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Open AccessArticle Sensitive Detection of α-Conotoxin GI in Human Plasma Using a Solid-Phase Extraction Column and LC-MS/MS

by Shuo Yu, Bo Yang, Liangping Yan and Qiuyun Dai

Toxins 2017, 9(8), 235; doi:10.3390/toxins9080235 (registering DOI)

Received: 5 July 2017 / Revised: 21 July 2017 / Accepted: 25 July 2017 / Published: 28 July 2017

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Abstract

α-conotoxin GI, a short peptide toxin in the venom of Conus geographus, is composed of 13 amino acids and two disulfide bonds. It is the most toxic component of Conus geographus venom with estimated lethal doses of 0.029–0.038 mg/kg for humans. There

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α-conotoxin GI, a short peptide toxin in the venom of Conus geographus, is composed of 13 amino acids and two disulfide bonds. It is the most toxic component of Conus geographus venom with estimated lethal doses of 0.029–0.038 mg/kg for humans. There is currently no reported analytical method for this toxin. In the present study, a sensitive detection method was developed to quantify GI in human plasma using a solid-phase extraction (SPE) column (polystyrene–divinyl benzene copolymer) combined with liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the multiple reaction monitoring (MRM) mode. The plasma samples were treated with a protein precipitating solvent (methanol: acetonitrile = 50:50, v/v). GI in the solvent was efficiently extracted with an SPE column and was further separated by a Grace Alltima HP C₁₈ (50 × 2.1 mm, 5 μm) column at a flow rate of 0.4 mL/min. Water (with 2% methanol) acetonitrile (with 0.1% acetic acid) was selected as the mobile phase combination used in a linear gradient system. α-Conotoxin GI was analyzed by an API 4000 triple quadrupole mass spectrometer. In the method validation, the linear calibration curve in the range of 2.0 to 300.0 ng/mL had correlation coefficients (r) above 0.996. The recovery was 57.6–66.8% for GI and the internal standard. The lower limit of quantification (LLOQ) was 2 ng/mL. The intra- and inter-batch precisions were below 6.31% and 8.61%, respectively, and the accuracies were all within acceptance. GI was stable in a bench-top autosampler through long-term storage and freeze/thaw cycles. Therefore, this method is specific, sensitive and reliable for quantitative analysis of α-conotoxin GI in human plasma. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle A Transcriptomic Survey of Ion Channel-Based Conotoxins in the Chinese Tubular Cone Snail (Conus betulinus)

by Yu Huang, Chao Peng, Yunhai Yi, Bingmiao Gao and Qiong Shi

Mar. Drugs 2017, 15(7), 228; doi:10.3390/md15070228

Received: 31 May 2017 / Revised: 10 July 2017 / Accepted: 13 July 2017 / Published: 18 July 2017

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Abstract

Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular

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Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular cone snail, C. betulinus. Here, based on the previous datasets of four transcriptomes from three venom ducts and one venom bulb, we explored ion channel-based conotoxins and predicted their related ion channel receptors. Homologous analysis was also performed for the most abundant ion channel protein, voltage-gated potassium (Kv; with Kv1.1 as the representative), and the most studied ion channel receptor, nicotinic acetylcholine receptor (nAChR; with α2-nAChR as the representative), in different animals. Our transcriptomic survey demonstrated that ion channel-based conotoxins and related ion channel proteins/receptors transcribe differentially between the venom duct and the venom bulb. In addition, we observed that putative κ-conotoxins were the most common conotoxins with the highest transcription levels in the examined C. betulinus. Furthermore, Kv1.1 and α2-nAChR were conserved in their functional domains of deduced protein sequences, suggesting similar effects of conotoxins via the ion channels in various species, including human beings. In a word, our present work suggests a high-throughput way to develop conotoxins as potential drugs for treatment of ion channel-associated human diseases. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Currents)

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Open AccessArticle Evaluation of Cyanea capillata Sting Management Protocols Using Ex Vivo and In Vitro Envenomation Models

by Thomas K. Doyle, Jasmine L. Headlam, Christie L. Wilcox, Eoin MacLoughlin and Angel A. Yanagihara

Toxins 2017, 9(7), 215; doi:10.3390/toxins9070215

Received: 2 June 2017 / Revised: 27 June 2017 / Accepted: 3 July 2017 / Published: 7 July 2017

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Abstract

Lion’s mane jellyfish (Cyanea capillata) stings cause severe pain and can lead to dangerous systemic effects, including Irukandji-like syndrome. As is the case for most cnidarian stings, recommended medical protocols in response to such stings lack rigorous scientific support. In this

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Lion’s mane jellyfish (Cyanea capillata) stings cause severe pain and can lead to dangerous systemic effects, including Irukandji-like syndrome. As is the case for most cnidarian stings, recommended medical protocols in response to such stings lack rigorous scientific support. In this study, we sought to evaluate potential first aid care protocols using previously described envenomation models that allow for direct measurements of venom activity. We found that seawater rinsing, the most commonly recommended method of tentacle removal for this species, induced significant increases in venom delivery, while rinsing with vinegar or Sting No More^® Spray did not. Post-sting temperature treatments affected sting severity, with 40 min of hot-pack treatment reducing lysis of sheep’s blood (in agar plates), a direct representation of venom load, by over 90%. Ice pack treatment had no effect on sting severity. These results indicate that sting management protocols for Cyanea need to be revised immediately to discontinue rinsing with seawater and include the use of heat treatment. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Screening and Validation of Highly-Efficient Insecticidal Conotoxins from a Transcriptome-Based Dataset of Chinese Tubular Cone Snail

by Bingmiao Gao, Chao Peng, Bo Lin, Qin Chen, Junqing Zhang and Qiong Shi

Toxins 2017, 9(7), 214; doi:10.3390/toxins9070214

Received: 2 June 2017 / Revised: 29 June 2017 / Accepted: 30 June 2017 / Published: 6 July 2017

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Abstract

Most previous studies have focused on analgesic and anti-cancer activities for the conotoxins identified from piscivorous and molluscivorous cone snails, but little attention has been devoted to insecticidal activity of conotoxins from the dominant vermivorous species. As a representative vermivorous cone snail, the

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Most previous studies have focused on analgesic and anti-cancer activities for the conotoxins identified from piscivorous and molluscivorous cone snails, but little attention has been devoted to insecticidal activity of conotoxins from the dominant vermivorous species. As a representative vermivorous cone snail, the Chinese tubular cone snail (Conus betulinus) is the dominant Conus species inhabiting the South China Sea. We sequenced related venom transcriptomes from C. betulinus using both the next-generation sequencing and traditional Sanger sequencing technologies, and a comprehensive library of 215 conotoxin transcripts was constructed. In our current study, six conotoxins with potential insecticidal activity were screened out from our conotoxin library by homologous search with a reported positive control (alpha-conotoxin ImI from C. imperialis) as the query. Subsequently, these conotoxins were synthesized by chemical solid-phase and oxidative folding for further insecticidal activity validation, such as MTT assay, insect bioassay and homology modeling. The final results proved insecticidal activities of our achieved six conotoxins from the transcriptome-based dataset. Interestingly, two of them presented a lot of high insecticidal activity, which supports their usefulness for a trial as insecticides in field investigations. In summary, our present work provides a good example for high throughput development of biological insecticides on basis of the accumulated genomic resources. Full article

(This article belongs to the collection Marine and Freshwater Toxins)

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Open AccessArticle Recombinant Phospholipase D from Loxosceles gaucho Binds to Platelets and Promotes Phosphatidylserine Exposure

by Daniel A. Fukuda, Maria C. Caporrino, Katia C. Barbaro, Maisa S. Della-Casa, Eliana L. Faquim-Mauro and Geraldo S. Magalhaes

Toxins 2017, 9(6), 191; doi:10.3390/toxins9060191

Received: 28 April 2017 / Revised: 7 June 2017 / Accepted: 9 June 2017 / Published: 13 June 2017

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Abstract

Spider envenomation, from the genus Loxosceles, is frequently reported as a cause of necrotic lesions in humans around the world. Among the many components found in the venom of Loxosceles genus, phospholipases D (PLDs) are the most investigated, since they can cause

