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Toxins, Volume 7, Issue 7 (July 2015) , Pages 2336-2700

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Open AccessArticle
Biochemical Characterization of a Recombinant UDP-glucosyltransferase from Rice and Enzymatic Production of Deoxynivalenol-3-O-β-D-glucoside
Toxins 2015, 7(7), 2685-2700; https://doi.org/10.3390/toxins7072685
Received: 11 June 2015 / Revised: 10 July 2015 / Accepted: 16 July 2015 / Published: 21 July 2015
Cited by 21 | Viewed by 2454 | PDF Full-text (731 KB) | HTML Full-text | XML Full-text
Abstract
Glycosylation is an important plant defense mechanism and conjugates of Fusarium mycotoxins often co-occur with their parent compounds in cereal-based food and feed. In case of deoxynivalenol (DON), deoxynivalenol-3-O-β-D-glucoside (D3G) is the most important masked mycotoxin. The toxicological significance of D3G [...] Read more.
Glycosylation is an important plant defense mechanism and conjugates of Fusarium mycotoxins often co-occur with their parent compounds in cereal-based food and feed. In case of deoxynivalenol (DON), deoxynivalenol-3-O-β-D-glucoside (D3G) is the most important masked mycotoxin. The toxicological significance of D3G is not yet fully understood so that it is crucial to obtain this compound in pure and sufficient quantities for toxicological risk assessment and for use as an analytical standard. The aim of this study was the biochemical characterization of a DON-inactivating UDP-glucosyltransferase from rice (OsUGT79) and to investigate its suitability for preparative D3G synthesis. Apparent Michaelis constants (Km) of recombinant OsUGT79 were 0.23 mM DON and 2.2 mM UDP-glucose. Substrate inhibition occurred at DON concentrations above 2 mM (Ki = 24 mM DON), and UDP strongly inhibited the enzyme. Cu2+ and Zn2+ (1 mM) inhibited the enzyme completely. Sucrose synthase AtSUS1 was employed to regenerate UDP-glucose during the glucosylation reaction. With this approach, optimal conversion rates can be obtained at limited concentrations of the costly co-factor UDP-glucose. D3G can now be synthesized in sufficient quantity and purity. Similar strategies may be of interest to produce β-glucosides of other toxins. Full article
(This article belongs to the Section Mycotoxins)
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Open AccessArticle
A Conformational Shift in the Dissociated Cholera Toxin A1 Subunit Prevents Reassembly of the Cholera Holotoxin
Toxins 2015, 7(7), 2674-2684; https://doi.org/10.3390/toxins7072674
Received: 11 June 2015 / Revised: 9 July 2015 / Accepted: 14 July 2015 / Published: 20 July 2015
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Abstract
Cholera toxin (CT) consists of a catalytic A1 subunit, an A2 linker, and a homopentameric cell-binding B subunit. The intact holotoxin moves by vesicle carriers from the cell surface to the endoplasmic reticulum (ER) where CTA1 is released from the rest of the [...] Read more.
Cholera toxin (CT) consists of a catalytic A1 subunit, an A2 linker, and a homopentameric cell-binding B subunit. The intact holotoxin moves by vesicle carriers from the cell surface to the endoplasmic reticulum (ER) where CTA1 is released from the rest of the toxin. The dissociated CTA1 subunit then shifts to an unfolded conformation, which triggers its export to the cytosol by a process involving the quality control system of ER-associated degradation (ERAD). We hypothesized that the unfolding of dissociated CTA1 would prevent its non-productive reassociation with CTA2/CTB5. To test this prediction, we monitored the real-time reassociation of CTA1 with CTA2/CTB5 by surface plasmon resonance. Folded but not disordered CTA1 could interact with CTA2/CTB5 to form a stable, functional holotoxin. Our data, thus, identified another role for the intrinsic instability of the isolated CTA1 polypeptide in host-toxin interactions: in addition to activating the ERAD translocation mechanism, the spontaneous unfolding of free CTA1 at 37 °C prevents the non-productive reassembly of a CT holotoxin in the ER. Full article
(This article belongs to the Special Issue The Cell Biology of Toxins and Effector Proteins from Vibrio cholerae)
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Open AccessReview
Treatment of Chronic Migraine with OnabotulinumtoxinA: Mode of Action, Efficacy and Safety
Toxins 2015, 7(7), 2659-2673; https://doi.org/10.3390/toxins7072659
Received: 28 May 2015 / Revised: 29 May 2015 / Accepted: 26 June 2015 / Published: 17 July 2015
Cited by 10 | Viewed by 2598 | PDF Full-text (318 KB) | HTML Full-text | XML Full-text
Abstract
Background: Chronic migraine is a common, highly disabling, underdiagnosed and undertreated entity of migraine. It affects 0.9%–2.2% of the general adult population. The present paper overviews the preclinical and clinical data regarding the therapeutic effect of onabotulinumtoxinA in chronic migraineurs. Methods: A literature [...] Read more.
