Toxins, Volume 13, Issue 7 (July 2021) – 74 articles

Allelopathy between phytoplankton species can promote cellular stress and programmed cell death (PCD). The raphidophyte Chattonella marina var. marina, and the dinoflagellates Margalefidinium polykrikoides and Gymnodinium impudicum have allelopathic effects on Gymnodinium catenatum; however, the physiological mechanisms are unknown. We evaluated whether the allelopathic effect promotes cellular stress and activates PCD in G. catenatum. Cultures of G. catenatum were exposed to cell-free media of C. marina var. marina, M. polykrikoides and G. impudicum. The mortality, superoxide radical (O₂^●−) production, thiobarbituric acid reactive substances (TBARS) levels, superoxide dismutase (SOD) activity, protein content, and caspase-3 activity were quantified. Mortality (between 57 and 79%) was registered in G. catenatum after exposure to cell-free media of the three species. The maximal O₂^●− production occurred with C. marina var. marina cell-free media. The highest TBARS levels and SOD activity in G. catenatum were recorded with cell-free media from G. impudicum. The highest protein content was recorded with cell-free media from M. polykrikoides. All cell-free media caused an increase in the activity of caspase-3. These results indicate that the allelopathic effect in G. catenatum promotes cell stress and caspase-3 activation, as a signal for the induction of programmed cell death. Full article

Parkinson’s patients often suffer from depression and anxiety, for which there are no optimal treatments. Hemiparkinsonian (hemi-PD) rats were used to test whether intrastriatal Botulinum neurotoxin-A (BoNT-A) application could also have antidepressant-like properties in addition to the known improvement of motor performance. To quantify depression- and anxiety-like behavior, the forced swim test, tail suspension test, open field test, and elevated plus maze test were applied to hemi-PD rats injected with BoNT-A or vehicle. Furthermore, we correlated the results in the forced swim test, open field test, and elevated plus maze test with the rotational behavior induced by apomorphine and amphetamine. Hemi-PD rats did not show significant anxiety-like behavior as compared with Sham 6-OHDA- + Sham BoNT-A-injected as well as with non-injected rats. However, hemi-PD rats demonstrated increased depression-like behaviors compared with Sham- or non-injected rats; this was seen by increased struggling frequency and increased immobility frequency. Hemi-PD rats intrastriatally injected with BoNT-A exhibited reduced depression-like behavior compared with the respective vehicle-receiving hemi-PD animals. The significant effects of intrastriatally applied BoNT-A seen in the forced swim test are reminiscent of those found after various antidepressant drug therapies. Our data correspond with the efficacy of BoNT-A treatment of glabellar frown lines in treating patients with major depression and suggest that also intrastriatal injected BoNT-A may have some antidepressant-like effect on hemi-PD. Full article

This paper assesses the effects of exposure to toxic concentrations (1200 to 6000 cells/mL) of the dinoflagellates Prorocentrum lima, Prorocentrum minimum, and Prorocentrum rhathymum and several concentrations of aqueous and organic extracts obtained from the same species (0 to 20 parts per thousand) on the Crassostrea gigas (5–7 mm) proteomic profile. Through comparative proteomic map analyses, several protein spots were detected with different expression levels, of which eight were selected to be identified by liquid chromatography–mass spectrometry (LC–MS/MS) analyses. The proteomic response suggests that, after 72 h of exposure to whole cells, the biological functions of C. gigas affected proteins in the immune system, stress response, contractile systems and cytoskeletal activities. The exposure to organic and aqueous extracts mainly showed effects on protein expressions in muscle contraction and cytoskeleton morphology. These results enrich the knowledge on early bivalve developmental stages. Therefore, they may be considered a solid base for new bioassays and/or generation of specific analytical tools that allow for some of the main effects of algal proliferation phenomena on bivalve mollusk development to be monitored, characterized and elucidated. Full article