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Spider envenomation, from the genus Loxosceles, is frequently reported as a cause of necrotic lesions in humans around the world. Among the many components found in the venom of Loxosceles genus, phospholipases D (PLDs) are the most investigated, since they can cause a massive inflammatory response, dermonecrosis, hemolysis and platelet aggregation, among other effects. Even though the PLDs induce strong platelet aggregation, there are no studies showing how the PLDs interact with platelets to promote this effect. Since many agonists must interact with specific receptors on the platelet membrane to induce aggregation, it is reasonable to expect that the PLDs may, in some way, also interact with platelets, to induce this activity. Therefore, to address this possibility, in this work, a recombinant PLD, called LgRec1, from L. gaucho was fused to enhanced green fluorescent protein (EGFP) and used as a probe to detect the interaction of LgRec1 to platelets, by fluorescence-activated cell sorter (FACS) and confocal microscopy. The preservation of biological activities of this chimera toxin was also analyzed. As a first, the results show that LgRec1 does not require plasma components to bind to platelets, although these components are necessary to LgRec1 to induce platelet aggregation. Also, the attachment of LgRec1 to human platelets’ cell membranes suggests that the exposure of phosphatidylserine (PS) may act as a scaffold for coagulation factors. Therefore, the results add new information about the binding of Loxosceles PLDs to platelets, which may help unravel how these toxins promote platelet aggregation. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Identification of a Novel O-Conotoxin Reveals an Unusual and Potent Inhibitor of the Human α9α10 Nicotinic Acetylcholine Receptor

by Shantong Jiang, Han-Shen Tae, Shaoqiong Xu, Xiaoxia Shao, David J. Adams and Chunguang Wang

Mar. Drugs 2017, 15(6), 170; doi:10.3390/md15060170

Received: 5 April 2017 / Revised: 30 May 2017 / Accepted: 6 June 2017 / Published: 9 June 2017

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Abstract

Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin

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Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin component, O-conotoxin GeXXVIIA, from the venom of Conus generalis. The native form of this component is a disulfide-linked homodimer of a 5-Cys-containing peptide. Surprisingly, our electrophysiological studies showed that, in comparison to the folded monomers, the linear peptide of this toxin had the highest inhibitory activity at the human α9α10 nicotinic acetylcholine receptor (nAChR), with an IC₅₀ of 16.2 ± 1.4 nM. The activities of the N-terminal and C-terminal halves of the linear toxin are markedly reduced compared with the full-length toxin, suggesting that the intact sequence is required to potently inhibit the hα9α10 nAChR. α9α10 nAChRs are expressed not only in the nervous system, but also in a variety of non-neuronal cells, such as cochlear hair cells, keratinocytes, epithelial and immune cells. A potent inhibitor of human α9α10 nAChRs, such as GeXXVIIA, would facilitate unraveling the functions of this nAChR subtype. Furthermore, this unusual nAChR inhibitor may lead to the development of novel α9α10 nAChR-targeting drugs. Full article

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Open AccessFeature PaperReview Preclinical Evaluation of the Efficacy of Antivenoms for Snakebite Envenoming: State-of-the-Art and Challenges Ahead

by José María Gutiérrez, Gabriela Solano, Davinia Pla, María Herrera, Álvaro Segura, Mariángela Vargas, Mauren Villalta, Andrés Sánchez, Libia Sanz, Bruno Lomonte, Guillermo León and Juan J. Calvete

Toxins 2017, 9(5), 163; doi:10.3390/toxins9050163

Received: 22 March 2017 / Revised: 17 April 2017 / Accepted: 10 May 2017 / Published: 13 May 2017

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Abstract

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical

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Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of “antivenomics”, which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeutics. Full article

(This article belongs to the Special Issue Use of Antibodies/Antivenom Against Envenoming)

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Open AccessFeature PaperReview Treatments for Latrodectism—A Systematic Review on Their Clinical Effectiveness

by Nicole M. Ryan, Nicholas A. Buckley and Andis Graudins

Toxins 2017, 9(4), 148; doi:10.3390/toxins9040148

Received: 21 February 2017 / Revised: 31 March 2017 / Accepted: 10 April 2017 / Published: 21 April 2017

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Abstract

Latrodectism or envenomation by widow-spiders is common and clinically significant worldwide. Alpha-latrotoxin is the mammalian-specific toxin in the venom that results in toxic effects observed in humans. Symptoms may be incapacitating and include severe pain that can persist for days. The management of

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Latrodectism or envenomation by widow-spiders is common and clinically significant worldwide. Alpha-latrotoxin is the mammalian-specific toxin in the venom that results in toxic effects observed in humans. Symptoms may be incapacitating and include severe pain that can persist for days. The management of mild to moderate latrodectism is primarily supportive while severe cases have variously been treated with intravenous calcium, muscle relaxants, widow-spider antivenom and analgesic opioids. The object of this systematic review is to examine the literature on the clinical effectiveness of past and current treatments for latrodectism. MEDLINE, EMBASE and Google Scholar were searched from 1946 to December 2016 to identify clinical studies on the treatment of latrodectism. Studies older than 40 years and not in English were not reviewed. There were only two full-publications and one abstract of placebo-controlled randomised trials on antivenom use for latrodectism. Another two randomised comparative trials compared the route of administration of antivenom for latrodectism. There were fourteen case series (including two abstracts), fourteen case reports and one letter investigating drug treatments for latrodectism with the majority of these also including antivenom for severe latrodectism. Antivenom with opioid analgesia is often the major treatment reported for latrodectism however; recent high quality evidence has cast doubt on the clinical effectiveness of this combination and suggests that other treatments need to be investigated. Full article

(This article belongs to the Special Issue Use of Antibodies/Antivenom Against Envenoming)

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Open AccessArticle Metabolomic Profiling of the Synergistic Effects of Melittin in Combination with Cisplatin on Ovarian Cancer Cells

by Sanad Alonezi, Jonans Tusiimire, Jennifer Wallace, Mark J. Dufton, John A. Parkinson, Louise C. Young, Carol J. Clements, Jin-Kyu Park, Jong-Woon Jeon, Valerie A. Ferro and David G. Watson

Metabolites 2017, 7(2), 14; doi:10.3390/metabo7020014

Received: 17 March 2017 / Revised: 10 April 2017 / Accepted: 12 April 2017 / Published: 14 April 2017

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Abstract

Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved

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Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg/mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed good separation between experimental groups and high-quality goodness of fit (R²) and goodness of prediction (Q²), respectively. The combination treatment induced significant changes in both cell lines involving reduction in the levels of metabolites in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, purine and pyrimidine metabolism, and the arginine/proline pathway. The combination of melittin with cisplatin that targets these pathways had a synergistic effect. The melittin-cisplatin combination had a stronger effect on the A2780 cell line in comparison with the A2780CR cell line. The metabolic effects of melittin and cisplatin in combination were very different from those of each agent alone. Full article

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Open AccessArticle Suppression of Hepatic Epithelial-to-Mesenchymal Transition by Melittin via Blocking of TGFβ/Smad and MAPK-JNK Signaling Pathways

by Ji-Hyun Park, Byoungduck Park and Kwan-Kyu Park

Toxins 2017, 9(4), 138; doi:10.3390/toxins9040138

Received: 31 January 2017 / Revised: 7 April 2017 / Accepted: 10 April 2017 / Published: 13 April 2017

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Abstract

Transforming growth factor (TGF)-β1 plays a crucial role in the epithelial-to-mesenchymal transition (EMT) in hepatocytes and hepatic stellate cells (HSC), which contributes to the pathogenesis of liver fibrosis. Melittin (MEL) is a major component of bee venom and is effective in rheumatoid arthritis,

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Transforming growth factor (TGF)-β1 plays a crucial role in the epithelial-to-mesenchymal transition (EMT) in hepatocytes and hepatic stellate cells (HSC), which contributes to the pathogenesis of liver fibrosis. Melittin (MEL) is a major component of bee venom and is effective in rheumatoid arthritis, pain relief, cancer cell proliferation, fibrosis and immune modulating activity. In this study, we found that MEL inhibits hepatic EMT in vitro and in vivo, regulating the TGFβ/Smad and TGFβ/nonSmad signaling pathways. MEL significantly inhibited TGF-β1-induced expression of EMT markers (E-cadherin reduction and vimentin induction) in vitro. These results were confirmed in CCl₄-induced liver in vivo. Treatment with MEL almost completely blocked the phosphorylation of Smad2/3, translocation of Smad4 and phosphorylation of JNK in vitro and in vivo. Taken together, these results suggest that MEL suppresses EMT by inhibiting the TGFβ/Smad and TGFβ/nonSmad-c-Jun N-terminal kinase (JNK)/Mitogen-activated protein kinase (MAPK) signaling pathways. These results indicated that MEL possesses potent anti-fibrotic and anti-EMT properties, which may be responsible for its effects on liver diseases. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Phospholipase D from Loxosceles laeta Spider Venom Induces IL-6, IL-8, CXCL1/GRO-α, and CCL2/MCP-1 Production in Human Skin Fibroblasts and Stimulates Monocytes Migration

by José M. Rojas, Tomás Arán-Sekul, Emmanuel Cortés, Romina Jaldín, Kely Ordenes, Patricio R. Orrego, Jorge González, Jorge E. Araya and Alejandro Catalán