Background: Chronic migraine is a common, highly disabling, underdiagnosed and undertreated entity of migraine. It affects 0.9%–2.2% of the general adult population. The present paper overviews the preclinical and clinical data regarding the therapeutic effect of onabotulinumtoxinA in chronic migraineurs. Methods: A literature search was conducted in the database of PubMed up to 20 May 2015 for articles related to the pathomechanism of chronic migraine, the mode of action, and the efficacy, safety and tolerability of onabotulinumtoxinA for the preventive treatment of chronic migraine. Results: The pathomechanism of chronic migraine has not been fully elucidated. The mode of action of onabotulinumtoxinA in the treatment of chronic migraine is suggested to be related to the inhibition of the release of calcitonin gene-related peptide and substance P in the trigeminovascular system. Randomized clinical trials demonstrated that long-term onabotulinumtoxinA fixed-site and fixed-dose (155–195 U) intramuscular injection therapy was effective and well tolerated for the prophylactic treatment of chronic migraine. Conclusions: Chronic migraine is a highly devastating entity of migraine. Its exact pathomechanism is unrevealed. Two-third of chronic migraineurs do not receive proper preventive medication. Recent clinical studies revealed that onabotulinumtoxinA was an efficacious and safe treatment for chronic migraine. Full article
(This article belongs to the collection Botulinum Toxins on Human Pain)
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Open AccessReview
Cabinet of Curiosities: Venom Systems and Their Ecological Function in Mammals, with a Focus on Primates
Toxins 2015, 7(7), 2639-2658; https://doi.org/10.3390/toxins7072639
Received: 29 April 2015 / Revised: 1 July 2015 / Accepted: 10 July 2015 / Published: 17 July 2015
Cited by 6 | Viewed by 2516 | PDF Full-text (701 KB) | HTML Full-text | XML Full-text
Abstract
Venom delivery systems (VDS) are common in the animal kingdom, but rare amongst mammals. New definitions of venom allow us to reconsider its diversity amongst mammals by reviewing the VDS of Chiroptera, Eulipotyphla, Monotremata, and Primates. All orders use modified anterior dentition as [...] Read more.
Venom delivery systems (VDS) are common in the animal kingdom, but rare amongst mammals. New definitions of venom allow us to reconsider its diversity amongst mammals by reviewing the VDS of Chiroptera, Eulipotyphla, Monotremata, and Primates. All orders use modified anterior dentition as the venom delivery apparatus, except Monotremata, which possesses a crural system. The venom gland in most taxa is a modified submaxillary salivary gland. In Primates, the saliva is activated when combined with brachial gland exudate. In Monotremata, the crural spur contains the venom duct. Venom functions include feeding, intraspecific competition, anti-predator defense and parasite defense. Including mammals in discussion of venom evolution could prove vital in our understanding protein functioning in mammals and provide a new avenue for biomedical and therapeutic applications and drug discovery. Full article
(This article belongs to the collection Evolution of Venom Systems)
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Open AccessArticle
Topographic Relationship between the Supratrochlear Nerve and Corrugator Supercilii Muscle—Can This Anatomical Knowledge Improve the Response to Botulinum Toxin Injections in Chronic Migraine?
Toxins 2015, 7(7), 2629-2638; https://doi.org/10.3390/toxins7072629
Received: 24 February 2015 / Revised: 10 July 2015 / Accepted: 13 July 2015 / Published: 17 July 2015
Cited by 6 | Viewed by 3646 | PDF Full-text (875 KB) | HTML Full-text | XML Full-text
Abstract
Chronic migraine has been related to the entrapment of the supratrochlear nerve within the corrugator supercilii muscle. Recently, research has shown that people who have undergone botulinum neurotoxin A injection in frontal regions reported disappearance or alleviation of their migraines. There have been [...] Read more.