Several factors contribute to renal-function decline in CKD patients, and the role of phosphate content in the diet is still a matter of debate. This study aims to analyze the mechanism by which phosphate, independent of protein, is associated with the progression of CKD. Adult Munich-Wistar rats were submitted to 5/6 nephrectomy (Nx), fed with a low-protein diet, and divided into two groups. Only phosphate content (low phosphate, LoP, 0.2%; high phosphate, HiP, 0.95%) differentiated diets. After sixty days, biochemical parameters and kidney histology were analyzed. The HiP group presented worse renal function, with higher levels of PTH, FGF-23, and fractional excretion of phosphate. In the histological analysis of the kidney tissue, they also showed a higher percentage of interstitial fibrosis, expression of α-actin, PCNA, and renal infiltration by macrophages. The LoP group presented higher expression of beclin-1 in renal tubule cells, a marker of autophagic flux, when compared to the HiP group. Our findings highlight the action of phosphate in the induction of kidney interstitial inflammation and fibrosis, contributing to the progression of renal disease. A possible effect of phosphate on the dysregulation of the renal cell autophagy mechanism needs further investigation with clinical studies. Full article

Meteorus pulchricornis (Ichneumonoidea, Braconidae) is an endoparasitoid wasp of lepidopteran caterpillars. Its parasitic success relies on vesicles (named M. pulchricornis Virus-Like Particles or MpVLPs) that are synthesized in the venom gland and injected into the parasitoid host along with the venom during oviposition. In order to define the content and understand the biogenesis of these atypical vesicles, we performed a transcriptome analysis of the venom gland and a proteomic analysis of the venom and purified MpVLPs. About half of the MpVLPs and soluble venom proteins identified were unknown and no similarity with any known viral sequence was found. However, MpVLPs contained a large number of proteins labelled as metalloproteinases while the most abundant protein family in the soluble venom was that of proteins containing the Domain of Unknown Function DUF-4803. The high number of these proteins identified suggests that a large expansion of these two protein families occurred in M. pulchricornis. Therefore, although the exact mechanism of MpVLPs formation remains to be elucidated, these vesicles appear to be “metalloproteinase bombs” that may have several physiological roles in the host including modifying the functions of its immune cells. The role of DUF4803 proteins, also present in the venom of other braconids, remains to be clarified. Full article

The voltage-gated sodium channel Nav1.8 is linked to neuropathic and inflammatory pain, highlighting the potential to serve as a drug target. However, the biophysical mechanisms that regulate Nav1.8 activation and inactivation gating are not completely understood. Progress has been hindered by a lack of biochemical tools for examining Nav1.8 gating mechanisms. Arizona bark scorpion (Centruroides sculpturatus) venom proteins inhibit Nav1.8 and block pain in grasshopper mice (Onychomys torridus). These proteins provide tools for examining Nav1.8 structure–activity relationships. To identify proteins that inhibit Nav1.8 activity, venom samples were fractioned using liquid chromatography (reversed-phase and ion exchange). A recombinant Nav1.8 clone expressed in ND7/23 cells was used to identify subfractions that inhibited Nav1.8 Na⁺ current. Mass-spectrometry-based bottom-up proteomic analyses identified unique peptides from inhibitory subfractions. A search of the peptides against the AZ bark scorpion venom gland transcriptome revealed four novel proteins between 40 and 60% conserved with venom proteins from scorpions in four genera (Centruroides, Parabuthus, Androctonus, and Tityus). Ranging from 63 to 82 amino acids, each primary structure includes eight cysteines and a “CXCE” motif, where X = an aromatic residue (tryptophan, tyrosine, or phenylalanine). Electrophysiology data demonstrated that the inhibitory effects of bioactive subfractions can be removed by hyperpolarizing the channels, suggesting that proteins may function as gating modifiers as opposed to pore blockers. Full article

A novel porous carbon adsorbent for the removal of deoxynivalenol was prepared from soybean dreg (SD). The new material was characterized by scanning electron microscopy equipped with energy dispersive X-ray spectroscopy (SEM-EDS), transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET) analysis, N₂ adsorption/desorption measurement techniques, X-ray diffraction (XRD), Raman spectroscopy, Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The specific surface area of the SDB-6-KOH was found to be 3655.95 m² g⁻¹, the pore volume was 1.936 cm³ g⁻¹ and the average pore size was 2.125 nm. The high specific surface area and effective functional groups of the carbon material promoted the adsorption of deoxynivalenol. By comparing the adsorption effect of SDB-6-X prepared with different activators (X: KOH, K₂CO₃, KHCO₃), SDB-6-KOH had the highest adsorption capacity. The maximum adsorption capacity of SDB-6-KOH to deoxynivalenol was 52.9877 µg mg⁻¹, and the removal efficiency reached 88.31% at 318 K. The adsorption kinetic and isotherm data were suitable for pseudo-second-order and Langmuir equations, and the results of this study show that the novel carbon material has excellent adsorptive ability and, thus, offers effective practical application potential for the removal of deoxynivalenol. Full article

