (including storage) and physical or chemical decontamination of feed and milk. However, no single strategy offers a complete solution to the issue. Full article
(This article belongs to the Collection Aflatoxins)
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Article
Menadione-Induced Oxidative Stress Re-Shapes the Oxylipin Profile of Aspergillus flavus and Its Lifestyle
Toxins 2015, 7(10), 4315-4329; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104315 - 23 Oct 2015
Cited by 18 | Viewed by 3156
Abstract
Aspergillus flavus is an efficient producer of mycotoxins, particularly aflatoxin B1, probably the most hepatocarcinogenic naturally-occurring compound. Although the inducing agents of toxin synthesis are not unanimously identified, there is evidence that oxidative stress is one of the main actors in [...] Read more.
Aspergillus flavus is an efficient producer of mycotoxins, particularly aflatoxin B1, probably the most hepatocarcinogenic naturally-occurring compound. Although the inducing agents of toxin synthesis are not unanimously identified, there is evidence that oxidative stress is one of the main actors in play. In our study, we use menadione, a quinone extensively implemented in studies on ROS response in animal cells, for causing stress to A. flavus. For uncovering the molecular determinants that drive A. flavus in challenging oxidative stress conditions, we have evaluated a wide spectrum of several different parameters, ranging from metabolic (ROS and oxylipin profile) to transcriptional analysis (RNA-seq). There emerges a scenario in which A. flavus activates several metabolic processes under oxidative stress conditions for limiting the ROS-associated detrimental effects, as well as for triggering adaptive and escape strategies. Full article
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Article
Detoxification of Aflatoxin-Contaminated Maize by Neutral Electrolyzed Oxidizing Water
Toxins 2015, 7(10), 4294-4314; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104294 - 23 Oct 2015
Cited by 25 | Viewed by 3462
Abstract
Aflatoxins, a group of extremely toxic mycotoxins produced by Aspergillus flavus, A. parasiticus and A. nomius, can occur as natural contaminants of certain agricultural commodities, particularly maize. These toxins have been shown to be hepatotoxic, carcinogenic, mutagenic and cause severe human [...] Read more.
Aflatoxins, a group of extremely toxic mycotoxins produced by Aspergillus flavus, A. parasiticus and A. nomius, can occur as natural contaminants of certain agricultural commodities, particularly maize. These toxins have been shown to be hepatotoxic, carcinogenic, mutagenic and cause severe human and animal diseases. The effectiveness of neutral electrolyzed oxidizing water (NEW) on aflatoxin detoxification was investigated in HepG2 cells using several validation methodologies such as the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay, the induction of lipid peroxidation, the oxidative damage by means of glutathione modulation, the Ames test and the alkaline Comet assay. Our results showed that, after the aflatoxin-contaminated maize containing 360 ng/g was soaked in NEW (60 mg/L available chlorine, pH 7.01) during 15 min at room temperature, the aflatoxin content did not decrease as confirmed by the immunoaffinity column and ultra performance liquid chromatography methods. Aflatoxin fluorescence strength of detoxified samples was similar to untreated samples. However, aflatoxin-associated cytotoxicity and OPEN ACCESS Toxins 2015, 7 4295 genotoxicity effects were markedly reduced upon treatment. According to these results, NEW can be effectively used to detoxify aflatoxin-contaminated maize. Full article
(This article belongs to the Collection Aflatoxins)
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Article
Long-Term Efficacy and Safety of Repeated Intravescial OnabotulinumtoxinA Injections Plus Hydrodistention in the Treatment of Interstitial Cystitis/Bladder Pain Syndrome
Toxins 2015, 7(10), 4283-4293; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104283 - 22 Oct 2015
Cited by 21 | Viewed by 2297
Abstract
Intravesical onabotulinumtoxinA (BoNT-A) injection can relieve symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks sustainability. Repeated injections have been shown to provide a superior outcome to a single injection, but data on long-term efficacy and safety is limited. In this prospective study, [...] Read more.
Intravesical onabotulinumtoxinA (BoNT-A) injection can relieve symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), but lacks sustainability. Repeated injections have been shown to provide a superior outcome to a single injection, but data on long-term efficacy and safety is limited. In this prospective study, we enrolled patients with refractory IC/BPS, and treated them with 100 U of BoNT-A injection plus hydrodistention followed by repeated injections every six months for up to two years or until the patient wished to discontinue. A “top-up” dose was offered after the fourth injection. Of these 104 participants, 56.7% completed four BoNT-A injections and 34% voluntarily received the fifth injection due to exacerbated IC symptoms. With a follow-up period of up to 79 months, O’Leary-Sant symptom and problem indexes (ICSI, ICPI, OSS), pain visual analogue scale (VAS) functional bladder capacity, frequency episodes, and global response assessment (GRA) all showed significant improvement (p < 0.0001). Those who received repeated injections had a better success rate during the long-term follow-up period. The incidence of adverse events did not rise with the increasing number of BoNT-A injections. A higher pre-treatment ICSI and ICPI score was predictive for successful response to repeated intravesical BoNT-A injections plus hydrodistention. Full article
(This article belongs to the Section Animal Venoms)
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Review
Comparative Ochratoxin Toxicity: A Review of the Available Data
Toxins 2015, 7(10), 4253-4282; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104253 - 22 Oct 2015
Cited by 129 | Viewed by 4287
Abstract
Ochratoxins are a group of mycotoxins produced by a variety of moulds. Ochratoxin A (OTA), the most prominent member of this toxin family, was first described by van der Merwe et al. in Nature in 1965. Dietary exposure to OTA represents a serious [...] Read more.