Toxins 2017, 9(4), 125; doi:10.3390/toxins9040125

Received: 18 December 2016 / Revised: 16 March 2017 / Accepted: 28 March 2017 / Published: 5 April 2017

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Abstract

Cutaneous loxoscelism envenomation by Loxosceles spiders is characterized by the development of a dermonecrotic lesion, strong inflammatory response, the production of pro-inflammatory mediators, and leukocyte migration to the bite site. The role of phospholipase D (PLD) from Loxosceles in the recruitment and migration

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Cutaneous loxoscelism envenomation by Loxosceles spiders is characterized by the development of a dermonecrotic lesion, strong inflammatory response, the production of pro-inflammatory mediators, and leukocyte migration to the bite site. The role of phospholipase D (PLD) from Loxosceles in the recruitment and migration of monocytes to the envenomation site has not yet been described. This study reports on the expression and production profiles of cytokines and chemokines in human skin fibroblasts treated with catalytically active and inactive recombinant PLDs from Loxosceles laeta (rLlPLD) and lipid inflammatory mediators ceramide 1-phosphate (C1P) and lysophosphatidic acid (LPA), and the evaluation of their roles in monocyte migration. Recombinant rLlPLD1 (active) and rLlPLD2 (inactive) isoforms induce interleukin (IL)-6, IL-8, CXCL1/GRO-α, and CCL2/monocyte chemoattractant protein-1 (MCP-1) expression and secretion in fibroblasts. Meanwhile, C1P and LPA only exhibited a minor effect on the expression and secretion of these cytokines and chemokines. Moreover, neutralization of both enzymes with anti-rLlPLD1 antibodies completely inhibited the secretion of these cytokines and chemokines. Importantly, conditioned media from fibroblasts, treated with rLlPLDs, stimulated the transmigration of THP-1 monocytes. Our data demonstrate the direct role of PLDs in chemotactic mediator synthesis for monocytes in human skin fibroblasts and indicate that inflammatory processes play an important role during loxoscelism. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Electrophysiological Characterization of the Antarease Metalloprotease from Tityus serrulatus Venom

by Irene Zornetta, Michele Scorzeto, Pablo Victor Mendes Dos Reis, Maria E. De Lima, Cesare Montecucco, Aram Megighian and Ornella Rossetto

Toxins 2017, 9(3), 81; doi:10.3390/toxins9030081

Received: 4 November 2016 / Revised: 15 February 2017 / Accepted: 20 February 2017 / Published: 27 February 2017

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Abstract

Scorpions are among the oldest venomous living organisms and the family Buthidae is the largest and most medically relevant one. Scorpion venoms include many toxic peptides, but recently, a metalloprotease from Tityus serrulatus called antarease was reported to be capable of cleaving VAMP2,

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Scorpions are among the oldest venomous living organisms and the family Buthidae is the largest and most medically relevant one. Scorpion venoms include many toxic peptides, but recently, a metalloprotease from Tityus serrulatus called antarease was reported to be capable of cleaving VAMP2, a protein involved in the neuroparalytic syndromes of tetanus and botulism. We have produced antarease and an inactive metalloprotease mutant in a recombinant form and analyzed their enzymatic activity on recombinant VAMP2 in vitro and on mammalian and insect neuromuscular junction. The purified recombinant antarease paralyzed the neuromuscular junctions of mice and of Drosophila melanogaster whilst the mutant was inactive. We were unable to demonstrate any cleavage of VAMP2 under conditions which leads to VAMP proteolysis by botulinum neurotoxin type B. Antarease caused a reduced release probability, mainly due to defects upstream of the synaptic vesicles fusion process. Paired pulse experiments indicate that antarease might proteolytically inactivate a voltage-gated calcium channel. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Antivenom Evaluation by Electrophysiological Analysis

by Rita Restano-Cassulini, Walter Garcia, Jorge F. Paniagua-Solís and Lourival D. Possani

Toxins 2017, 9(3), 74; doi:10.3390/toxins9030074

Received: 31 January 2017 / Revised: 21 February 2017 / Accepted: 21 February 2017 / Published: 23 February 2017

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Abstract

Scorpion stings on humans are medically relevant because they may contain toxins that specifically target ion channels. During antivenom production, pharmaceutical companies must use a large number of experimental animals to ensure the antivenom’s efficacy according to pharmacopeia methods. Here we present an

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Scorpion stings on humans are medically relevant because they may contain toxins that specifically target ion channels. During antivenom production, pharmaceutical companies must use a large number of experimental animals to ensure the antivenom’s efficacy according to pharmacopeia methods. Here we present an electrophysiological alternative for the evaluation of horse antivenoms produced against two species of Moroccan scorpions: Buthus mardochei and Androctonus mauretanicus. Human sodium and potassium channels and acetylcholine nicotinic receptors were analyzed by standard patch-clamp techniques. The results showed that the antivenom is capable of reversing ion current disruption caused by the venom application. We propose the use of this in vitro technique for antivenom evaluation as an alternative to using a large number of live animals. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Bee Venom Phospholipase A2 Ameliorates House Dust Mite Extract Induced Atopic Dermatitis Like Skin Lesions in Mice

by Kyung-Hwa Jung, Hyunjung Baek, Manho Kang, Namsik Kim, Seung Young Lee and Hyunsu Bae

Toxins 2017, 9(2), 68; doi:10.3390/toxins9020068

Received: 3 January 2017 / Revised: 13 February 2017 / Accepted: 16 February 2017 / Published: 18 February 2017

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Abstract

Atopic dermatitis (AD) is a biphasic inflammatory skin disease that is provoked by epidermal barrier defects, immune dysregulation, and increased skin infections. Previously, we have demonstrated that bvPLA2 evoked immune tolerance by inducing regulatory T cells (Treg), and thus alleviated Th2 dominant allergic

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Atopic dermatitis (AD) is a biphasic inflammatory skin disease that is provoked by epidermal barrier defects, immune dysregulation, and increased skin infections. Previously, we have demonstrated that bvPLA2 evoked immune tolerance by inducing regulatory T cells (Treg), and thus alleviated Th2 dominant allergic asthma in mice. Here, we would like to determine whether treatment with bvPLA2 exacerbates the AD-like allergic inflammations induced by house dust mite extract (DFE) in a murine model. Epidermal thickness, immune cell infiltration, serum immunoglobulin, and cytokines were measured. Ear swelling, skin lesions, and the levels of total serum IgE and Th1/Th2 cytokines were elevated in DFE/DNCB-induced AD mice. Topical application of bvPLA2 elicited significant suppression of the increased AD symptoms, including ear thickness, serum IgE concentration, inflammatory cytokines, and histological changes. Furthermore, bvPLA2 treatment inhibited mast cell infiltration into the ear. On the other hand, Treg cell depletion abolished the anti-atopic effects of bvPLA2, suggesting that the effects of bvPLA2 depend on the existence of Tregs. Taken together, the results revealed that topical exposure to bvPLA2 aggravated atopic skin inflammation, suggesting that bvPLA2 might be a candidate for the treatment of AD. Full article

(This article belongs to the Special Issue Animal Venoms and Pain)

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Open AccessArticle Functional Elucidation of Nemopilema nomurai and Cyanea nozakii Nematocyst Venoms’ Lytic Activity Using Mass Spectrometry and Zymography

by Yang Yue, Huahua Yu, Rongfeng Li, Ronge Xing, Song Liu, Kecheng Li, Xueqin Wang, Xiaolin Chen and Pengcheng Li

Toxins 2017, 9(2), 47; doi:10.3390/toxins9020047

Received: 6 September 2016 / Revised: 20 January 2017 / Accepted: 20 January 2017 / Published: 26 January 2017

Abstract

Background: Medusozoans utilize explosively discharging penetrant nematocysts to inject venom into prey. These venoms are composed of highly complex proteins and peptides with extensive bioactivities, as observed in vitro. Diverse enzymatic toxins have been putatively identified in the venom of jellyfish, Nemopilema nomurai

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Background: Medusozoans utilize explosively discharging penetrant nematocysts to inject venom into prey. These venoms are composed of highly complex proteins and peptides with extensive bioactivities, as observed in vitro. Diverse enzymatic toxins have been putatively identified in the venom of jellyfish, Nemopilema nomurai and Cyanea nozakii, through examination of their proteomes and transcriptomes. However, functional examination of putative enzymatic components identified in proteomic approaches to elucidate potential bioactivities is critically needed. Methods: In this study, enzymatic toxins were functionally identified using a combined approach consisting of in gel zymography and liquid chromatography tandem mass spectrometry (LC-MS/MS). The potential roles of metalloproteinases and lipases in hemolytic activity were explored using specific inhibitors. Results: Zymography indicated that nematocyst venom possessed protease-, lipase- and hyaluronidase-class activities. Further, proteomic approaches using LC-MS/MS indicated sequence homology of proteolytic bands observed in zymography to extant zinc metalloproteinase-disintegrins and astacin metalloproteinases. Moreover, pre-incubation of the metalloproteinase inhibitor batimastat with N. nomurai nematocyst venom resulted in an approximate 62% reduction of hemolysis compared to venom exposed sheep erythrocytes, suggesting that metalloproteinases contribute to hemolytic activity. Additionally, species within the molecular mass range of 14–18 kDa exhibited both egg yolk and erythrocyte lytic activities in gel overlay assays. Conclusion: For the first time, our findings demonstrate the contribution of jellyfish venom metalloproteinase and suggest the involvement of lipase species to hemolytic activity. Investigations of this relationship will facilitate a better understanding of the constituents and toxicity of jellyfish venom. Full article