Mycotoxin contamination of cereals used for feed can cause intoxication, especially in farm animals; therefore, efficient analytical tools for the qualitative and quantitative analysis of toxic fungal metabolites in feed are required. Current trends in food/feed analysis are focusing on the application of biosensor technologies that offer fast and highly selective and sensitive detection with minimal sample treatment and reagents required. The article presents an overview of the recent progress of the development of biosensors for deoxynivalenol and zearalenone determination in cereals and feed. Novel biosensitive materials and highly sensitive detection methods applied for the sensors and the application of these sensors to food/feed products, the limit, and the time of detection are discussed. Full article

Buthus martensii Karsch (BmK), is a kind of traditional Chinese medicine, which has been used for a long history for the treatment of many diseases, such as inflammation, pain and cancer. In this study, DKK-SP1/2/3 genes were screened and extracted from the cDNA library of BmK. The DKK-SP1/2/3 were expressed by using plasmid pSYPU-1b in E. coli BL21, and recombinant proteins were obtained by column chromatography. In the xylene-induced mouse ear swelling and carrageenan-induced rat paw swelling model, DKK-SP1 exerted a significant anti-inflammatory effect by inhibiting the expression of Nav1.8 channel. Meanwhile, the release of pro-inflammatory cytokines (COX-2, IL-6) was decreased significantly and the release of anti-inflammatory cytokines (IL-10) were elevated significantly. Moreover, DKK-SP1 could significantly decrease the Nav1.8 current in acutely isolated rat DRG neurons. In the acetic acid-writhing and ION-CCI model, DKK-SP2 displayed significant analgesic activity by inhibiting the expression of the Nav1.7 channel. Moreover, DKK-SP2 could significantly inhibit the Nav1.7 current in the hNav1.7-CHO cells. Full article

Citrinin (CIT) is secondary metabolite of filamentous molds. This mycotoxin has nephrotoxic, hepatotoxic, embryocidal, and fetotoxic properties. It is also produced by several species of the three genera Penicillium spp., Aspergillus spp., and Monascus spp., which are used to make red yeast rice (RYR). The material for this study consisted of 15 dietary supplements containing an extract of fermented red rice, available on the Polish market. Samples were extracted using a MeOH–H₂O mixture, cleaned-up with an immunoaffinity CitriTest HPLC column, and quantified by HPLC–FLD. None of the analyzed samples contained CIT above the established limit of detection (LOD). Studies on the presence of toxic metabolites in red yeast rice show the importance of regulating this product and of clear information on the label regarding the standardized amounts of monacolin. Full article

Visceral pain is one of the most common symptoms associated with functional gastrointestinal (GI) disorders. Although the origin of these symptoms has not been clearly defined, the implication of both the central and peripheral nervous systems in visceral hypersensitivity is well established. The role of several pathways in visceral nociception has been explored, as well as the influence of specific receptors on afferent neurons, such as voltage-gated sodium channels (VGSCs). VGSCs initiate action potentials and dysfunction of these channels has recently been associated with painful GI conditions. Current treatments for visceral pain generally involve opioid based drugs, which are associated with important side-effects and a loss of effectiveness or tolerance. Hence, efforts have been intensified to find new, more effective and longer-lasting therapies. The implication of VGSCs in visceral hypersensitivity has drawn attention to tetrodotoxin (TTX), a relatively selective sodium channel blocker, as a possible and promising molecule to treat visceral pain and related diseases. As such, here we will review the latest information regarding this toxin that is relevant to the treatment of visceral pain and the possible advantages that it may offer relative to other treatments, alone or in combination. Full article