Ochratoxins are a group of mycotoxins produced by a variety of moulds. Ochratoxin A (OTA), the most prominent member of this toxin family, was first described by van der Merwe et al. in Nature in 1965. Dietary exposure to OTA represents a serious health issue and has been associated with several human and animal diseases including poultry ochratoxicosis, porcine nephropathy, human endemic nephropathies and urinary tract tumours in humans. More than 30 years ago, OTA was shown to be carcinogenic in rodents and since then extensive research has been performed in order to investigate its mode of action, however, this is still under debate. OTA is regarded as the most toxic family member, however, other ochratoxins or their metabolites and, in particular, ochratoxin mixtures or combinations with other mycotoxins may represent serious threats to human and animal health. This review summarises and evaluates current knowledge about the differential and comparative toxicity of the ochratoxin group. Full article
(This article belongs to the Collection Ochratoxins-Collection)
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Article
UV-B Exposure Affects the Biosynthesis of Microcystin in Toxic Microcystis aeruginosa Cells and Its Degradation in the Extracellular Space
Toxins 2015, 7(10), 4238-4252; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104238 - 20 Oct 2015
Cited by 7 | Viewed by 3573
Abstract
Microcystins (MCs) are cyclic hepatotoxic heptapeptides produced by cyanobacteria that can be toxic to aquatic and terrestrial organisms. MC synthesis and degradation are thought to be influenced by several different physical and environmental parameters. In this study, the effects of different intensities of [...] Read more.
Microcystins (MCs) are cyclic hepatotoxic heptapeptides produced by cyanobacteria that can be toxic to aquatic and terrestrial organisms. MC synthesis and degradation are thought to be influenced by several different physical and environmental parameters. In this study, the effects of different intensities of UV-B radiation on MC biosynthesis in Microcystis cells and on its extracellular degradation were investigated by mRNA analysis and degradation experiments. Exposure to UV-B at intensities of 1.02 and 1.45 W/m2 not only remarkably inhibited the growth of Microcystis, but also led to a decrease in the MC concentration. In addition, mcyD transcription was decreased under the same UV-B intensities. These results demonstrated that the effects of UV-B exposure on the biosynthesis of MCs in Microcystis cells could be attributed to the regulation of mcy gene transcription. Moreover, the MC concentration was decreased significantly after exposure to different intensities of UV-B radiation. Of the three MC variants (MC-LR, -RR and -YR, L, R and Y are abbreviations of leucine, arginine and tyrosine), MC-LR and MC-YR were sensitive to UV-B radiation, whereas MC-RR was not. In summary, our results showed that UV-B radiation had a negative effect on MC production in Microcystis cells and MC persistence in the extracellular space. Full article
(This article belongs to the Collection Marine and Freshwater Toxins)
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Editorial
Introduction to the Toxins Special Issue on Ergot Alkaloids
Toxins 2015, 7(10), 4232-4237; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104232 - 20 Oct 2015
Cited by 10 | Viewed by 2786
Abstract
Ergot alkaloids are among the most relevant natural products in the history of toxins and pharmaceuticals. Until the late 20th century, human and livestock exposure to ergot alkaloids was primarily through ingestion of “ergots,” which are spur-shaped or seed-like resting structures (sclerotia) of [...] Read more.
Ergot alkaloids are among the most relevant natural products in the history of toxins and pharmaceuticals. Until the late 20th century, human and livestock exposure to ergot alkaloids was primarily through ingestion of “ergots,” which are spur-shaped or seed-like resting structures (sclerotia) of ergot fungi, the Claviceps species. Because ergots have similar density to grains, traditional threshing techniques generally failed to remove them, and outbreaks of ergot typically led to mass poisonings. [...] Full article
(This article belongs to the Special Issue Ergot Alkaloids: Chemistry, Biology and Toxicology)
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Article
A Magnetic Nanoparticle Based Enzyme-Linked Immunosorbent Assay for Sensitive Quantification of Zearalenone in Cereal and Feed Samples
Toxins 2015, 7(10), 4216-4231; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104216 - 20 Oct 2015
Cited by 30 | Viewed by 3050
Abstract
A novel enzyme-linked immunosorbent assay based on magnetic nanoparticles and biotin/streptavidin-HRP (MNP-bsELISA) was developed for rapid and sensitive detection of zearalenone (ZEN). The detection signal was enhanced and the sensitivity of the assay was improved by combined use of antibody-conjugated magnetic nanoparticles and [...] Read more.