(This article belongs to the Section Marine and Freshwater Toxins)

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Open AccessArticle A Survey of Snakebite Knowledge among Field Forces in China

by Chulin Chen, Li Gui, Ting Kan, Shuang Li and Chen Qiu

Int. J. Environ. Res. Public Health 2017, 14(1), 15; doi:10.3390/ijerph14010015

Received: 5 September 2016 / Revised: 22 November 2016 / Accepted: 20 December 2016 / Published: 26 December 2016

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Abstract

Background: A snakebite is a neglected extrinsic injury associated with high morbidity and global mortality. Members of Chinese field forces are at high risk of snakebites, and their perception and knowledge of snakebites are unknown. The aim of this study is to assess

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Background: A snakebite is a neglected extrinsic injury associated with high morbidity and global mortality. Members of Chinese field forces are at high risk of snakebites, and their perception and knowledge of snakebites are unknown. The aim of this study is to assess perception and knowledge of snakebites in field forces in southeast China; Methods: A cross-sectional questionnaire-based survey was conducted in July 2016. A total of 216 field force members participated in this study; Results: A total of 10.3% had experienced snakebites and 86.4% rated their demands for knowledge about snakebite as “high”. No significant correlation between the actual and perceived snakebite knowledge status was detected (κ = 0.0237, p = 0.3852). Ineffective and harmful traditional first-aid methods, such as the application of tourniquets, sucking the venom out of the wound, and making local incisions, were used by more than three quarters of the respondents. However, pressure immobilization bandages were applied by only 17.3% of members. The proportion of responses for each question was not significantly different among the respondents when considering separate demographic groups; Conclusions: Snakebite knowledge among Chinese field force members is inadequate and in some cases misleading, when focusing on manifestation, prevention, and first-aid. A pragmatic, intensive educational scheme should be undertaken in at-risk populations. Full article

(This article belongs to the Section Global Health)

Open AccessArticle Transcriptome Analysis to Understand the Toxicity of Latrodectus tredecimguttatus Eggs

by Dehong Xu and Xianchun Wang

Toxins 2016, 8(12), 378; doi:10.3390/toxins8120378

Received: 22 August 2016 / Revised: 2 December 2016 / Accepted: 13 December 2016 / Published: 20 December 2016

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Abstract

Latrodectus tredecimguttatus is a kind of highly venomous black widow spider, with toxicity coming from not only venomous glands but also other parts of its body as well as newborn spiderlings and eggs. Up to date, although L. tredecimguttatus eggs have been demonstrated

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Latrodectus tredecimguttatus is a kind of highly venomous black widow spider, with toxicity coming from not only venomous glands but also other parts of its body as well as newborn spiderlings and eggs. Up to date, although L. tredecimguttatus eggs have been demonstrated to be rich in proteinaceous toxins, there is no systematic investigation on such active components at transcriptome level. In this study, we performed a high-throughput transcriptome sequencing of L. tredecimguttatus eggs with Illumina sequencing technology. As a result, 53,284 protein-coding unigenes were identified, of which 14,185 unigenes produced significant hits in the available databases, including 280 unigenes encoding proteins or peptides homologous to known proteinaceous toxins. GO term and KEGG pathway enrichment analyses of the 280 unigenes showed that 375 GO terms and 18 KEGG pathways were significantly enriched. Functional analysis indicated that these unigene-coded toxins have the bioactivities to degrade tissue proteins, inhibit ion channels, block neuromuscular transmission, provoke anaphylaxis, induce apoptosis and hyperalgesia, etc. No known typical proteinaceous toxins in L. tredecimguttatus venomous glands, such as latrotoxins, were identified, suggesting that the eggs have a different toxicity mechanism from that of the venom. Our present transcriptome analysis not only helps to reveal the gene expression profile and toxicity mechanism of the L. tredecimguttatus eggs, but also provides references for the further related researches. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Evolution of the Cytolytic Pore-Forming Proteins (Actinoporins) in Sea Anemones

by Jason Macrander and Marymegan Daly

Toxins 2016, 8(12), 368; doi:10.3390/toxins8120368

Received: 14 September 2016 / Revised: 28 October 2016 / Accepted: 23 November 2016 / Published: 8 December 2016

Abstract

Sea anemones (Cnidaria, Anthozoa, and Actiniaria) use toxic peptides to incapacitate and immobilize prey and to deter potential predators. Their toxin arsenal is complex, targeting a variety of functionally important protein complexes and macromolecules involved in cellular homeostasis. Among these, actinoporins are one

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Sea anemones (Cnidaria, Anthozoa, and Actiniaria) use toxic peptides to incapacitate and immobilize prey and to deter potential predators. Their toxin arsenal is complex, targeting a variety of functionally important protein complexes and macromolecules involved in cellular homeostasis. Among these, actinoporins are one of the better characterized toxins; these venom proteins form a pore in cellular membranes containing sphingomyelin. We used a combined bioinformatic and phylogenetic approach to investigate how actinoporins have evolved across three superfamilies of sea anemones (Actinioidea, Metridioidea, and Actinostoloidea). Our analysis identified 90 candidate actinoporins across 20 species. We also found clusters of six actinoporin-like genes in five species of sea anemone (Nematostella vectensis, Stomphia coccinea, Epiactis japonica, Heteractis crispa, and Diadumene leucolena); these actinoporin-like sequences resembled actinoporins but have a higher sequence similarity with toxins from fungi, cone snails, and Hydra. Comparative analysis of the candidate actinoporins highlighted variable and conserved regions within actinoporins that may pertain to functional variation. Although multiple residues are involved in initiating sphingomyelin recognition and membrane binding, there is a high rate of replacement for a specific tryptophan with leucine (W112L) and other hydrophobic residues. Residues thought to be involved with oligomerization were variable, while those forming the phosphocholine (POC) binding site and the N-terminal region involved with cell membrane penetration were highly conserved. Full article

(This article belongs to the collection Evolution of Venom Systems)

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Open AccessConference Report Priority Actions and Progress to Substantially and Sustainably Reduce the Mortality, Morbidity and Socioeconomic Burden of Tropical Snakebite

by Robert A. Harrison and José María Gutiérrez

Toxins 2016, 8(12), 351; doi:10.3390/toxins8120351

Received: 25 October 2016 / Revised: 9 November 2016 / Accepted: 18 November 2016 / Published: 24 November 2016

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Abstract

The deliberations and conclusions of a Hinxton Retreat convened in September 2015, entitled “Mechanisms to reverse the public health neglect of snakebite victims” are reported. The participants recommended that the following priority actions be included in strategies to reduce the global impact of

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The deliberations and conclusions of a Hinxton Retreat convened in September 2015, entitled “Mechanisms to reverse the public health neglect of snakebite victims” are reported. The participants recommended that the following priority actions be included in strategies to reduce the global impact of snake envenoming: (a) collection of accurate global snakebite incidence, mortality and morbidity data to underpin advocacy efforts and help design public health campaigns; (b) promotion of (i) public education prevention campaigns; (ii) transport systems to improve access to hospitals and (iii) establishment of regional antivenom-efficacy testing facilities to ensure antivenoms’ effectiveness and safety; (c) exploration of funding models for investment in the production of antivenoms to address deficiencies in some regions; (d) establishment of (i) programs for training in effective first aid, hospital management and post-treatment care of victims; (ii) a clinical network to generate treatment guidelines and (iii) a clinical trials system to improve the clinical management of snakebite; (e) development of (i) novel treatments of the systemic and local tissue-destructive effects of envenoming and (ii) affordable, simple, point-of-care snakebite diagnostic kits to improve the accuracy and rapidity of treatment; (f) devising and implementation of interventions to help the people and communities affected by physical and psychological sequelae of snakebite. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Novel Conopeptides of Largely Unexplored Indo Pacific Conus sp.

by Eline K. M. Lebbe, Maarten G. K. Ghequire, Steve Peigneur, Bea G. Mille, Prabha Devi, Samuthirapandian Ravichandran, Etienne Waelkens, Lisette D’Souza, René De Mot and Jan Tytgat