Chronic migraine has been related to the entrapment of the supratrochlear nerve within the corrugator supercilii muscle. Recently, research has shown that people who have undergone botulinum neurotoxin A injection in frontal regions reported disappearance or alleviation of their migraines. There have been numerous anatomical studies conducted on Caucasians revealing possible anatomical problems leading to migraine; on the other hand, relatively few anatomical studies have been conducted on Asians. Thus, the aim of the present study was to determine the topographic relationship between the supratrochlear nerve and corrugator supercilii muscle in the forehead that may be the cause of migraine. Fifty-eight hemifaces from Korean and Thai cadavers were used for this study. The supratrochlear nerve entered the corrugator supercilii muscle in every case. Type I, in which the supratrochlear nerve emerged separately from the supraorbital nerve at the medial one-third portion of the orbit, was observed in 69% (40/58) of cases. Type II, in which the supratrochlear nerve emerged from the orbit at the same location as the supraorbital nerve, was observed in 31% (18/58) of cases. Full article
(This article belongs to the collection Botulinum Toxins on Human Pain)
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Open AccessReview
Treatment of Chronic Migraine with Focus on Botulinum Neurotoxins
Toxins 2015, 7(7), 2615-2628; https://doi.org/10.3390/toxins7072615
Received: 1 June 2015 / Revised: 2 July 2015 / Accepted: 8 July 2015 / Published: 14 July 2015
Cited by 8 | Viewed by 3199 | PDF Full-text (959 KB) | HTML Full-text | XML Full-text
Abstract
Migraine is the most common neurological disorder, and contributes to disability and large healthcare costs in the United States and the world. The treatment of migraine until recently has focused on medications, both abortive and prophylactic, but treatment of chronic migraine has been [...] Read more.
Migraine is the most common neurological disorder, and contributes to disability and large healthcare costs in the United States and the world. The treatment of migraine until recently has focused on medications, both abortive and prophylactic, but treatment of chronic migraine has been revolutionized with the introduction of botulinum toxin injection therapy. In this review, we explore the current understanding of migraine pathophysiology, and the evolution of the use of botulinum toxin therapy including proposed pathophysiological mechanisms through animal data. We also discuss the similarities and differences between three injection techniques. Full article
(This article belongs to the collection Botulinum Toxins on Human Pain)
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Open AccessArticle
Different Roles of N-Terminal and C-Terminal Domains in Calmodulin for Activation of Bacillus anthracis Edema Factor
Toxins 2015, 7(7), 2598-2614; https://doi.org/10.3390/toxins7072598
Received: 29 April 2015 / Revised: 29 June 2015 / Accepted: 6 July 2015 / Published: 13 July 2015
Cited by 2 | Viewed by 2173 | PDF Full-text (669 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bacillus anthracis adenylyl cyclase toxin edema factor (EF) is one component of the anthrax toxin and is essential for establishing anthrax disease. EF activation by the eukaryotic Ca2+-sensor calmodulin (CaM) leads to massive cAMP production resulting in edema. cAMP also inhibits [...] Read more.
Bacillus anthracis adenylyl cyclase toxin edema factor (EF) is one component of the anthrax toxin and is essential for establishing anthrax disease. EF activation by the eukaryotic Ca2+-sensor calmodulin (CaM) leads to massive cAMP production resulting in edema. cAMP also inhibits the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, thus reducing production of reactive oxygen species (ROS) used for host defense in activated neutrophils and thereby facilitating bacterial growth. Methionine (Met) residues in CaM, important for interactions between CaM and its binding partners, can be oxidized by ROS. We investigated the impact of site-specific oxidation of Met in CaM on EF activation using thirteen CaM-mutants (CaM-mut) with Met to leucine (Leu) substitutions. EF activation shows high resistance to oxidative modifications in CaM. An intact structure in the C-terminal region of oxidized CaM is sufficient for major EF activation despite altered secondary structure in the N-terminal region associated with Met oxidation. The secondary structures of CaM-mut were determined and described in previous studies from our group. Thus, excess cAMP production and the associated impairment of host defence may be afforded even under oxidative conditions in activated neutrophils. Full article
(This article belongs to the collection Anthrax Toxins)
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Open AccessArticle
Veal Calves Produce Less Antibodies against C. Perfringens Alpha Toxin Compared to Beef Calves
Toxins 2015, 7(7), 2586-2597; https://doi.org/10.3390/toxins7072586
Received: 28 May 2015 / Revised: 30 June 2015 / Accepted: 7 July 2015 / Published: 10 July 2015
Cited by 3 | Viewed by 1965 | PDF Full-text (344 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Enterotoxaemia is a disease with a high associated mortality rate, affecting beef and veal calves worldwide, caused by C. perfringens alpha toxin and perfringolysin. A longitudinal study was conducted to determine the dynamics of antibodies against these toxins in 528 calves on 4 [...] Read more.