Phthalic acid esters (PAEs) are a class of lipophilic chemicals widely used as plasticizers and additives to improve various products’ mechanical extensibility and flexibility. At present, synthesized PAEs, which are considered to cause potential hazards to ecosystem functioning and public health, have been easily detected in the atmosphere, water, soil, and sediments; PAEs are also frequently discovered in plant and microorganism sources, suggesting the possibility that they might be biosynthesized in nature. In this review, we summarize that PAEs have not only been identified in the organic solvent extracts, root exudates, and essential oils of a large number of different plant species, but also isolated and purified from various algae, bacteria, and fungi. Dominant PAEs identified from natural sources generally include di-n-butyl phthalate, diethyl phthalate, dimethyl phthalate, di(2-ethylhexyl) phthalate, diisobutyl phthalate, diisooctyl phthalate, etc. Further studies reveal that PAEs can be biosynthesized by at least several algae. PAEs are reported to possess allelopathic, antimicrobial, insecticidal, and other biological activities, which might enhance the competitiveness of plants, algae, and microorganisms to better accommodate biotic and abiotic stress. These findings suggest that PAEs should not be treated solely as a “human-made pollutant” simply because they have been extensively synthesized and utilized; on the other hand, synthesized PAEs entering the ecosystem might disrupt the metabolic process of certain plant, algal, and microbial communities. Therefore, further studies are required to elucidate the relevant mechanisms and ecological consequences. Full article

Botulinum toxin serotype-A (BoNT-A) preparations are widely used to improve the appearance of wrinkles. While effective and well tolerated, patients require retreatment over time to re-establish the effects. There is growing interest from patients as to whether higher doses can prolong response without significantly increasing side effects. We reviewed the efficacy and safety evidence for high-dose BoNT-A treatment of glabellar lines, by evaluating high-dose studies published since 2015. Toxins approved for glabellar line treatment in the US or Europe were considered. “High-dose” indicated doses above the licensed dose for each BoNT-A preparation. Five studies met the inclusion criteria and most were randomized, double-blind trials; designs and population sizes varied. Findings suggested that higher-dose BoNT-A treatment is feasible and may improve response duration without increased safety issues. Around 9 months’ median duration was achieved with a 2–2.5-fold increase of the abobotulinumtoxinA on-label dose, or with a 5-fold increase in incobotulinumtoxinA dose. A 2–4-fold increase of the onabotulinumtoxinA on-label dose yielded a median duration of around 6 months. Importantly, patient satisfaction and natural look remained with increasing abobotulinumtoxinA doses. While more data are needed, these findings may lead to more effective, individually tailored treatment plans to meet patient expectations. Full article

This study analyses the influence of the course of the disease of idiopathic cervical dystonia (CD) before botulinum toxin (BoNT) therapy on long-term outcomes. 74 CD-patients who were treated on a regular basis in the botulinum toxin outpatient department of the University of Düsseldorf and had received at least 3 injections were consecutively recruited after written informed consent. Patients were asked to rate the amount of change of CD in relation to the severity of CD at begin of BoNT therapy (IMPQ). Then they had to draw the course of disease of CD from onset of symptoms until initiation of BoNT therapy (CoDB-graph) on a sheet of paper into a square of 10 × 10 cm² size. Remaining severity of CD was estimated by the treating physician using the TSUI-score. Demographical and treatment related data were extracted from the charts of the patients. Depending on the curvature four different types of CoDB-graphs could be distinguished. Time to BoNT therapy, increase of dose and improvement during BoNT treatment were significantly (p < 0.05) different when patients were split up according to CoDB-graph types. The lower the age at onset of symptoms, the shorter was the time to therapy (p < 0.02). Initial dose (p < 0.04) and actual dose (p < 0.009) were negatively correlated with the age of the patients at recruitment. The course of disease of CD before BoNT therapy has influence on long-term outcome. This has implications on patient management and information on the efficacy of BoNT treatment. Full article

In the past centuries consumption of bread made of ergot-infected flour resulted in mass poisonings and miscarriages. The reason was the sclerotia of Claviceps purpurea (Fr.) Tul.—a source of noxious ergot alkaloids (ergotamine and ergovaline). The authors have searched the 19th century medical literature in order to find information on the following topics: dosage forms of drugs based on ergot and their application in official gynecology and obstetrics. The authors also briefly address the relevant data from the previous periods as well as the 20th century research on ergot. The research resulted in a conclusion that applications of ergot in gynecology and obstetrics in the 19th century were limited to controlling excessive uterine bleeding and irregular spasms, treatment of fibrous tumors of the uterus, and prevention of miscarriage, abortion, and amenorrhoea. The most common dosage forms mentioned in the works included in our review were the following: tinctures, water extracts (Wernich’s and Squibb’s watery extract of ergot), pills, and powders. The information documented in this paper will be helpful for further research and helpful in broadening the understanding of the historical application of the described controversial crude drugs. Ergot alkaloids were widely used in obstetrics, but in modern times they are not used in developed countries anymore. They may, however, play a significant role in developing countries where, in some cases, they can be used as an anti-hemorrhage agent during labor. Full article