A novel enzyme-linked immunosorbent assay based on magnetic nanoparticles and biotin/streptavidin-HRP (MNP-bsELISA) was developed for rapid and sensitive detection of zearalenone (ZEN). The detection signal was enhanced and the sensitivity of the assay was improved by combined use of antibody-conjugated magnetic nanoparticles and biotin-streptavidin system. Under the optimized conditions, the regression equation for quantification of ZEN was y = −0.4287x + 0.3132 (R2 = 0.9904). The working range was 0.07–2.41 ng/mL. The detection limit was 0.04 ng/mL and IC50 was 0.37 ng/mL. The recovery rates of intra-assay and inter-assay ranged from 92.8%–111.9% and 91.7%–114.5%, respectively, in spiked corn samples. Coefficients of variation were less than 10% in both cases. Parallel analysis of cereal and feed samples showed good correlation between MNP-bsELISA and liquid chromatograph-tandem mass spectrometry (R2 = 0.9283). We conclude that this method is suitable for rapid detection of zearalenone in cereal and feed samples in relevant laboratories. Full article
(This article belongs to the Collection Biorecognition Assays for Mycotoxins)
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Article
High Sensitivity of Aged Mice to Deoxynivalenol (Vomitoxin)-Induced Anorexia Corresponds to Elevated Proinflammatory Cytokine and Satiety Hormone Responses
Toxins 2015, 7(10), 4199-4215; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104199 - 19 Oct 2015
Cited by 17 | Viewed by 2695
Abstract
Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 [...] Read more.
Deoxynivalenol (DON), a trichothecene mycotoxin that commonly contaminates cereal grains, is a public health concern because of its adverse effects on the gastrointestinal and immune systems. The objective of this study was to compare effects of DON on anorectic responses in aged (22 mos) and adult (3 mos) mice. Aged mice showed increased feed refusal with both acute i.p. (1 mg/kg and 5 mg/kg) and dietary (1, 2.5, 10 ppm) DON exposure in comparison to adult mice. In addition to greater suppression of food intake from dietary DON exposure, aged mice also exhibited greater but transient body weight suppression. When aged mice were acutely exposed to 1 mg/kg bw DON i.p., aged mice displayed elevated DON and DON3GlcA tissue levels and delayed clearance in comparison with adult mice. Acute DON exposure also elicited higher proinflammatory cytokine and satiety hormone responses in the plasma of the aged group compared with the adult group. Increased susceptibility to DON-induced anorexia in aged mice relative to adult mice suggests that advanced life stage could be a critical component in accurate human risk assessments for DON and other trichothecenes. Full article
(This article belongs to the Special Issue Mycotoxins and Human Diseases 2015)
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Review
Bioactive Mimetics of Conotoxins and other Venom Peptides
Toxins 2015, 7(10), 4175-4198; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104175 - 16 Oct 2015
Cited by 20 | Viewed by 3683
Abstract
Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and [...] Read more.
Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties. Full article
(This article belongs to the Special Issue Conotoxins: Novel Pharmacologies for Nervous System Disorders)
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Article
Risk Assessment on Dietary Exposure to Aflatoxin B1 in Post-Harvest Peanuts in the Yangtze River Ecological Region
Toxins 2015, 7(10), 4157-4174; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104157 - 15 Oct 2015
Cited by 22 | Viewed by 3450
Abstract
Based on the 2983 peanut samples from 122 counties in six provinces of China’s Yangtze River ecological region collected between 2009–2014, along with the dietary consumption data in Chinese resident nutrition and health survey reports from 2002 and 2004, dietary aflatoxin exposure and [...] Read more.
Based on the 2983 peanut samples from 122 counties in six provinces of China’s Yangtze River ecological region collected between 2009–2014, along with the dietary consumption data in Chinese resident nutrition and health survey reports from 2002 and 2004, dietary aflatoxin exposure and percentiles in the corresponding statistics were calculated by non-parametric probability assessment, Monte Carlo simulation and bootstrap sampling methods. Average climatic conditions in the Yangtze River ecological region were calculated based on the data from 118 weather stations via the Thiessen polygon method. The survey results found that the aflatoxin contamination of peanuts was significantly high in 2013. The determination coefficient (R2) of multiple regression reflected by the aflatoxin B1 content with average precipitation and mean temperature in different periods showed that climatic conditions one month before harvest had the strongest impact on aflatoxin B1 contamination, and that Hunan and Jiangxi provinces were greatly influenced. The simulated mean aflatoxin B1 intake from peanuts at the mean peanut consumption level was 0.777–0.790 and 0.343–0.349 ng/(kg·d) for children aged 2–6 and standard adults respectively. Moreover, the evaluated cancer risks were 0.024 and 0.011/(100,000 persons·year) respectively, generally less than China’s current liver cancer incidence of 24.6 cases/(100,000 persons·year). In general, the dietary risk caused by peanut production and harvest was low. Further studies would focus on the impacts of peanut circulation and storage on aflatoxin B1 contamination risk assessment in order to protect peanut consumers’ safety and boost international trade. Full article
(This article belongs to the Special Issue Mycotoxins and Human Diseases 2015)
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Article
The Inhibitory Effect of Botulinum Toxin Type A on Rat Pyloric Smooth Muscle Contractile Response to Substance P In Vitro
Toxins 2015, 7(10), 4143-4156; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104143 - 15 Oct 2015
Cited by 4 | Viewed by 3055
Abstract
A decrease in pyloric myoelectrical activity and pyloric substance P (SP) content following intrasphincteric injection of botulinum toxin type A (BTX-A) in free move rats have been demonstrated in our previous studies. The aim of the present study was to investigate the inhibitory [...] Read more.