Enterotoxaemia is a disease with a high associated mortality rate, affecting beef and veal calves worldwide, caused by C. perfringens alpha toxin and perfringolysin. A longitudinal study was conducted to determine the dynamics of antibodies against these toxins in 528 calves on 4 beef and 15 veal farms. The second study aimed to determine the effect of solid feed intake on the production of antibodies against alpha toxin and perfringolysin. The control group only received milk replacer, whereas in the test group solid feed was provided. Maternal antibodies for alpha toxin were present in 45% of the veal calves and 66% of the beef calves. In beef calves a fluent transition from maternal to active immunity was observed for alpha toxin, whereas almost no veal calves developed active immunity. Perfringolysin antibodies significantly declined both in veal and beef calves. In the second study all calves were seropositive for alpha toxin throughout the experiment and solid feed intake did not alter the dynamics of alpha and perfringolysin antibodies. In conclusion, the present study showed that veal calves on a traditional milk replacer diet had significantly lower alpha toxin antibodies compared to beef calves in the risk period for enterotoxaemia, whereas no differences were noticed for perfringolysin. Full article
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Open AccessArticle
Repetitive Treatment with Diluted Bee Venom Attenuates the Induction of Below-Level Neuropathic Pain Behaviors in a Rat Spinal Cord Injury Model
Toxins 2015, 7(7), 2571-2585; https://doi.org/10.3390/toxins7072571
Received: 11 May 2015 / Revised: 24 June 2015 / Accepted: 7 July 2015 / Published: 10 July 2015
Cited by 7 | Viewed by 2611 | PDF Full-text (331 KB) | HTML Full-text | XML Full-text
Abstract
The administration of diluted bee venom (DBV) into an acupuncture point has been utilized traditionally in Eastern medicine to treat chronic pain. We demonstrated previously that DBV has a potent anti-nociceptive efficacy in several rodent pain models. The present study was designed to [...] Read more.
The administration of diluted bee venom (DBV) into an acupuncture point has been utilized traditionally in Eastern medicine to treat chronic pain. We demonstrated previously that DBV has a potent anti-nociceptive efficacy in several rodent pain models. The present study was designed to examine the potential anti-nociceptive effect of repetitive DBV treatment in the development of below-level neuropathic pain in spinal cord injury (SCI) rats. DBV was applied into the Joksamli acupoint during the induction and maintenance phase following thoracic 13 (T13) spinal hemisection. We examined the effect of repetitive DBV stimulation on SCI-induced bilateral pain behaviors, glia expression and motor function recovery. Repetitive DBV stimulation during the induction period, but not the maintenance, suppressed pain behavior in the ipsilateral hind paw. Moreover, SCI-induced increase in spinal glia expression was also suppressed by repetitive DBV treatment in the ipsilateral dorsal spinal cord. Finally, DBV injection facilitated motor function recovery as indicated by the Basso–Beattie–Bresnahan rating score. These results indicate that the repetitive application of DBV during the induction phase not only decreased neuropathic pain behavior and glia expression, but also enhanced locomotor functional recovery after SCI. This study suggests that DBV acupuncture can be a potential clinical therapy for SCI management. Full article
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Open AccessReview
Facing Hymenoptera Venom Allergy: From Natural to Recombinant Allergens
Toxins 2015, 7(7), 2551-2570; https://doi.org/10.3390/toxins7072551
Received: 20 April 2015 / Revised: 16 May 2015 / Accepted: 23 June 2015 / Published: 9 July 2015
Cited by 12 | Viewed by 2506 | PDF Full-text (634 KB) | HTML Full-text | XML Full-text
Abstract
Along with food and drug allergic reactions, a Hymenoptera insect Sting (Apoidea, Vespidae, Formicidae) is one of the most common causes of anaphylaxis worldwide. Diagnoses of Hymenoptera venom allergy (HVA) and specific immunotherapy (SIT) have been based on the use of crude venom [...] Read more.
Along with food and drug allergic reactions, a Hymenoptera insect Sting (Apoidea, Vespidae, Formicidae) is one of the most common causes of anaphylaxis worldwide. Diagnoses of Hymenoptera venom allergy (HVA) and specific immunotherapy (SIT) have been based on the use of crude venom extracts. However, the incidence of cross-reactivity and low levels of sensibility during diagnosis, as well as the occurrence of nonspecific sensitization and undesired side effects during SIT, encourage the search for novel allergenic materials. Recombinant allergens are an interesting approach to improve allergy diagnosis and SIT because they circumvent major problems associated with the use of crude venom. Production of recombinant allergens depends on the profound molecular characterization of the natural counterpart by combining some “omics” approaches with high-throughput screening techniques and the selection of an appropriate system for heterologous expression. To date, several clinically relevant allergens and novel venom toxins have been identified, cloned and characterized, enabling a better understanding of the whole allergenic and envenoming processes. Here, we review recent findings on identification, molecular characterization and recombinant expression of Hymenoptera venom allergens and on the evaluation of these heterologous proteins as valuable tools for tackling remaining pitfalls on HVA diagnosis and immunotherapy. Full article
(This article belongs to the collection Evolution of Venom Systems)
Open AccessArticle
Revealing the Function and the Structural Model of Ts4: Insights into the “Non-Toxic” Toxin from Tityus serrulatus Venom
Toxins 2015, 7(7), 2534-2550; https://doi.org/10.3390/toxins7072534
Received: 20 May 2015 / Revised: 20 June 2015 / Accepted: 25 June 2015 / Published: 6 July 2015
Cited by 15 | Viewed by 2314 | PDF Full-text (2104 KB) | HTML Full-text | XML Full-text
Abstract
The toxin, previously described as a “non-toxic” toxin, was isolated from the scorpion venom of Tityus serrulatus (Ts), responsible for the most severe and the highest number of accidents in Brazil. In this study, the subtype specificity and selectivity of Ts4 was investigated [...] Read more.