Mar. Drugs 2016, 14(11), 199; doi:10.3390/md14110199

Received: 18 August 2016 / Revised: 13 September 2016 / Accepted: 15 October 2016 / Published: 27 October 2016

Abstract

Cone snails are predatory creatures using venom as a weapon for prey capture and defense. Since this venom is neurotoxic, the venom gland is considered as an enormous collection of pharmacologically interesting compounds having a broad spectrum of targets. As such, cone snail

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Cone snails are predatory creatures using venom as a weapon for prey capture and defense. Since this venom is neurotoxic, the venom gland is considered as an enormous collection of pharmacologically interesting compounds having a broad spectrum of targets. As such, cone snail peptides represent an interesting treasure for drug development. Here, we report five novel peptides isolated from the venom of Conus longurionis, Conus asiaticus and Conus australis. Lo6/7a and Lo6/7b were retrieved from C. longurionis and have a cysteine framework VI/VII. Lo6/7b has an exceptional amino acid sequence because no similar conopeptide has been described to date (similarity percentage <50%). A third peptide, Asi3a from C. asiaticus, has a typical framework III Cys arrangement, classifying the peptide in the M-superfamily. Asi14a, another peptide of C. asiaticus, belongs to framework XIV peptides and has a unique amino acid sequence. Finally, AusB is a novel conopeptide from C. australis. The peptide has only one disulfide bond, but is structurally very different as compared to other disulfide-poor peptides. The peptides were screened on nAChRs, Na_V and K_V channels depending on their cysteine framework and proposed classification. No targets could be attributed to the peptides, pointing to novel functionalities. Moreover, in the quest of identifying novel pharmacological targets, the peptides were tested for antagonistic activity against a broad panel of Gram-negative and Gram-positive bacteria, as well as two yeast strains. Full article

(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)

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Open AccessFeature PaperArticle Metabolomic Profiling of the Effects of Melittin on Cisplatin Resistant and Cisplatin Sensitive Ovarian Cancer Cells Using Mass Spectrometry and Biolog Microarray Technology

by Sanad Alonezi, Jonans Tusiimire, Jennifer Wallace, Mark J. Dufton, John A. Parkinson, Louise C. Young, Carol J. Clements, Jin Kyu Park, Jong Woon Jeon, Valerie A. Ferro and David G. Watson

Metabolites 2016, 6(4), 35; doi:10.3390/metabo6040035

Received: 7 September 2016 / Revised: 10 October 2016 / Accepted: 11 October 2016 / Published: 13 October 2016

Abstract

In the present study, liquid chromatography-mass spectrometry (LC-MS) was employed to characterise the metabolic profiles of two human ovarian cancer cell lines A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant) in response to their exposure to melittin, a cytotoxic peptide from bee venom. In addition, the

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In the present study, liquid chromatography-mass spectrometry (LC-MS) was employed to characterise the metabolic profiles of two human ovarian cancer cell lines A2780 (cisplatin-sensitive) and A2780CR (cisplatin-resistant) in response to their exposure to melittin, a cytotoxic peptide from bee venom. In addition, the metabolomics data were supported by application of Biolog microarray technology to examine the utilisation of carbon sources by the two cell lines. Data extraction with MZmine 2.14 and database searching were applied to provide metabolite lists. Principal component analysis (PCA) gave clear separation between the cisplatin-sensitive and resistant strains and their respective controls. The cisplatin-resistant cells were slightly more sensitive to melittin than the sensitive cells with IC₅₀ values of 4.5 and 6.8 μg/mL respectively, although the latter cell line exhibited the greatest metabolic perturbation upon treatment. The changes induced by melittin in the cisplatin-sensitive cells led mostly to reduced levels of amino acids in the proline/glutamine/arginine pathway, as well as to decreased levels of carnitines, polyamines, adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD+). The effects on energy metabolism were supported by the data from the Biolog assays. The lipid compositions of the two cell lines were quite different with the A2780 cells having higher levels of several ether lipids than the A2780CR cells. Melittin also had some effect on the lipid composition of the cells. Overall, this study suggests that melittin might have some potential as an adjuvant therapy in cancer treatment. Full article

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Open AccessArticle A Combinational Strategy upon RNA Sequencing and Peptidomics Unravels a Set of Novel Toxin Peptides in Scorpion Mesobuthus martensii

by Ning Luan, Wang Shen, Jie Liu, Bo Wen, Zhilong Lin, Shilong Yang, Ren Lai, Siqi Liu and Mingqiang Rong

Toxins 2016, 8(10), 286; doi:10.3390/toxins8100286

Received: 22 August 2016 / Accepted: 21 September 2016 / Published: 5 October 2016

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Abstract

Scorpion venom is deemed to contain many toxic peptides as an important source of natural compounds. Out of the two hundred proteins identiﬁed in Mesobuthus martensii (M. martensii), only a few peptide toxins have been found so far. Herein, a combinational approach

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Scorpion venom is deemed to contain many toxic peptides as an important source of natural compounds. Out of the two hundred proteins identiﬁed in Mesobuthus martensii (M. martensii), only a few peptide toxins have been found so far. Herein, a combinational approach based upon RNA sequencing and Liquid chromatography-mass spectrometry/mass spectrometry (LC MS/MS) was employed to explore the venom peptides in M. martensii. A total of 153 proteins were identiﬁed from the scorpion venom, 26 previously known and 127 newly identiﬁed. Of the novel toxins, 97 proteins exhibited sequence similarities to known toxins, and 30 were never reported. Combining peptidomic and transcriptomic analyses, the peptide sequence of BmKKx1 was reannotated and four disulﬁde bridges were conﬁrmed within it. In light of the comparison of conservation and variety of toxin amino acid sequences, highly conserved and variable regions were perceived in 24 toxins that were parts of two sodium channel and two potassium channel toxins families. Taking all of this evidences together, the peptidomic analysis on M. martensii indeed identiﬁed numerous novel scorpion peptides, expanded our knowledge towards the venom diversity, and afforded a set of pharmaceutical candidates. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Metalloproteases Affecting Blood Coagulation, Fibrinolysis and Platelet Aggregation from Snake Venoms: Definition and Nomenclature of Interaction Sites

by R. Manjunatha Kini and Cho Yeow Koh

Toxins 2016, 8(10), 284; doi:10.3390/toxins8100284

Received: 8 September 2016 / Revised: 21 September 2016 / Accepted: 22 September 2016 / Published: 29 September 2016

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Abstract

Snake venom metalloproteases, in addition to their contribution to the digestion of the prey, affect various physiological functions by cleaving specific proteins. They exhibit their activities through activation of zymogens of coagulation factors, and precursors of integrins or receptors. Based on their structure–function

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Snake venom metalloproteases, in addition to their contribution to the digestion of the prey, affect various physiological functions by cleaving specific proteins. They exhibit their activities through activation of zymogens of coagulation factors, and precursors of integrins or receptors. Based on their structure–function relationships and mechanism of action, we have defined classification and nomenclature of functional sites of proteases. These metalloproteases are useful as research tools and in diagnosis and treatment of various thrombotic and hemostatic conditions. They also contribute to our understanding of molecular details in the activation of specific factors involved in coagulation, platelet aggregation and matrix biology. This review provides a ready reference for metalloproteases that interfere in blood coagulation, fibrinolysis and platelet aggregation. Full article

(This article belongs to the Special Issue Snake Venom Metalloproteinases) Printed Edition available

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Open AccessArticle BmP02 Atypically Delays Kv4.2 Inactivation: Implication for a Unique Interaction between Scorpion Toxin and Potassium Channel

by Bin Wu, Yan Zhu, Jian Shi, Jie Tao and Yonghua Ji

Toxins 2016, 8(10), 280; doi:10.3390/toxins8100280

Received: 7 July 2016 / Accepted: 20 September 2016 / Published: 27 September 2016

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Abstract

BmP02, a short-chain peptide with 28 residues from the venom of Chinese scorpion Buthus martensi Karsch, has been reported to inhibit the transient outward potassium currents (I_to) in rat ventricular muscle cells. However, it remains unclear whether BmP02 modulates the Kv4.2