A decrease in pyloric myoelectrical activity and pyloric substance P (SP) content following intrasphincteric injection of botulinum toxin type A (BTX-A) in free move rats have been demonstrated in our previous studies. The aim of the present study was to investigate the inhibitory effect of BTX-A on rat pyloric muscle contractile response to SP in vitro and the distributions of SP and neurokinin 1 receptor (NK1R) immunoreactive (IR) cells and fibers within pylorus. After treatment with atropine, BTX-A (10 U/mL), similar to [D-Arg1, D-Phe5, D-Trp7,9, Leu11]-SP (APTL-SP, 1 μmol/L) which is an NK1R antagonist, decreased electric field stimulation (EFS)-induced contractile tension and frequency, whereas, subsequent administration of APTL-SP did not act on contractility. Incubation with BTX-A at 4 and 10 U/mL for 4 h respectively decreased SP (1 μmol/L)-induced contractions by 26.64% ± 5.12% and 74.92% ± 3.62%. SP-IR fibers and NK1R-IR cells both located within pylorus including mucosa and circular muscle layer. However, fewer SP-fibers were observed in pylorus treated with BTX-A (10 U/mL). In conclusion, BTX-A inhibits SP release from enteric terminals in pylorus and EFS-induced contractile responses when muscarinic cholinergic receptors are blocked by atropine. In addition, BTX-A concentration- and time-dependently directly inhibits SP-induced pyloric smooth muscle contractility. Full article
(This article belongs to the Collection Botulinum Toxins on Human Pain)
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Article
EDIN-B Promotes the Translocation of Staphylococcus aureus to the Bloodstream in the Course of Pneumonia
Toxins 2015, 7(10), 4131-4142; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104131 - 15 Oct 2015
Cited by 10 | Viewed by 2557
Abstract
It is crucial to define risk factors that contribute to host invasion by Staphylococcus aureus. Here, we demonstrate that the chromosomally encoded EDIN-B isoform from S. aureus contributes to the onset of bacteremia during the course of pneumonia. Deletion of edinB in [...] Read more.
It is crucial to define risk factors that contribute to host invasion by Staphylococcus aureus. Here, we demonstrate that the chromosomally encoded EDIN-B isoform from S. aureus contributes to the onset of bacteremia during the course of pneumonia. Deletion of edinB in a European lineage community-acquired methicillin resistant S. aureus (CA-MRSA) strain (ST80-MRSA-IV) dramatically decreased the frequency and magnitude of bacteremia in mice suffering from pneumonia. This deletion had no effect on the bacterial burden in both blood circulation and lung tissues. Re-expression of wild-type EDIN-B, unlike the catalytically inactive mutant EDIN-R185E, restored the invasive characteristics of ST80-MRSA-IV. Full article
(This article belongs to the Collection Staphylococcus aureus Toxins)
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Review
Nation-Based Occurrence and Endogenous Biological Reduction of Mycotoxins in Medicinal Herbs and Spices
Toxins 2015, 7(10), 4111-4130; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104111 - 14 Oct 2015
Cited by 21 | Viewed by 5306
Abstract
Medicinal herbs have been increasingly used for therapeutic purposes against a diverse range of human diseases worldwide. Moreover, the health benefits of spices have been extensively recognized in recent studies. However, inevitable contaminants, including mycotoxins, in medicinal herbs and spices can cause serious [...] Read more.
Medicinal herbs have been increasingly used for therapeutic purposes against a diverse range of human diseases worldwide. Moreover, the health benefits of spices have been extensively recognized in recent studies. However, inevitable contaminants, including mycotoxins, in medicinal herbs and spices can cause serious problems for humans in spite of their health benefits. Along with the different nation-based occurrences of mycotoxins, the ultimate exposure and toxicities can be diversely influenced by the endogenous food components in different commodities of the medicinal herbs and spices. The phytochemicals in these food stuffs can influence mold growth, mycotoxin production and biological action of the mycotoxins in exposed crops, as well as in animal and human bodies. The present review focuses on the occurrence of mycotoxins in medicinal herbs and spices and the biological interaction between mold, mycotoxin and herbal components. These networks will provide insights into the methods of mycotoxin reduction and toxicological risk assessment of mycotoxin-contaminated medicinal food components in the environment and biological organisms. Full article
(This article belongs to the Collection Understanding Mycotoxin Occurrence in Food and Feed Chains)
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Article
Using S. cerevisiae as a Model System to Investigate V. cholerae VopX-Host Cell Protein Interactions and Phenotypes
Toxins 2015, 7(10), 4099-4110; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104099 - 14 Oct 2015
Cited by 6 | Viewed by 3047
Abstract
Most pathogenic, non-O1/non-O139 serogroup Vibrio cholerae strains cause diarrheal disease in the absence of cholera toxin. Instead, many use Type 3 Secretion System (T3SS) mediated mechanisms to disrupt host cell homeostasis. We identified a T3SS effector protein, VopX, which is translocated into mammalian [...] Read more.