The toxin, previously described as a “non-toxic” toxin, was isolated from the scorpion venom of Tityus serrulatus (Ts), responsible for the most severe and the highest number of accidents in Brazil. In this study, the subtype specificity and selectivity of Ts4 was investigated using six mammalian Nav channels (Nav1.2→Nav1.6 and Nav1.8) and two insect Nav channels (DmNav1 and BgNav). The electrophysiological assays showed that Ts4 specifically inhibited the fast inactivation of Nav1.6 channels, the most abundant sodium channel expressed in the adult central nervous system, and can no longer be classified as a “non-toxic peptide”. Based on the results, we could classify the Ts4 as a classical α-toxin. The Ts4 3D-structural model was built based on the solved X-ray Ts1 3D-structure, the major toxin from Ts venom with which it shares high sequence identity (65.57%). The Ts4 model revealed a flattened triangular shape constituted by three-stranded antiparallel β-sheet and one α-helix stabilized by four disulfide bonds. The absence of a Lys in the first amino acid residue of the N-terminal of Ts4 is probably the main responsible for its low toxicity. Other key amino acid residues important to the toxicity of α- and β-toxins are discussed here. Full article
(This article belongs to the Special Issue Arthropod Venoms)
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Open AccessArticle
Culture-Independent Study of the Late-Stage of a Bloom of the Toxic Dinoflagellate Ostreopsis cf. ovata: Preliminary Findings Suggest Genetic Differences at the Sub-Species Level and Allow ITS2 Structure Characterization
Toxins 2015, 7(7), 2514-2533; https://doi.org/10.3390/toxins7072514
Received: 26 March 2015 / Revised: 6 June 2015 / Accepted: 24 June 2015 / Published: 30 June 2015
Cited by 2 | Viewed by 2045 | PDF Full-text (1822 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Available genomic data for the toxic, bloom-forming, benthic Ostreopsis spp. are traditionally obtained from isolates rather than from individuals originally present in environmental samples. Samples from the final phase of the first reported Ostreopsis bloom in European North Atlantic waters (Algarve, south coast [...] Read more.
Available genomic data for the toxic, bloom-forming, benthic Ostreopsis spp. are traditionally obtained from isolates rather than from individuals originally present in environmental samples. Samples from the final phase of the first reported Ostreopsis bloom in European North Atlantic waters (Algarve, south coast of Portugal) were studied and characterized, using a culture-independent approach. In the first instance, a microscopy-based analysis revealed the intricate complexity of the samples. Then, we evaluated the adequacy of commonly used molecular tools (i.e., primers and nuclear ribosomal markers) for the study of Ostreopsis diversity in natural samples. A PCR-based methodology previously developed to identify/detect common Ostreopsis species was tested, including one new combination of existing PCR primers. Two sets of environmental rRNA sequences were obtained, one of them (1052 bp) with the newly tested primer set. These latter sequences encompass both the ITS1-5.8S-ITS2 region and the D1/D2 domain of the LSU rRNA gene, leading us to an accurate identification of ITS2. In turn, this allowed us to predict and show for the first time the ITS2 secondary structure of Ostreopsis. With 92 bp in length and a two-helix structure, the ITS2 of this genus revealed to be unique among the dinoflagellates. Both the PCR approach as the phylogenetic analyses allowed to place the Ostreopsis cells observed in the samples within the O. cf. ovata phylospecies’ complex, discarding the presence of O. cf. siamensis. The (phylo)genetic results point out a certain level of nucleotide sequence divergence, but were inconclusive in relation to a possible geographic origin of the O. cf. ovata population from the Algarve’s bloom. Full article
(This article belongs to the Section Marine and Freshwater Toxins)
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Open AccessArticle
Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula
Toxins 2015, 7(7), 2494-2513; https://doi.org/10.3390/toxins7072494
Received: 15 April 2015 / Revised: 19 June 2015 / Accepted: 24 June 2015 / Published: 30 June 2015
Cited by 15 | Viewed by 3681 | PDF Full-text (2437 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom [...] Read more.