Staphylococcus aureus is one of the predominant bacteria isolated from skin and soft tissue infections and a common cause of bloodstream infections. The aim of this study was to compare the rate of resistance to various antimicrobial agents and virulence patterns in a total of 200 S. aureus strains isolated from patients with bacteremia and chronic wounds. Disk diffusion assay and in the case of vancomycin and teicoplanin-microdilution assay, were performed to study the antimicrobial susceptibility of the isolates. The prevalence of genes encoding six enterotoxins, two exfoliative toxins, the Panton–Valentine leukocidin and the toxic shock syndrome toxin was determined by PCR. Of the 100 blood strains tested, the highest percentage (85.0%, 31.0%, and 29.0%) were resistant to benzylpenicillin, erythromycin and clindamycin, respectively. Out of the 100 chronic wound strains, the highest percentage (86.0%, 32.0%, 31.0%, 31.0%, 30.0%, and 29.0%) were confirmed as resistant to benzylpenicillin, tobramycin, amikacin, norfloxacin, erythromycin, and clindamycin, respectively. A significantly higher prevalence of resistance to amikacin, gentamicin, and tobramycin was noted in strains obtained from chronic wounds. Moreover, a significant difference in the distribution of sea and sei genes was found. These genes were detected in 6.0%, 46.0% of blood strains and in 19.0%, and 61.0% of wound strains, respectively. Our results suggest that S. aureus strains obtained from chronic wounds seem to be more often resistant to antibiotics and harbor more virulence genes compared to strains isolated from blood. Full article

Bacterial type I toxin-antitoxin systems are two-component genetic modules that encode a stable toxic protein whose ectopic overexpression can lead to growth arrest or cell death, and an unstable RNA antitoxin that inhibits toxin translation during growth. These systems are widely spread among bacterial species. Type I antitoxins are cis- or trans-encoded antisense small RNAs that interact with toxin-encoding mRNAs by pairing, thereby inhibiting toxin mRNA translation and/or inducing its degradation. Under environmental stress conditions, the up-regulation of the toxin and/or the antitoxin degradation by specific RNases promote toxin translation. Most type I toxins are small hydrophobic peptides with a predicted α-helical transmembrane domain that induces membrane depolarization and/or permeabilization followed by a decrease of intracellular ATP, leading to plasmid maintenance, growth adaptation to environmental stresses, or persister cell formation. In this review, we describe the current state of the art on the folding and the membrane interactions of these membrane-associated type I toxins from either Gram-negative or Gram-positive bacteria and establish a chronology of their toxic effects on the bacterial cell. This review also includes novel structural results obtained by NMR concerning the sprG1-encoded membrane peptides that belong to the sprG1/SprF1 type I TA system expressed in Staphylococcus aureus and discusses the putative membrane interactions allowing the lysis of competing bacteria and host cells. Full article

Arthropods and specifically beetles can synthesize and/or sequester metabolites from dietary sources. In beetle families such as Tenebrionidae and Meloidae, a few studies have reported species with toxic defensive substances and antiparasitic properties that are consumed by birds. Here we have studied the antiparasitic activity of extracts from beetle species present in the habitat of the Great Bustard (Otis tarda) against four pathogen models (Aspergillus niger, Meloidogyne javanica, Hyalomma lusitanicum, and Trichomonas gallinae). The insect species extracted were Tentyria peiroleri, Scaurus uncinus, Blaps lethifera (Tenebrionidae), and Mylabris quadripunctata (Meloidae). M. quadripunctata exhibited potent activity against M. javanica and T. gallinae, while T. peiroleri exhibited moderate antiprotozoal activity. The chemical composition of the insect extracts was studied by gas chromatography coupled with mass spectrometry (GC-MS) analysis. The most abundant compounds in the four beetle extracts were hydrocarbons and fatty acids such as palmitic acid, myristic acid and methyl linoleate, which are characteristic of insect cuticles. The presence of cantharidin (CTD) in the M. quadripunctata meloid and ethyl oleate (EO) in T. peiroleri accounted for the bioactivity of their extracts. Full article