Most pathogenic, non-O1/non-O139 serogroup Vibrio cholerae strains cause diarrheal disease in the absence of cholera toxin. Instead, many use Type 3 Secretion System (T3SS) mediated mechanisms to disrupt host cell homeostasis. We identified a T3SS effector protein, VopX, which is translocated into mammalian cells during in vitro co-culture. In a S. cerevisiae model system, we found that expression of VopX resulted in a severe growth defect that was partially suppressed by a deletion of RLM1, encoding the terminal transcriptional regulator of the Cell Wall Integrity MAP kinase (CWI) regulated pathway. Growth of yeast cells in the presence of sorbitol also suppressed the defect, supporting a role for VopX in destabilizing the cell wall. Expression of VopX activated expression of β-galactosidase from an RLM1-reponsive element reporter fusion, but failed to do so in cells lacking MAP kinases upstream of Rlm1. The results suggest that VopX inhibits cell growth by stimulating the CWI pathway through Rlm1. Rlm1 is an ortholog of mammalian MEF2 transcription factors that are proposed to regulate cell differentiation, proliferation, and apoptosis. The collective findings suggest that VopX contributes to disease by activating MAP kinase cascades that elicit changes in cellular transcriptional programs. Full article
(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)
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Review
Man-Made Synthetic Receptors for Capture and Analysis of Ochratoxin A
Toxins 2015, 7(10), 4083-4098; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104083 - 10 Oct 2015
Cited by 12 | Viewed by 2703
Abstract
Contemporary analytical methods have the sensitivity required for Ochratoxin A detection and quantification, but direct application of these methods on real samples can be rarely performed because of matrix complexity. Thus, efficient sample pre-treatment methods are needed. Recent years have seen the increasing [...] Read more.
Contemporary analytical methods have the sensitivity required for Ochratoxin A detection and quantification, but direct application of these methods on real samples can be rarely performed because of matrix complexity. Thus, efficient sample pre-treatment methods are needed. Recent years have seen the increasing use of artificial recognition systems as a viable alternative to natural receptors, because these materials seem to be particularly suitable for applications where selectivity for Ochratoxin A is essential. In this review, molecularly imprinted polymers, aptamers and tailor-made peptides for Ochratoxin A capture and analysis with particular attention to solid phase extraction applications will be discussed. Full article
(This article belongs to the Collection Ochratoxins-Collection)
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Article
Mutagenic Deimmunization of Diphtheria Toxin for Use in Biologic Drug Development
Toxins 2015, 7(10), 4067-4082; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104067 - 10 Oct 2015
Cited by 24 | Viewed by 2893
Abstract
Background: Targeted toxins require multiple treatments and therefore must be deimmunized. We report a method of protein deimmunization based on the point mutation of highly hydrophilic R, K, D, E, and Q amino acids on the molecular surface of truncated diphtheria-toxin (DT390). Methods: [...] Read more.
Background: Targeted toxins require multiple treatments and therefore must be deimmunized. We report a method of protein deimmunization based on the point mutation of highly hydrophilic R, K, D, E, and Q amino acids on the molecular surface of truncated diphtheria-toxin (DT390). Methods: Based on their surface position derived from an X-ray-crystallographic model, residues were chosen for point mutation that were located in prominent positions on the molecular surface and away from the catalytic site. Mice were immunized with a targeted toxin containing either a mutated DT390 containing seven critical point mutations or the non-mutated parental toxin form. Results: Serum analysis revealed a significant 90% reduction in anti-toxin antibodies in mice immunized with the mutant, but not the parental drug form despite multiple immunizations. The experiment was repeated in a second strain of mice with a different MHC-haplotype to address whether point mutation removed T or B cell epitopes. Findings were identical indicating that B cell epitopes were eliminated from DT. The mutant drug form lost only minimal activity in vitro as well as in vivo. Conclusion: These findings indicate that this method may be effective for deimmunizing of other proteins and that discovery of a deimmunized form of DT may lead to the development of more effective targeted toxin. Full article
(This article belongs to the Section Bacterial Toxins)
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Article
The Effects of Shiga Toxin 1, 2 and Their Subunits on Cytokine and Chemokine Expression by Human Macrophage-Like THP-1 Cells
Toxins 2015, 7(10), 4054-4066; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104054 - 09 Oct 2015
Cited by 13 | Viewed by 2935
Abstract
Infection by Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) results in severe diarrhea, hemorrhagic colitis, and, occasionally, hemolytic-uremic syndrome (HUS). HUS is associated with an increase in pro-inflammatory cytokines and chemokines, many of which are produced by macrophages in the kidneys, indicating that [...] Read more.
Infection by Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli (EHEC) results in severe diarrhea, hemorrhagic colitis, and, occasionally, hemolytic-uremic syndrome (HUS). HUS is associated with an increase in pro-inflammatory cytokines and chemokines, many of which are produced by macrophages in the kidneys, indicating that localized host innate immunity likely plays a role in renal pathogenesis. EHEC serotypes may express one or two classes of serologically defined but structurally and functionally-related Shiga toxins called Stx1 and Stx2. Of these, Stx2 appears to be linked to higher rates of HUS than Stx1. To investigate a possible reason for this, we exposed human macrophage-like THP-1 cells to Stx1 or Stx2 and then used the Luminex multiplex system to assess cytokine/chemokine concentrations in culture supernatant solutions. This analysis revealed that, relative to Stx1, Stx2 significantly caused increased expression of GRO, G-CSF, IL-1β, IL-8 and TNFα in macrophage-like THP-1 cells. This was determined to not be due to a difference in cytotoxicity since both Stx1 and Stx2 displayed similar cytotoxic activities on macrophage-like THP-1 cells. These observations indicate that, in vitro, Stx2 can provoke a greater pro-inflammatory response than Stx1 in macrophages and provides a possible partial explanation for higher rates of HUS in patients infected with EHEC strains expressing Stx2. To begin to determine a mechanism for Shiga toxin-mediated cytokine production, we exposed macrophage-like THP-1 cells to Stx1 or Stx2 A and B subunits. Luminex analysis of cytokines in cell culture supernatant solutions demonstrated that neither subunit alone induced a cytokine response in THP-1 cells. Full article
(This article belongs to the Collection Shiga Toxins)
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Article
HGT-Finder: A New Tool for Horizontal Gene Transfer Finding and Application to Aspergillus genomes
Toxins 2015, 7(10), 4035-4053; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104035 - 09 Oct 2015
Cited by 16 | Viewed by 4569
Abstract
Horizontal gene transfer (HGT) is a fast-track mechanism that allows genetically unrelated organisms to exchange genes for rapid environmental adaptation. We developed a new phyletic distribution-based software, HGT-Finder, which implements a novel bioinformatics algorithm to calculate a horizontal transfer index and a probability [...] Read more.