Voltage-gated sodium (NaV) channels are responsible for propagating action potentials in excitable cells. NaV1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of NaV channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of NaV1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human NaV1.7 (hNaV1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNaV1.7 with IC50 values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat NaV1.2 and hNaV1.5. Although similarly potent at hNaV1.7 (IC50 333 nM), Phlo2a was less selective, as it also potently inhibited rNaV1.2 and hNaV1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNaV1.7 activation. Full article
(This article belongs to the Special Issue Selected Papers from the 5th Venoms to Drugs Meeting)
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Open AccessArticle
Onabotulinumtoxin A Treatment of Drooling in Children with Cerebral Palsy: A Prospective, Longitudinal Open-Label Study
Toxins 2015, 7(7), 2481-2493; https://doi.org/10.3390/toxins7072481
Received: 23 May 2015 / Revised: 14 June 2015 / Accepted: 19 June 2015 / Published: 30 June 2015
Cited by 4 | Viewed by 2291 | PDF Full-text (810 KB) | HTML Full-text | XML Full-text
Abstract
The aim of this prospective open-label study was to treat disabling drooling in children with cerebral palsy (CP) with onabotulinumtoxin A (A/Ona, Botox®) into submandibular and parotid glands and find the lowest effective dosage and least invasive method. A/Ona was injected [...] Read more.
The aim of this prospective open-label study was to treat disabling drooling in children with cerebral palsy (CP) with onabotulinumtoxin A (A/Ona, Botox®) into submandibular and parotid glands and find the lowest effective dosage and least invasive method. A/Ona was injected in 14 children, Mean age 9 years, SD 3 years, under ultrasonic guidance in six successive Series, with at least six months between injections. Doses and gland involvement increased from Series A to F (units (U) per submandibular/parotid gland: A, 10/0; B, 15/0; C, 20/0; D, 20/20; E, 30/20; and F, 30/30). The effect was assessed 2, 4, 8, 12, and 20 weeks after A/Ona (drooling problems (VAS), impact (0–7), treatment effect (0–5), unstimulated whole saliva (UWS) flow and composition)) and analyzed by two-way ANOVA. The effect was unchanged–moderate in A to moderate–marked in F. Changes in all parameters were significant in E and F, but with swallowing problems ≤5 weeks in 3 of 28 treatments. F had largest VAS and UWS reduction (64% and 49%). We recommend: Start with dose D A/Ona (both submandibular and parotid glands and a total of 80 U) and increase to E and eventually F (total 120 U) without sufficient response. Full article
(This article belongs to the collection Botulinum Toxins on Human Pain)
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Open AccessReview
Botulinum Toxin Type A for the Treatment of Neuropathic Pain in Neuro-Rehabilitation
Toxins 2015, 7(7), 2454-2480; https://doi.org/10.3390/toxins7072454
Received: 23 March 2015 / Revised: 22 May 2015 / Accepted: 23 June 2015 / Published: 30 June 2015
Cited by 9 | Viewed by 3007 | PDF Full-text (597 KB) | HTML Full-text | XML Full-text
Abstract
Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP) results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in [...] Read more.
Pain is a natural protective mechanism and has a warning function signaling imminent or actual tissue damage. Neuropathic pain (NP) results from a dysfunction and derangement in the transmission and signal processing along the nervous system and it is a recognized disease in itself. The prevalence of NP is estimated to be between 6.9% and 10% in the general population. This condition can complicate the recovery from stroke, multiple sclerosis, spinal cord lesions, and several neuropathies promoting persistent disability and poor quality of life. Subjects suffering from NP describe it as burning, itching, lancing, and numbness, but hyperalgesia and allodynia represent the most bothersome symptoms. The management of NP is a clinical challenge and several non-pharmacological and pharmacological interventions have been proposed with variable benefits. Botulinum toxin (BTX) as an adjunct to other interventions can be a useful therapeutic tool for the treatment of disabled people. Although BTX-A is predominantly used to reduce spasticity in a neuro-rehabilitation setting, it has been used in several painful conditions including disorders characterized by NP. The underlying pharmacological mechanisms that operate in reducing pain are still unclear and include blocking nociceptor transduction, the reduction of neurogenic inflammation by inhibiting neural substances and neurotransmitters, and the prevention of peripheral and central sensitization. Some neurological disorders requiring rehabilitative intervention can show neuropathic pain resistant to common analgesic treatment. This paper addresses the effect of BTX-A in treating NP that complicates frequent disorders of the central and peripheral nervous system such as spinal cord injury, post-stroke shoulder pain, and painful diabetic neuropathy, which are commonly managed in a rehabilitation setting. Furthermore, BTX-A has an effect in relief pain that may characterize less common neurological disorders including post-traumatic neuralgia, phantom limb, and complex regional pain syndrome with focal dystonia. The use of BTX-A could represent a novel therapeutic strategy in caring for neuropathic pain whenever common pharmacological tools have been ineffective. However, large and well-designed clinical trials are needed to recommend BTX-A use in the relief of neuropathic pain. Full article
(This article belongs to the collection Botulinum Toxins on Human Pain)
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Open AccessReview
Botulinum Toxin as a Pain Killer: Players and Actions in Antinociception
Toxins 2015, 7(7), 2435-2453; https://doi.org/10.3390/toxins7072435
Received: 31 May 2015 / Revised: 19 June 2015 / Accepted: 23 June 2015 / Published: 30 June 2015
Cited by 14 | Viewed by 2950 | PDF Full-text (831 KB) | HTML Full-text | XML Full-text
Abstract
Botulinum neurotoxins (BoNTs) have been widely used to treat a variety of clinical ailments associated with pain. The inhibitory action of BoNTs on synaptic vesicle fusion blocks the releases of various pain-modulating neurotransmitters, including glutamate, substance P (SP), and calcitonin gene-related peptide (CGRP), [...] Read more.