The real-world use of onabotulinumtoxinA and incobotulinumtoxinA for cervical dystonia and blepharospasm treatment was assessed in two separate retrospective studies using identical protocols (TRUDOSE and TRUDOSE II). The studies were conducted in Mexico, Norway, and United Kingdom and designed to evaluate dose utilization of the two botulinum toxins in clinical practice. Eighty-three patients treated with both onabotulinumtoxinA and incobotulinumtoxinA for ≥2 years for each botulinum toxin were included, (52, cervical dystonia; 31, blepharospasm). All patients switched from onabotulinumtoxinA to incobotulinumtoxinA for administrative/financial reasons. A range of dose ratios (incobotulinumtoxinA to onabotulinumtoxinA) was reported; with the majority of dose ratios being >1. The mean dose ratio was >1 regardless of the study site or underlying clinical condition. The inter-injection interval was significantly longer for onabotulinumtoxinA versus incobotulinumtoxinA when assessed for all patients (15.5 vs. 14.3 weeks; p = 0.006), resulting in fewer onabotulinumtoxinA treatments over the study time period. Consistent with product labeling, no single fixed-dose ratio exists between incobotulinumtoxinA and onabotulinumtoxinA. The dosage of each should be individualized based on patient needs and used as per product labeling. These real-world utilization data may have pharmacoeconomic implications. Full article

Huntington’s disease (HD) is caused by a CAG-repeat expansion mutation in the Huntingtin (HTT) gene. It is characterized by progressive psychiatric and neurological symptoms in combination with a progressive movement disorder. Despite the ubiquitous expression of HTT, pathological changes occur quite selectively in the central nervous system. Since the discovery of HD more than 150 years ago, a lot of research on molecular mechanisms contributing to neurotoxicity has remained the focal point. While traditionally, the protein encoded by the HTT gene remained the cynosure for researchers and was extensively reviewed elsewhere, several studies in the last few years clearly indicated the contribution of the mutant RNA transcript to cellular dysfunction as well. In this review, we outline recent studies on RNA-mediated molecular mechanisms that are linked to cellular dysfunction in HD models. These mechanisms include mis-splicing, aberrant translation, deregulation of the miRNA machinery, deregulated RNA transport and abnormal regulation of mitochondrial RNA. Furthermore, we summarize recent therapeutical approaches targeting the mutant HTT transcript. While currently available treatments are of a palliative nature only and do not halt the disease progression, recent clinical studies provide hope that these novel RNA-targeting strategies will lead to better therapeutic approaches. Full article

Mycotoxins are secondary metabolites that are produced by molds during their development. According to fungal physiological particularities, mycotoxins can contaminate crops before harvest or during storage. Among toxins that represent a real public health issue, those produced by Fusarium genus in cereals before harvest are of great importance since they are the most frequent in European productions. Among them, deoxynivalenol (DON) and fumonisins (FUM) frequently contaminate maize. In recent years, numerous studies have investigated whether food processing techniques can be exploited to reduce the levels of these two mycotoxins, which would allow the identification and quantification of parameters affecting mycotoxin stability. The particularity of the popcorn process is that it associates heat treatment with a particular physical phenomenon (i.e., expansion). Three methods exist to implement the popcorn transformation process: hot air, hot oil, and microwaves, all of which are tested in this study. The results show that all popping modes significantly reduce FUM contents in both Mushroom and Butterfly types of popcorn. The mean initial contamination of 1351 µg/kg was reduced by 91% on average after popping. For DON, the reduction was less important despite a lower initial contamination than for FUM (560 µg/kg). Only the hot oil popping for the Mushroom type significantly reduced the contamination up to 78% compared to unpopped controls. Hot oil popping appears to provide the most important reduction for the two considered mycotoxins for both types of popcorn (−98% and −58% average reduction for FUM and DON, respectively). Full article

Helicobacter pylori is a pathogenic microorganism that successfully inhabits the human stomach, colonizing it by producing several virulence factors responsible for preventing host self-defense mechanisms. The adherence mechanism to gastric mucosal tissue is one of the most important processes for effective colonization in the stomach. The blood group antigen-binding adhesion (BabA) and sialic acid-binding adherence (SabA) are two H. pylori outer membrane proteins able to interact with antigens in the gastroduodenal tract. H. pylori possesses several mechanisms to control the regulation of both BabA and SabA in either the transcriptional or translational level. BabA is believed to be the most important protein in the early infection phase due to its ability to interact with various Lewis antigens, whereas SabA interaction with sialylated Lewis antigens may prove important for the adherence process in the inflamed gastric mucosal tissue in the ongoing-infection phase. The adherence mechanisms of BabA and SabA allow H. pylori to anchor in the gastric mucosa and begin the colonization process. Full article