Horizontal gene transfer (HGT) is a fast-track mechanism that allows genetically unrelated organisms to exchange genes for rapid environmental adaptation. We developed a new phyletic distribution-based software, HGT-Finder, which implements a novel bioinformatics algorithm to calculate a horizontal transfer index and a probability value for each query gene. Applying this new tool to the Aspergillus fumigatus, Aspergillus flavus, and Aspergillus nidulans genomes, we found 273, 542, and 715 transferred genes (HTGs), respectively. HTGs have shorter length, higher guanine-cytosine (GC) content, and relaxed selection pressure. Metabolic process and secondary metabolism functions are significantly enriched in HTGs. Gene clustering analysis showed that 61%, 41% and 74% of HTGs in the three genomes form physically linked gene clusters (HTGCs). Overlapping manually curated, secondary metabolite gene clusters (SMGCs) with HTGCs found that 9 of the 33 A. fumigatus SMGCs and 31 of the 65 A. nidulans SMGCs share genes with HTGCs, and that HTGs are significantly enriched in SMGCs. Our genome-wide analysis thus presented very strong evidence to support the hypothesis that HGT has played a very critical role in the evolution of SMGCs. The program is freely available at http://cys.bios.niu.edu/HGTFinder/ HGTFinder.tar.gz. Full article
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Article
Main Ustilaginoidins and Their Distribution in Rice False Smut Balls
Toxins 2015, 7(10), 4023-4034; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104023 - 09 Oct 2015
Cited by 21 | Viewed by 2717
Abstract
Rice false smut has become an increasingly serious fungal disease in rice (Oryza sativa L.) production worldwide. Ustilaginoidins are bis-naphtho-γ-pyrone mycotoxins previously isolated from the rice false smut balls (FSBs) infected by the pathogen Villosiclava virens in rice spikelets on panicles. To [...] Read more.
Rice false smut has become an increasingly serious fungal disease in rice (Oryza sativa L.) production worldwide. Ustilaginoidins are bis-naphtho-γ-pyrone mycotoxins previously isolated from the rice false smut balls (FSBs) infected by the pathogen Villosiclava virens in rice spikelets on panicles. To investigate the main ustilaginoidins and their distribution in rice FSBs, five main bis-naphtho-γ-pyrones, namely ustilaginoidins A (1), G (2), B (3), I (4) and C (5), were isolated and identified by NMR and high-resolution mass spectrometry as well as by comparison with the data in the literature. The rice FSBs at early, middle and late maturity stages were divided into their different parts and the contents of five main ustilaginoidins for each part were determined by HPLC analysis. The results revealed that the highest levels of ustilaginoidins were in late stage rice FSBs, followed by those at middle stage. Most ustilaginoidins, 96.4% of the total quantity, were distributed in the middle layer at early stage. However, ustilaginoidins were mainly distributed in the outer and middle layers at middle and late stages. Small amounts of ustilaginoidins A (1) and G (2) were found in the inner part of rice FSBs at each maturity stage. The contents of ustilaginoidins A (1) and G (2) without hydroxymethyl groups at C-2 and C-2’ of the γ-pyrone rings in rice FSBs were relatively high at early stage, while the contents of ustilaginoidins B (3), I (4), and C (5) with hydroxymethyl groups at C-2 or C-2’ were relatively high at late stage. Full article
(This article belongs to the Section Mycotoxins)
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Article
Activity and Transcriptional Responses of Hepatopancreatic Biotransformation and Antioxidant Enzymes in the Oriental River Prawn Macrobrachium nipponense Exposed to Microcystin-LR
Toxins 2015, 7(10), 4006-4022; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7104006 - 08 Oct 2015
Cited by 17 | Viewed by 2259
Abstract
Microcystins (MCs) are a major group of cyanotoxins with side effects in many organisms; thus, compounds in this group are recognized as potent stressors and health hazards in aquatic ecosystems. In order to assess the toxicity of MCs and detoxification mechanism of freshwater [...] Read more.