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BmP02, a short-chain peptide with 28 residues from the venom of Chinese scorpion Buthus martensi Karsch, has been reported to inhibit the transient outward potassium currents (I_to) in rat ventricular muscle cells. However, it remains unclear whether BmP02 modulates the Kv4.2 channel, one of the main contributors to I_to. The present study investigated the effects of BmP02 on Kv4.2 kinetics and its underlying molecular mechanism. The electrophysiological recordings showed that the inactivation of Kv4.2 expressed in HEK293T cells was significantly delayed by BmP02 in a dose-response manner with EC₅₀ of ~850 nM while the peak current, activation and voltage-dependent inactivation of Kv4.2 were not affected. Meanwhile, the recovery from inactivation of Kv4.2 was accelerated and the deactivation was slowed after the application of BmP02. The site-directed mutagenesis combined with computational modelling identified that K347 and K353, located in the turret motif of the Kv4.2, and E4/E5, D20/D21 in BmP02 are key residues to interact with BmP02 through electrostatic force. These findings not only reveal a novel interaction between Kv4.2 channel and its peptidyl modulator, but also provide valuable information for design of highly-selective Kv4.2 modulators. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Polyamines as Snake Toxins and Their Probable Pharmacological Functions in Envenomation

by Steven D. Aird, Alejandro Villar Briones, Michael C. Roy and Alexander S. Mikheyev

Toxins 2016, 8(10), 279; doi:10.3390/toxins8100279

Received: 13 July 2016 / Accepted: 5 September 2016 / Published: 26 September 2016

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Abstract

While decades of research have focused on snake venom proteins, far less attention has been paid to small organic venom constituents. Using mostly pooled samples, we surveyed 31 venoms (six elapid, six viperid, and 19 crotalid) for spermine, spermidine, putrescine, and cadaverine. Most

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While decades of research have focused on snake venom proteins, far less attention has been paid to small organic venom constituents. Using mostly pooled samples, we surveyed 31 venoms (six elapid, six viperid, and 19 crotalid) for spermine, spermidine, putrescine, and cadaverine. Most venoms contained all four polyamines, although some in essentially trace quantities. Spermine is a potentially significant component of many viperid and crotalid venoms (≤0.16% by mass, or 7.9 µmol/g); however, it is almost completely absent from elapid venoms assayed. All elapid venoms contained larger molar quantities of putrescine and cadaverine than spermine, but still at levels that are likely to be biologically insignificant. As with venom purines, polyamines impact numerous physiological targets in ways that are consistent with the objectives of prey envenomation, prey immobilization via hypotension and paralysis. Most venoms probably do not contain sufficient quantities of polyamines to induce systemic effects in prey; however, local effects seem probable. A review of the pharmacological literature suggests that spermine could contribute to prey hypotension and paralysis by interacting with N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, nicotinic and muscarinic acetylcholine receptors, γ-Aminobutyric acid (GABA) receptors, blood platelets, ryanodine receptors, and Ca²⁺-ATPase. It also blocks many types of cation-permeable channels by interacting with negatively charged amino acid residues in the channel mouths. The site of envenomation probably determines which physiological targets assume the greatest importance; however, venom-induced liberation of endogenous, intracellular stores of polyamines could potentially have systemic implications and may contribute significantly to envenomation sequelae. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessComment Create Guidelines for Characterization of Venom Peptides

by Volker Herzig

Toxins 2016, 8(9), 252; doi:10.3390/toxins8090252

Received: 18 May 2016 / Revised: 21 June 2016 / Accepted: 23 August 2016 / Published: 30 August 2016

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Abstract In the course of my duties as a curator for the ArachnoServer database [1,2], I recently came across the article published by Binda et al. in Toxins [3].[...] Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Peptide Toxins in Solitary Wasp Venoms

by Katsuhiro Konno, Kohei Kazuma and Ken-ichi Nihei

Toxins 2016, 8(4), 114; doi:10.3390/toxins8040114

Received: 30 January 2016 / Revised: 5 April 2016 / Accepted: 8 April 2016 / Published: 18 April 2016

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Abstract

Solitary wasps paralyze insects or spiders with stinging venom and feed the paralyzed preys to their larva. Accordingly, the venoms should contain a variety of constituents acting on nervous systems. However, only a few solitary wasp venoms have been chemically studied despite thousands

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Solitary wasps paralyze insects or spiders with stinging venom and feed the paralyzed preys to their larva. Accordingly, the venoms should contain a variety of constituents acting on nervous systems. However, only a few solitary wasp venoms have been chemically studied despite thousands of species inhabiting the planet. We have surveyed bioactive substances in solitary wasp venoms found in Japan and discovered a variety of novel bioactive peptides. Pompilidotoxins (PMTXs), in the venoms of the pompilid wasps Anoplius samariensis and Batozonellus maculifrons, are small peptides consisting of 13 amino acids without a disulfide bond. PMTXs slowed Na⁺ channel inactivation, in particular against neuronal type Na⁺ channels, and were rather selective to the Na_v1.6 channel. Mastoparan-like cytolytic and antimicrobial peptides are the major components of eumenine wasp venoms. They are rich in hydrophobic and basic amino acids, adopting a α-helical secondary structure, and showing mast cell degranulating, antimicrobial and hemolytic activities. The venom of the spider wasp Cyphononyx fulvognathus contained four bradykinin-related peptides. They are hyperalgesic and, dependent on the structure, differently associated with B₁ or B₂ receptors. Further survey led to the isolation of leucomyosuppressin-like FMRFamide peptides from the venoms of the digger wasps Sphex argentatus and Isodontia harmandi. These results of peptide toxins in solitary wasp venoms from our studies are summarized. Full article

(This article belongs to the Special Issue Arthropod Venoms)

Open AccessEditorial Toxins: State of Journal Report, 2016

by Vernon L. Tesh and Bryan Grieg Fry

Toxins 2015, 7(12), 5459-5461; doi:10.3390/toxins7124895

Received: 9 December 2015 / Accepted: 9 December 2015 / Published: 15 December 2015

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Abstract

In the “Message from the Editor-in-Chief” posted on the Toxins website (see www.mdpi.com/journal/toxins/toxins-flyer.pdf), we wrote: “The editorial board and staff of Toxins are dedicated to providing a timely, peer-reviewed outlet for exciting, innovative primary research articles and concise, informative reviews from investigators in

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In the “Message from the Editor-in-Chief” posted on the Toxins website (see www.mdpi.com/journal/toxins/toxins-flyer.pdf), we wrote: “The editorial board and staff of Toxins are dedicated to providing a timely, peer-reviewed outlet for exciting, innovative primary research articles and concise, informative reviews from investigators in the myriad of disciplines contributing to our knowledge on toxins. [...] Full article

Open AccessArticle The Cystine Knot Is Responsible for the Exceptional Stability of the Insecticidal Spider Toxin ω-Hexatoxin-Hv1a

by Volker Herzig and Glenn F. King

Toxins 2015, 7(10), 4366-4380; doi:10.3390/toxins7104366

Received: 25 August 2015 / Revised: 14 October 2015 / Accepted: 21 October 2015 / Published: 26 October 2015

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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

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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)

Open AccessCommunication Antivenom Cross-Neutralization of the Venoms of Hydrophis schistosus and Hydrophis curtus, Two Common Sea Snakes in Malaysian Waters

by Choo Hock Tan, Nget Hong Tan, Kae Yi Tan and Kok Onn Kwong

Toxins 2015, 7(2), 572-581; doi:10.3390/toxins7020572

Received: 25 November 2014 / Revised: 8 January 2015 / Accepted: 15 January 2015 / Published: 16 February 2015

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Abstract

Sea snake envenomation is a serious occupational hazard in tropical waters. In Malaysia, the beaked sea snake (Hydrophis schistosus, formerly known as Enhydrina schistosa) and the spine-bellied sea snake (Hydrophis curtus, formerly known as Lapemis curtus or Lapemis

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Sea snake envenomation is a serious occupational hazard in tropical waters. In Malaysia, the beaked sea snake (Hydrophis schistosus, formerly known as Enhydrina schistosa) and the spine-bellied sea snake (Hydrophis curtus, formerly known as Lapemis curtus or Lapemis hardwickii) are two commonly encountered species. Australian CSL sea snake antivenom is the definitive treatment for sea snake envenomation; it is unfortunately extremely costly locally and is not widely available or adequately stocked in local hospitals. This study investigated the cross-neutralizing potential of three regionally produced anti-cobra antivenoms against the venoms of Malaysian H. schistosus and H. curtus. All three antivenoms conferred paraspecific protection from sea snake venom lethality in mice, with potency increasing in the following order: Taiwan bivalent antivenom < Thai monocled cobra monovalent antivenom < Thai neuro polyvalent antivenom (NPAV). NPAV demonstrated cross-neutralizing potencies of 0.4 mg/vial for H. schistosus venom and 0.8 mg/vial for H. curtus, which translates to a dose of less than 20 vials of NPAV to neutralize an average amount of sea snake venom per bite (inferred from venom milking). The cross-neutralization activity was supported by ELISA cross-reactivity between NPAV and the venoms of H. schistosus (58.4%) and H. curtus (70.4%). These findings revealed the potential of NPAV as a second-line treatment for sea snake envenomation in the region. Further profiling of the cross-neutralization activity should address the antivenomic basis using purified toxin-based assays. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Quo Vadis Venomics? A Roadmap to Neglected Venomous Invertebrates

by Bjoern Marcus von Reumont, Lahcen I. Campbell and Ronald A. Jenner

Toxins 2014, 6(12), 3488-3551; doi:10.3390/toxins6123488

Received: 10 October 2014 / Revised: 21 November 2014 / Accepted: 2 December 2014 / Published: 19 December 2014