Acute neonatal hyperammonemia is associated with poor neurological outcomes and high mortality. We developed, based on kinetic modeling, a user-friendly and widely applicable algorithm to tailor the treatment of acute neonatal hyperammonemia. A single compartmental model was calibrated assuming a distribution volume equal to the patient’s total body water (V), as calculated using Wells’ formula, and dialyzer clearance as derived from the measured ammonia time–concentration curves during 11 dialysis sessions in four patients (3.2 ± 0.4 kg). Based on these kinetic simulations, dialysis protocols could be derived for clinical use with different body weights, start concentrations, dialysis machines/dialyzers and dialysis settings (e.g., blood flow Q_B). By a single measurement of ammonia concentration at the dialyzer inlet and outlet, dialyzer clearance (K) can be calculated as K = Q_B∙[(C_inlet − C_outlet)/C_inlet]. The time (T) needed to decrease the ammonia concentration from a predialysis start concentration C_start to a desired target concentration C_target is then equal to T = (−V/K)∙LN(C_target/C_start). By implementing these formulae in a simple spreadsheet, medical staff can draw an institution-specific flowchart for patient-tailored treatment of hyperammonemia. Full article

Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype Na_V1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype Na_V1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs. Full article

Despite recent reviews of best practice for the treatment of Australian venomous bites and stings, there is controversy about some aspects of care, particularly the use of antivenom. Our aim was to understand current attitudes and practice in the management of suspected snake envenoming. A single-stage, cross-sectional survey of Australian emergency care physicians who had treated snake envenomation in the previous 36 months was conducted. Hospital pharmacists were also invited to complete a survey about antivenom availability, usage, and wastage in Australian hospitals. The survey was available between 5 March and 16 June 2019. A total of 121 snake envenoming cases were reported, and more than a third (44.6%) of patients were not treated with antivenom. For those treated with antivenom (n = 67), 29 patients (43%) received more than one ampoule. Nearly a quarter of respondents (21%) identified that antivenom availability was, or could be, a barrier to manage snake envenoming, while cost was identified as the least important factor. Adverse reactions following antivenom use were described in 11.9% of cases (n = 8). The majority of patients with suspected envenoming did not receive antivenom. We noted variation in dosage, sources of information, beliefs, and approaches to the care of the envenomed patient. Full article

Deoxynivalenol (DON) is a major mycotoxin with high toxicity that often contaminates grains, foods and feeds. The traditional approaches for DON removal are difficult to meet industry and agriculture demands due to the high stability of the DON molecule. Therefore, there is an urgent need to develop green and effective strategies for DON degradation. In this study, a batch of photocatalytic nanomaterials of cerium (Ce) doped titanium dioxide (TiO₂) were successfully prepared by sol-gel method. The catalysts were systematically characterized by XRD, HRTEM, FT-IR, UV-Vis and XPS. The catalyst 0.5Ce-TiO₂ showed superior photocatalytic activity for DON degradation in aqueous solution under ultraviolet light irradiation, better than that of traditional photocatalyst pure TiO₂, and 96% DON with initial concentration of 5.0 mg/L could be degraded in 4 h. In addition, the two possible degradation intermediate products C₅H₈O₃ and C₁₇H₁₈O₆ were identified, the photocatalytic degradation mechanism and degradation pathway were studied. The results indicate that Ce doped TiO₂ photocatalyst can be used to reduce DON effectively. Full article

Bordetella pertussis causes the severe childhood disease whooping cough, by releasing several toxins, including pertussis toxin (PT) as a major virulence factor. PT is an AB₅-type toxin, and consists of the enzymatic A-subunit PTS1 and five B-subunits, which facilitate binding to cells and transport of PTS1 into the cytosol. PTS1 ADP-ribosylates α-subunits of inhibitory G-proteins (Gαi) in the cytosol, which leads to disturbed cAMP signaling. Since PT is crucial for causing severe courses of disease, our aim is to identify new inhibitors against PT, to provide starting points for novel therapeutic approaches. Here, we investigated the effect of human antimicrobial peptides of the defensin family on PT. We demonstrated that PTS1 enzyme activity in vitro was inhibited by α-defensin-1 and -5, but not β-defensin-1. The amount of ADP-ribosylated Gαi was significantly reduced in PT-treated cells, in the presence of α-defensin-1 and -5. Moreover, both α-defensins decreased PT-mediated effects on cAMP signaling in the living cell-based interference in the Gαi-mediated signal transduction (iGIST) assay. Taken together, we identified the human peptides α-defensin-1 and -5 as inhibitors of PT activity, suggesting that these human peptides bear potential for developing novel therapeutic strategies against whooping cough. Full article