Microcystins (MCs) are a major group of cyanotoxins with side effects in many organisms; thus, compounds in this group are recognized as potent stressors and health hazards in aquatic ecosystems. In order to assess the toxicity of MCs and detoxification mechanism of freshwater shrimp Macrobrachium nipponense, the full-length cDNAs of the glutathione S-transferase (gst) and catalase (cat) genes were isolated from the hepatopancreas. The transcription level and activity changes in the biotransformation enzyme (glutathione S-transferase (GST)) and antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx)) in the hepatopancreas of M. nipponense exposed to MC-LR (0.2, 1, 5, and 25 μg/L) for 12, 24, 72 and 96 h were analyzed. The results showed that the isolated full-length cDNAs of cat and gst genes from M. nipponense displayed a high similarity to other crustaceans, and their mRNAs were mainly expressed in the hepatopancreas. MC-LR caused significant increase of GST activity following 48–96 h (p < 0.05) and an increase in SOD activity especially in 24- and 48-h exposures. CAT activity was activated when exposed to MC-LR in 12-, 24- and 48-h exposures and then it was inhibited at 96-h exposure. There was no significant effect on GPx activity after the 12- and 24-h exposures, whereas it was significantly stimulated after the 72- and 96-h exposures (p < 0.05). The transcription was altered similarly to enzyme activity, but the transcriptional response was generally more immediate and had greater amplitude than enzymatic response, particularly for GST. All of the results suggested that MC-LR can induce antioxidative modulation variations in M. nipponense hepatopancreas in order to eliminate oxidative damage. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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Article
Cytotoxic Activity and Antiproliferative Effects of Crude Skin Secretion from Physalaemus nattereri (Anura: Leptodactylidae) on in vitro Melanoma Cells
Toxins 2015, 7(10), 3989-4005; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7103989 - 08 Oct 2015
Cited by 5 | Viewed by 2564
Abstract
Anuran secretions are rich sources of bioactive molecules, including antimicrobial and antitumoral compounds. The aims of this study were to investigate the therapeutic potential of Physalaemus nattereri skin secretion against skin cancer cells, and to assess its cytotoxic action mechanisms on the murine [...] Read more.
Anuran secretions are rich sources of bioactive molecules, including antimicrobial and antitumoral compounds. The aims of this study were to investigate the therapeutic potential of Physalaemus nattereri skin secretion against skin cancer cells, and to assess its cytotoxic action mechanisms on the murine melanoma cell line B16F10. Our results demonstrated that the crude secretion reduced the viability of B16F10 cells, causing changes in cell morphology (e.g., round shape and structure shrinkage), reduction in mitochondrial membrane potential, increase in phosphatidylserine exposure, and cell cycle arrest in S-phase. Together, these changes suggest that tumor cells die by apoptosis. This skin secretion was also subjected to chromatographic fractioning using RP-HPLC, and eluted fractions were assayed for antiproliferative and antibacterial activities. Three active fractions showed molecular mass components in a range compatible with peptides. Although the specific mechanisms causing the reduced cell viability and cytotoxicity after the treatment with crude secretion are still unknown, it may be considered that molecules, such as the peptides found in the secretion, are effective against B16F10 tumor cells. Considering the growing need for new anticancer drugs, data presented in this study strongly reinforce the validity of P. nattereri crude secretion as a rich source of new anticancer molecules. Full article
(This article belongs to the Section Animal Venoms)
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Article
Study of Adsorption and Flocculation Properties of Natural Clays to Remove Prorocentrum lima
Toxins 2015, 7(10), 3977-3988; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7103977 - 29 Sep 2015
Cited by 8 | Viewed by 3141
Abstract
High accumulations of phytoplankton species that produce toxins are referred to as harmful algal blooms (HABs). HABs represent one of the most important sources of contamination in marine environments, as well as a serious threat to public health, fisheries, aquaculture-based industries, and tourism. [...] Read more.
High accumulations of phytoplankton species that produce toxins are referred to as harmful algal blooms (HABs). HABs represent one of the most important sources of contamination in marine environments, as well as a serious threat to public health, fisheries, aquaculture-based industries, and tourism. Therefore, methods effectively controlling HABs with minimal impact on marine ecology are required. Marine dinoflagellates of the genera Dinophysis and Prorocentrum are representative producers of okadaic acid (OA) and dinophysistoxins responsible for the diarrhetic shellfish poisoning (DSP) which is a human intoxication caused by the consumption of shellfish that bioaccumulate those toxins. In this work we explore the use of natural clay for removing Prorocentrum lima. We evaluate the adsorption properties of clays in seawater containing the dinoflagellates. The experimental results confirmed the cell removal through the flocculation of algal and mineral particles leading to the formation of aggregates, which rapidly settle and further entrain cells during their descent. Moreover, the microscopy images of the samples enable one to observe the clays in aggregates of two or more cells where the mineral particles were bound to the outer membranes of the dinoflagellates. Therefore, this preliminary data offers promising results to use these clays for the mitigation of HABs. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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Article
Passive Immunotherapy Protects against Enteric Invasion and Lethal Sepsis in a Murine Model of Gastrointestinal Anthrax
Toxins 2015, 7(10), 3960-3976; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7103960 - 29 Sep 2015
Cited by 3 | Viewed by 2537
Abstract
The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal [...] Read more.