Abstract

Venomics research is being revolutionized by the increased use of sensitive -omics techniques to identify venom toxins and their transcripts in both well studied and neglected venomous taxa. The study of neglected venomous taxa is necessary both for understanding the full diversity of

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Venomics research is being revolutionized by the increased use of sensitive -omics techniques to identify venom toxins and their transcripts in both well studied and neglected venomous taxa. The study of neglected venomous taxa is necessary both for understanding the full diversity of venom systems that have evolved in the animal kingdom, and to robustly answer fundamental questions about the biology and evolution of venoms without the distorting effect that can result from the current bias introduced by some heavily studied taxa. In this review we draw the outlines of a roadmap into the diversity of poorly studied and understood venomous and putatively venomous invertebrates, which together represent tens of thousands of unique venoms. The main groups we discuss are crustaceans, flies, centipedes, non-spider and non-scorpion arachnids, annelids, molluscs, platyhelminths, nemerteans, and echinoderms. We review what is known about the morphology of the venom systems in these groups, the composition of their venoms, and the bioactivities of the venoms to provide researchers with an entry into a large and scattered literature. We conclude with a short discussion of some important methodological aspects that have come to light with the recent use of new -omics techniques in the study of venoms. Full article

(This article belongs to the collection Evolution of Venom Systems)

Open AccessReview Omics Meets Biology: Application to the Design and Preclinical Assessment of Antivenoms

by Juan J. Calvete, Libia Sanz, Davinia Pla, Bruno Lomonte and José María Gutiérrez

Toxins 2014, 6(12), 3388-3405; doi:10.3390/toxins6123388

Received: 8 November 2014 / Revised: 3 December 2014 / Accepted: 9 December 2014 / Published: 15 December 2014

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Abstract

Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor

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Snakebite envenoming represents a neglected tropical disease that has a heavy public health impact worldwide, mostly affecting poor people involved in agricultural activities in Africa, Asia, Latin America and Oceania. A key issue that complicates the treatment of snakebite envenomings is the poor availability of the only validated treatment for this disease, antivenoms. Antivenoms can be an efficacious treatment for snakebite envenoming, provided they are safe, effective, affordable, accessible and administered appropriately. The shortage of antivenoms in various regions, particularly in Sub-Saharan Africa and some parts of Asia, can be significantly alleviated by optimizing the use of current antivenoms and by the generation of novel polyspecific antivenoms having a wide spectrum of efficacy. Complementing preclinical testing of antivenom efficacy using in vivo and in vitro functional neutralization assays, developments in venomics and antivenomics are likely to revolutionize the design and preclinical assessment of antivenoms by being able to test new antivenom preparations and to predict their paraspecific neutralization to the level of species-specific toxins. Full article

(This article belongs to the Special Issue Antivenom and Venom Therapeutics)

Open AccessArticle Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a) Interacting with Voltage-Gated Sodium Channel Subtype Na_V1.4

by Ji Luo, Yiya Zhang, Mengting Gong, Shanshan Lu, Yifeng Ma, Xiongzhi Zeng and Songping Liang

Toxins 2014, 6(7), 2177-2193; doi:10.3390/toxins6072177

Received: 15 May 2014 / Revised: 24 June 2014 / Accepted: 3 July 2014 / Published: 23 July 2014

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Abstract

Voltage-gated sodium channels (VGSCs; Na_V1.1–Na_V1.9) have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The

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Voltage-gated sodium channels (VGSCs; Na_V1.1–Na_V1.9) have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure–function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX)-V (also known as β-theraphotoxin-Cj2a) is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK) motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC₅₀ values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on Na_V1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC₅₀ value of 5.12 nM, compared with IC₅₀ values of 61.7–2700 nM for other heterologously expressed Na_V1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on Na_V1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7) and two cationic (R20 and K22) residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels. Full article

Open AccessArticle Evaluation of the Lethal Potency of Scorpion and Snake Venoms and Comparison between Intraperitoneal and Intravenous Injection Routes

by Naoual Oukkache, Rachid El Jaoudi, Noreddine Ghalim, Fatima Chgoury, Balkiss Bouhaouala, Naima El Mdaghri and Jean-Marc Sabatier

Toxins 2014, 6(6), 1873-1881; doi:10.3390/toxins6061873

Received: 6 May 2014 / Revised: 26 May 2014 / Accepted: 27 May 2014 / Published: 12 June 2014

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Abstract

Scorpion stings and snake bites are major health hazards that lead to suffering of victims and high mortality. Thousands of injuries associated with such stings and bites of venomous animals occur every year worldwide. In North Africa, more than 100,000 scorpion stings and

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Scorpion stings and snake bites are major health hazards that lead to suffering of victims and high mortality. Thousands of injuries associated with such stings and bites of venomous animals occur every year worldwide. In North Africa, more than 100,000 scorpion stings and snake bites are reported annually. An appropriate determination of the 50% lethal doses (LD₅₀) of scorpion and snake venoms appears to be an important step to assess (and compare) venom toxic activity. Such LD₅₀ values are also commonly used to evaluate the neutralizing capacity of specific anti-venom batches. In the present work, we determined experimentally the LD₅₀ values of reference scorpion and snake venoms in Swiss mice, and evaluated the influence of two main venom injection routes (i.e., intraperitoneal (IP) versus intravenous (IV)). The analysis of experimental LD₅₀ values obtained with three collected scorpion venoms indicates that Androctonus mauretanicus (Am) is intrinsically more toxic than Androctonus australis hector (Aah) species, whereas the latter is more toxic than Buthus occitanus (Bo). Similar analysis of three representative snake venoms of the Viperidae family shows that Cerastes cerastes (Cc) is more toxic than either Bitis arietans (Ba) or Macrovipera lebetina (Ml) species. Interestingly, the venom of Elapidae cobra snake Naja haje (Nh) is far more toxic than viper venoms Cc, Ml and Ba, in agreement with the known severity of cobra-related envenomation. Also, our data showed that viper venoms are about three-times less toxic when injected IP as compared to IV, distinct from cobra venom Nh which exhibited a similar toxicity when injected IP or IV. Overall, this study clearly highlights the usefulness of procedure standardization, especially regarding the administration route, for evaluating the relative toxicity of individual animal venoms. It also evidenced a marked difference in lethal activity between venoms of cobra and vipers, which, apart from the nature of toxins, might be attributed to the rich composition of high molecular weight enzymes in the case of viper venoms. Full article

(This article belongs to the Section Animal Venoms)

Open AccessReview Conotoxins Targeting Nicotinic Acetylcholine Receptors: An Overview

by Eline K. M. Lebbe, Steve Peigneur, Isuru Wijesekara and Jan Tytgat

Mar. Drugs 2014, 12(5), 2970-3004; doi:10.3390/md12052970

Received: 31 March 2014 / Revised: 24 April 2014 / Accepted: 28 April 2014 / Published: 22 May 2014

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Abstract

Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide

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Marine snails of the genus Conus are a large family of predatory gastropods with an unparalleled molecular diversity of pharmacologically active compounds in their venom. Cone snail venom comprises of a rich and diverse cocktail of peptide toxins which act on a wide variety of ion channels such as voltage-gated sodium- (Na_V), potassium- (K_V), and calcium- (Ca_V) channels as well as nicotinic acetylcholine receptors (nAChRs) which are classified as ligand-gated ion channels. The mode of action of several conotoxins has been the subject of investigation, while for many others this remains unknown. This review aims to give an overview of the knowledge we have today on the molecular pharmacology of conotoxins specifically interacting with nAChRs along with the structure–function relationship data. Full article

(This article belongs to the collection Bioactive Compounds from Marine Invertebrates)

Open AccessArticle Recombinant Expression and Functional Characterization of Martentoxin: A Selective Inhibitor for BK Channel (α + β4)

by Jie Tao, Zhi Lei Zhou, Bin Wu, Jian Shi, Xiao Ming Chen and Yong Hua Ji

Toxins 2014, 6(4), 1419-1433; doi:10.3390/toxins6041419

Received: 18 February 2014 / Revised: 27 March 2014 / Accepted: 1 April 2014 / Published: 22 April 2014

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Abstract

Martentoxin (MarTX), a 37-residue peptide purified from the venom of East-Asian scorpion (Buthus martensi Karsch), was capable of blocking large-conductance Ca²⁺-activated K⁺ (BK) channels. Here, we report an effective expression and purification approach for this toxin. The cDNA encoding