Patients with chronic kidney disease (CKD), especially those undergoing hemodialysis, are at a considerably high risk of bone fracture events. Experimental data indicate that uremic toxins intricately involved in bone-related proteins exert multi-faced toxicity on bone cells and tissues, leading to chronic kidney disease–mineral and bone disorder (CKD-MBD). Nonetheless, information regarding the association between p-cresyl sulfate (PCS), non-hepatic alkaline phosphatase (NHALP) and skeletal events remains elusive. We aim to explore the association between PCS, NHALP and risk of bone fracture (BF) in patients with hemodialysis. Plasma concentrations of PCS and NHALP were ascertained at study entry. Cox proportional hazard regression analyses were used to determine unadjusted and adjusted hazard ratios (aHRs) of PCS for BF risk. In multivariable analysis, NHALP was associated with incremental risks of BFs [aHR: 1.06 (95% CI: 1.01–1.11)]. The association between the highest PCS tertile and BF risk remained robust [aHR: 2.87 (95% CI: 1.02–8.09)]. With respect to BF events, the interaction between NHALP and PCS was statistically significant (p value for the interaction term < 0.05). In addition to mineral dysregulation and hyperparathyroidism in hemodialysis patients, higher circulating levels of PCS and NHALP are intricately associated with incremental risk of BF events, indicating that a joint evaluation is more comprehensive than single marker. In light of the extremely high prevalence of CKD-MBD in the hemodialysis population, PCS may act as a pro-osteoporotic toxin and serve as a potential surrogate marker for skeletal events. Full article

Ochratoxins (OTs) are mycotoxins frequently found in wines, and their contamination can occur during any stage of the winemaking process. Ochratoxin A (OTA) has been the most widely reported and the only one whose concentrations are legislated in this beverage. However, ochratoxin B, ochratoxin A methyl ester, ochratoxin B methyl ester, ochratoxin A ethyl ester, ochratoxin B ethyl ester, ochratoxin α, ochratoxin β, OTα methyl ester, OTA ethyl amide, and OTA glucose ester have also been reported in wines. Thus, detecting only OTA would lead to the underestimation of ochratoxin levels, which is a risk to human health. Considering the threat represented by the presence of ochratoxins in wines and the long-term health problems that they can cause in wine drinkers, this paper aims to review reports of the last 10 years regarding the presence of different ochratoxins in wines and how the winemaking process influences the degree of contamination, mainly by OTA. Additionally, toxicity from human exposure due to the consumption of contaminated wines is addressed. Full article

Exposure to environmental contaminants might play an important role in neurodegenerative disease pathogenesis, such as Parkinson´s disease (PD) and Alzheimer´s disease (AD). For the first time in Spain, the plasmatic levels of 19 mycotoxins from patients diagnosed with a neurodegenerative disease (44 PD and 24 AD) and from their healthy companions (25) from La Rioja region were analyzed. The studied mycotoxins were aflatoxins B1, B2, G1, G2 and M1, T-2 and HT-2, ochratoxins A (OTA) and B (OTB), zearalenone, sterigmatocystin (STER), nivalenol, deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, deepoxy-deoxynivalenol, neosolaniol, diacetoxyscirpenol and fusarenon-X. Samples were analyzed by LC-MS/MS before and after treatment with β-glucuronidase/arylsulfatase in order to detect potential metabolites. Only OTA, OTB and STER were detected in the samples. OTA was present before (77% of the samples) and after (89%) the enzymatic treatment, while OTB was only detectable before (13%). Statistically significant differences in OTA between healthy companions and patients were observed but the observed differences might seem more related to gender (OTA levels higher in men, p-value = 0.0014) than the disease itself. STER appeared only after enzymatic treatment (88%). Statistical analysis on STER, showed distributions always different between healthy controls and patients (patients’ group > controls, p-value < 0.0001). Surprisingly, STER levels weakly correlated positively with age in women (rho = 0.3384), while OTA correlation showed a decrease of levels with age especially in the men with PD (rho = −0.4643). Full article