Botulinum neurotoxins (BoNTs) have been widely used to treat a variety of clinical ailments associated with pain. The inhibitory action of BoNTs on synaptic vesicle fusion blocks the releases of various pain-modulating neurotransmitters, including glutamate, substance P (SP), and calcitonin gene-related peptide (CGRP), as well as the addition of pain-sensing transmembrane receptors such as transient receptor potential (TRP) to neuronal plasma membrane. In addition, growing evidence suggests that the analgesic and anti-inflammatory effects of BoNTs are mediated through various molecular pathways. Recent studies have revealed that the detailed structural bases of BoNTs interact with their cellular receptors and SNAREs. In this review, we discuss the molecular and cellular mechanisms related to the efficacy of BoNTs in alleviating human pain and insights on engineering the toxins to extend therapeutic interventions related to nociception. Full article
(This article belongs to the collection Botulinum Toxins on Human Pain)
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Open AccessArticle
Analgesic Effects of Bee Venom Derived Phospholipase A2 in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain
Toxins 2015, 7(7), 2422-2434; https://doi.org/10.3390/toxins7072422
Received: 15 May 2015 / Revised: 11 June 2015 / Accepted: 23 June 2015 / Published: 29 June 2015
Cited by 14 | Viewed by 2287 | PDF Full-text (235 KB) | HTML Full-text | XML Full-text
Abstract
A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various [...] Read more.
A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A2 (bvPLA2) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA2, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA2-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA2 treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system. Full article
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Open AccessReview
Therapeutic Effects of Bee Venom on Immunological and Neurological Diseases
Toxins 2015, 7(7), 2413-2421; https://doi.org/10.3390/toxins7072413
Received: 15 May 2015 / Revised: 16 May 2015 / Accepted: 24 June 2015 / Published: 29 June 2015
Cited by 18 | Viewed by 3065 | PDF Full-text (319 KB) | HTML Full-text | XML Full-text
Abstract
Bee Venom (BV) has long been used in Korea to relieve pain symptoms and to treat inflammatory diseases, such as rheumatoid arthritis. The underlying mechanisms of the anti-inflammatory and analgesic actions of BV have been proved to some extent. Additionally, recent clinical and [...] Read more.
Bee Venom (BV) has long been used in Korea to relieve pain symptoms and to treat inflammatory diseases, such as rheumatoid arthritis. The underlying mechanisms of the anti-inflammatory and analgesic actions of BV have been proved to some extent. Additionally, recent clinical and experimental studies have demonstrated that BV and BV-derived active components are applicable to a wide range of immunological and neurodegenerative diseases, including autoimmune diseases and Parkinson’s disease. These effects of BV are known to be mediated by modulating immune cells in the periphery, and glial cells and neurons in the central nervous system. This review will introduce the scientific evidence of the therapeutic effects of BV and its components on several immunological and neurological diseases, and describe their detailed mechanisms involved in regulating various immune responses and pathological changes in glia and neurons. Full article
Open AccessReview
Venom Proteins from Parasitoid Wasps and Their Biological Functions
Toxins 2015, 7(7), 2385-2412; https://doi.org/10.3390/toxins7072385
Received: 20 May 2015 / Revised: 16 June 2015 / Accepted: 16 June 2015 / Published: 26 June 2015
Cited by 40 | Viewed by 2536 | PDF Full-text (573 KB) | HTML Full-text | XML Full-text
Abstract
Parasitoid wasps are valuable biological control agents that suppress their host populations. Factors introduced by the female wasp at parasitization play significant roles in facilitating successful development of the parasitoid larva either inside (endoparasitoid) or outside (ectoparasitoid) the host. Wasp venoms consist of [...] Read more.