The principal portal for anthrax infection in natural animal outbreaks is the digestive tract. Enteric exposure to anthrax, which is difficult to detect or prevent in a timely manner, could be exploited as an act of terror through contamination of human or animal food. Our group has developed a novel animal model of gastrointestinal (GI) anthrax for evaluation of disease pathogenesis and experimental therapeutics, utilizing vegetative Bacillus anthracis (Sterne strain) administered to A/J mice (a complement-deficient strain) by oral gavage. We hypothesized that a humanized recombinant monoclonal antibody (mAb) * that neutralizes the protective antigen (PA) component of B. anthracis lethal toxin (LT) and edema toxin (ET) could be an effective treatment. Although the efficacy of this anti-anthrax PA mAb has been shown in animal models of inhalational anthrax, its activity in GI infection had not yet been ascertained. We hereby demonstrate that passive immunotherapy with anti-anthrax PA mAb, administered at the same time as gastrointestinal exposure to B. anthracis, prevents lethal sepsis in nearly all cases (>90%), while a delay of up to forty-eight hours in treatment still greatly reduces mortality following exposure (65%). Moreover, passive immunotherapy protects against enteric invasion, associated mucosal injury and subsequent dissemination by gastrointestinal B. anthracis, indicating that it acts to prevent the initial stages of infection. * Expired raxibacumab being cycled off the Strategic National Stockpile; biological activity confirmed by in vitro assay. Full article
(This article belongs to the Collection Anthrax Toxins)
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Communication
Detection of Dinophysistoxin-1 in Clonal Culture of Marine Dinoflagellate Prorocentrum foraminosum (Faust M.A., 1993) from the Sea of Japan
Toxins 2015, 7(10), 3947-3959; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7103947 - 28 Sep 2015
Cited by 17 | Viewed by 2179
Abstract
For the first time the presence of dinophysistoxin-1 (DTX-1) in a culture of Prorocentrum foraminosum was revealed in cells and in the culture medium. The clone was isolated from coastal waters of the Sea of Japan and identified by molecular analyses of SSU [...] Read more.
For the first time the presence of dinophysistoxin-1 (DTX-1) in a culture of Prorocentrum foraminosum was revealed in cells and in the culture medium. The clone was isolated from coastal waters of the Sea of Japan and identified by molecular analyses of SSU and D1/D2 regions of LSU rDNA. The concentration of DTX-1 in cells was 8.4 ± 2.5 pg/cell and, in cell-free media, 27.9 ± 14.7 µg/L. The toxin presence was confirmed by HPLC with high-resolution tandem mass-spectrometry. Full article
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Article
Exploring Protein Binding of Uremic Toxins in Patients with Different Stages of Chronic Kidney Disease and during Hemodialysis
Toxins 2015, 7(10), 3933-3946; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7103933 - 28 Sep 2015
Cited by 70 | Viewed by 3602
Abstract
As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were [...] Read more.
As protein binding of uremic toxins is not well understood, neither in chronic kidney disease (CKD) progression, nor during a hemodialysis (HD) session, we studied protein binding in two cross-sectional studies. Ninety-five CKD 2 to 5 patients and ten stable hemodialysis patients were included. Blood samples were taken either during the routine ambulatory visit (CKD patients) or from blood inlet and outlet line during dialysis (HD patients). Total (CT) and free concentrations were determined of p-cresylglucuronide (pCG), hippuric acid (HA), indole-3-acetic acid (IAA), indoxyl sulfate (IS) and p-cresylsulfate (pCS), and their percentage protein binding (%PB) was calculated. In CKD patients, %PB/CT resulted in a positive correlation (all p < 0.001) with renal function for all five uremic toxins. In HD patients, %PB was increased after 120 min of dialysis for HA and at the dialysis end for the stronger (IAA) and the highly-bound (IS and pCS) solutes. During one passage through the dialyzer at 120 min, %PB was increased for HA (borderline), IAA, IS and pCS. These findings explain why protein-bound solutes are difficult to remove by dialysis: a combination of the fact that (i) only the free fraction can pass the filter and (ii) the equilibrium, as it was pre-dialysis, cannot be restored during the dialysis session, as it is continuously disturbed. Full article
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Review
Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management?
Toxins 2015, 7(10), 3916-3932; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins7103916 - 28 Sep 2015
Cited by 30 | Viewed by 3135
Abstract
The α9α10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the α9α10-nAChR in pain is conflicted. This receptor was first implicated in pain with [...] Read more.
The α9α10-nicotinic acetylcholine receptor (nAChR) has been implicated in pain and has been proposed to be a novel target for analgesics. However, the evidence to support the involvement of the α9α10-nAChR in pain is conflicted. This receptor was first implicated in pain with the characterisation of conotoxin Vc1.1, which is highly selective for α9α10-nAChRs and is an efficacious analgesic in chronic pain models with restorative capacities and no reported side effects. Numerous other analgesic conotoxin and non-conotoxin molecules have been subsequently characterised that also inhibit α9α10-nAChRs. However, there is evidence that α9α10-nAChR inhibition is neither necessary nor sufficient for analgesia. α9α10-nAChR-inhibiting analogues of Vc1.1 have no analgesic effects. Genetically-modified α9-nAChR knockout mice have a phenotype that is markedly different from the analgesic profile of Vc1.1 and similar conotoxins, suggesting that the conotoxin effects are largely independent of α9α10-nAChRs. Furthermore, an alternative mechanism of analgesia by Vc1.1 and other similar conotoxins involving non-canonical coupling of GABAB receptors to voltage-gated calcium channels is known. Additional incongruities regarding α9α10-nAChRs in analgesia are discussed. A more comprehensive characterisation of the role of α9α10-nAChRs in pain is crucial for understanding the analgesic action of conotoxins and for improved drug design. Full article
(This article belongs to the Special Issue Conotoxins: Novel Pharmacologies for Nervous System Disorders)
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