Parasitoid wasps are valuable biological control agents that suppress their host populations. Factors introduced by the female wasp at parasitization play significant roles in facilitating successful development of the parasitoid larva either inside (endoparasitoid) or outside (ectoparasitoid) the host. Wasp venoms consist of a complex cocktail of proteinacious and non-proteinacious components that may offer agrichemicals as well as pharmaceutical components to improve pest management or health related disorders. Undesirably, the constituents of only a small number of wasp venoms are known. In this article, we review the latest research on venom from parasitoid wasps with an emphasis on their biological function, applications and new approaches used in venom studies. Full article
Open AccessArticle
Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge
Toxins 2015, 7(7), 2371-2384; https://doi.org/10.3390/toxins7072371
Received: 21 May 2015 / Revised: 15 June 2015 / Accepted: 18 June 2015 / Published: 25 June 2015
Cited by 2 | Viewed by 2073 | PDF Full-text (500 KB) | HTML Full-text | XML Full-text
Abstract
Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. [...] Read more.
Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities. Full article
(This article belongs to the collection Anthrax Toxins)
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Open AccessArticle
A Highly Specific Monoclonal Antibody for Botulinum Neurotoxin Type A-Cleaved SNAP25
Toxins 2015, 7(7), 2354-2370; https://doi.org/10.3390/toxins7072354
Received: 16 May 2015 / Revised: 12 June 2015 / Accepted: 17 June 2015 / Published: 24 June 2015
Cited by 6 | Viewed by 2641 | PDF Full-text (2550 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Botulinum neurotoxin type-A (BoNT/A), as onabotulinumtoxinA, is approved globally for 11 major therapeutic and cosmetic indications. While the mechanism of action for BoNT/A at the presynaptic nerve terminal has been established, questions remain regarding intracellular trafficking patterns and overall fate of the toxin. [...] Read more.
Botulinum neurotoxin type-A (BoNT/A), as onabotulinumtoxinA, is approved globally for 11 major therapeutic and cosmetic indications. While the mechanism of action for BoNT/A at the presynaptic nerve terminal has been established, questions remain regarding intracellular trafficking patterns and overall fate of the toxin. Resolving these questions partly depends on the ability to detect BoNT/A’s location, distribution, and movement within a cell. Due to BoNT/A’s high potency and extremely low concentrations within neurons, an alternative approach has been employed. This involves utilizing specific antibodies against the BoNT/A-cleaved SNAP25 substrate (SNAP25197) to track the enzymatic activity of toxin within cells. Using our highly specific mouse monoclonal antibody (mAb) against SNAP25197, we generated human and murine recombinant versions (rMAb) using specific backbone immunoglobulins. In this study, we validated the specificity of our anti-SNAP25197 rMAbs in several different assays and performed side-by-side comparisons to commercially-available and in-house antibodies against SNAP25. Our rMAbs were highly specific for SNAP25197 in all assays and on several different BoNT/A-treated tissues, showing no cross-reactivity with full-length SNAP25. This was not the case with other reportedly SNAP25197-selective antibodies, which were selective in some, but not all assays. The rMAbs described herein represent effective new tools for detecting BoNT/A activity within cells. Full article
(This article belongs to the collection Rapid Detection of Bacterial Toxins)
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Open AccessArticle
Development of Plate Reader and On-Line Microfluidic Screening to Identify Ligands of the 5-Hydroxytryptamine Binding Protein in Venoms
Toxins 2015, 7(7), 2336-2353; https://doi.org/10.3390/toxins7072336
Received: 27 March 2015 / Revised: 6 May 2015 / Accepted: 16 June 2015 / Published: 24 June 2015
Cited by 2 | Viewed by 2164 | PDF Full-text (1542 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The 5-HT3 receptor is a ligand-gated ion channel, which is expressed in the nervous system. Its antagonists are used clinically for treatment of postoperative- and radiotherapy-induced emesis and irritable bowel syndrome. In order to better understand the structure and function of the [...] Read more.
The 5-HT3 receptor is a ligand-gated ion channel, which is expressed in the nervous system. Its antagonists are used clinically for treatment of postoperative- and radiotherapy-induced emesis and irritable bowel syndrome. In order to better understand the structure and function of the 5-HT3 receptor, and to allow for compound screening at this receptor, recently a serotonin binding protein (5HTBP) was engineered with the Acetylcholine Binding Protein as template. In this study, a fluorescence enhancement assay for 5HTBP ligands was developed in plate-reader format and subsequently used in an on-line microfluidic format. Both assay types were validated using an existing radioligand binding assay. The on-line microfluidic assay was coupled to HPLC via a post-column split which allowed parallel coupling to a mass spectrometer to collect MS data. This high-resolution screening (HRS) system is well suitable for compound mixture analysis. As a proof of principle, the venoms of Dendroapsis polylepis, Pseudonaja affinis and Pseudonaja inframacula snakes were screened and the accurate masses of the found bioactives were established. To demonstrate the subsequent workflow towards structural identification of bioactive proteins and peptides, the partial amino acid sequence of one of the bioactives from the Pseudonaja affinis venom was determined using a bottom-up proteomics approach. Full article
(This article belongs to the Special Issue Selected Papers from the 5th Venoms to Drugs Meeting)
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