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Martentoxin (MarTX), a 37-residue peptide purified from the venom of East-Asian scorpion (Buthus martensi Karsch), was capable of blocking large-conductance Ca²⁺-activated K⁺ (BK) channels. Here, we report an effective expression and purification approach for this toxin. The cDNA encoding martentoxin was expressed by the prokaryotic expression system pGEX-4T-3 which was added an enterokinase cleavage site by PCR. The fusion protein (GST-rMarTX) was digested by enterokinase to release hetero-expressed toxin and further purified via reverse-phase HPLC. The molecular weight of the hetero-expressed rMarTX was 4059.06 Da, which is identical to that of the natural peptide isolated from scorpion venom. Functional characterization through whole-cell patch clamp showed that rMarTX selectively and potently inhibited the currents of neuronal BK channels (α + β4) (IC₅₀ = 186 nM), partly inhibited mKv1.3, but hardly having any significant effect on hKv4.2 and hKv3.1a even at 10 μM. Successful expression of martentoxin lays basis for further studies of structure-function relationship underlying martentoxin or other potassium-channel specific blockers. Full article

(This article belongs to the Special Issue Ion Channel Neurotoxins)

Open AccessReview Overview of Scorpion Species from China and Their Toxins

by Zhijian Cao, Zhiyong Di, Yingliang Wu and Wenxin Li

Toxins 2014, 6(3), 796-815; doi:10.3390/toxins6030796

Received: 13 December 2013 / Revised: 16 January 2014 / Accepted: 18 January 2014 / Published: 26 February 2014

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Abstract

Scorpions are one of the most ancient groups of terrestrial animals. They have maintained a steady morphology over more than 400 million years of evolution. Their venom arsenals for capturing prey and defending against predators may play a critical role in their ancient

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Scorpions are one of the most ancient groups of terrestrial animals. They have maintained a steady morphology over more than 400 million years of evolution. Their venom arsenals for capturing prey and defending against predators may play a critical role in their ancient and conservative appearance. In the current review, we present the scorpion fauna of China: 53 species covering five families and 12 genera. We also systematically list toxins or genes from Chinese scorpion species, involving eight species covering four families. Furthermore, we review the diverse functions of typical toxins from Chinese scorpion species, involving Na⁺ channel modulators, K⁺ channel blockers, antimicrobial peptides and protease inhibitors. Using scorpion species and their toxins from China as an example, we build the bridge between scorpion species and their toxins, which helps us to understand the molecular and functional diversity of scorpion venom arsenal, the dynamic and functional evolution of scorpion toxins, and the potential relationships of scorpion species and their toxins. Full article

(This article belongs to the Special Issue Scorpion Toxins)

Open AccessArticle Miniaturized Bioaffinity Assessment Coupled to Mass Spectrometry for Guided Purification of Bioactives from Toad and Cone Snail

by Ferry Heus, Reka A. Otvos, Ruud L. E. G. Aspers, Rene van Elk, Jenny I. Halff, Andreas W. Ehlers, Sébastien Dutertre, Richard J. Lewis, Sybren Wijmenga, August B. Smit, Wilfried M. A. Niessen and Jeroen Kool

Biology 2014, 3(1), 139-156; doi:10.3390/biology3010139

Received: 9 December 2013 / Revised: 23 January 2014 / Accepted: 26 January 2014 / Published: 13 February 2014

Abstract

A nano-flow high-resolution screening platform, featuring a parallel chip-based microfluidic bioassay and mass spectrometry coupled to nano-liquid chromatography, was applied to screen animal venoms for nicotinic acetylcholine receptor like (nAChR) affinity by using the acetylcholine binding protein, a mimic of the nAChR. The

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A nano-flow high-resolution screening platform, featuring a parallel chip-based microfluidic bioassay and mass spectrometry coupled to nano-liquid chromatography, was applied to screen animal venoms for nicotinic acetylcholine receptor like (nAChR) affinity by using the acetylcholine binding protein, a mimic of the nAChR. The potential of this microfluidic platform is demonstrated by profiling the Conus textile venom proteome, consisting of over 1,000 peptides. Within one analysis (<90 min, 500 ng venom injected), ligands are detected and identified. To show applicability for non-peptides, small molecular ligands such as steroidal ligands were identified in skin secretions from two toad species (Bufo alvarius and Bufo marinus). Bioactives from the toad samples were subsequently isolated by MS-guided fractionation. The fractions analyzed by NMR and a radioligand binding assay with α7-nAChR confirmed the identity and bioactivity of several new ligands. Full article

(This article belongs to the Special Issue Screening for Biologically Active Compounds)

Open AccessArticle Influence of Disulfide Connectivity on Structure and Bioactivity of α-Conotoxin TxIA

by Yong Wu, Xiaosa Wu, Jinpeng Yu, Xiaopeng Zhu, Dongting Zhangsun and Sulan Luo

Molecules 2014, 19(1), 966-979; doi:10.3390/molecules19010966

Received: 8 November 2013 / Revised: 7 January 2014 / Accepted: 9 January 2014 / Published: 15 January 2014

Cited by 5 | Viewed by 1806 | PDF Full-text (1336 KB) | HTML Full-text | XML Full-text

Abstract

Cone snails express a sophisticated arsenal of small bioactive peptides known as conopeptides or conotoxins (CTxs). Through evolutionary selection, these peptides have gained the ability to interact with a range of ion channels and receptors, such as nicotinic acetylcholine receptors (nAChRs). Here, we

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Cone snails express a sophisticated arsenal of small bioactive peptides known as conopeptides or conotoxins (CTxs). Through evolutionary selection, these peptides have gained the ability to interact with a range of ion channels and receptors, such as nicotinic acetylcholine receptors (nAChRs). Here, we used reversed-phase high performance liquid chromatography (RP-HPLC) and electrospray ionization-mass spectrometry (ESI-MS) to explore the venom peptide diversity of Conus textile, a species of cone snail native to Hainan, China. One fraction of C. textile crude venom potently blocked α3β2 nAChRs. Subsequent purification, synthesis, and tandem mass spectrometric analysis demonstrated that the most active compound in this fraction was identical to α-CTx TxIA, an antagonist of α3β2 nAChRs. Then three disulfide isoforms of α-CTx TxIA were synthesized and their activities were investigated systematically for the first time. As we observed, disulfide isomerisation was particularly important for α-CTx TxIA potency. Although both globular and ribbon isomers showed similar retention times in RP-HPLC, globular TxIA potently inhibited α3β2 nAChRs with an IC₅₀ of 5.4 nM, while ribbon TxIA had an IC₅₀ of 430 nM. In contrast, beads isomer had little activity towards α3β2 nAChRs. Two-step oxidation synthesis produced the highest yield of α-CTx TxIA native globular isomer, while a one-step production process based on random oxidation folding was not suitable. In summary, this study demonstrated the relationship between conotoxin activity and disulfide connectivity on α-CTx TxIA. Full article

(This article belongs to the Section Natural Products)

Open AccessArticle Conopeptides from Cape Verde Conus crotchii

by Jorge Neves, Alexandre Campos, Hugo Osório, Agostinho Antunes and Vitor Vasconcelos

Mar. Drugs 2013, 11(6), 2203-2215; doi:10.3390/md11062203

Received: 1 April 2013 / Revised: 20 May 2013 / Accepted: 27 May 2013 / Published: 19 June 2013

Cited by 4 | Viewed by 2299 | PDF Full-text (705 KB) | HTML Full-text | XML Full-text

Abstract

Marine Cone snails of the genus Conus contain complex peptide toxins in their venom. Living in tropical habitats, they usually use the powerful venom for self-defense and prey capture. Here, we study Conus crotchii venom duct using a peptide mass-matching approach. The C.

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Marine Cone snails of the genus Conus contain complex peptide toxins in their venom. Living in tropical habitats, they usually use the powerful venom for self-defense and prey capture. Here, we study Conus crotchii venom duct using a peptide mass-matching approach. The C. crotchii was collected on the Cape Verde archipelago in the Boa Vista Island. The venom was analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). About 488 molecular masses between 700 Da and 3000 Da were searched bymatching with known peptide sequences from UniProtKB protein sequence database. Through this method we were able to identify 12 conopeptides. For validation we considered the error between the experimental molecular mass (monoisotopic) and the calculated mass of less than 0.5 Da. All conopeptides detected belong to the A-, O1-, O2-, O3-, T- and D-superfamilies, which can block Ca²⁺ channels, inhibit K⁺channels and act on nicotinic acetylcholine receptors (nAChRs). Only a few of the detected peptides have a 100% UniProtKB database similarity, suggesting that several of them could be newly discovered marine drugs. Full article

(This article belongs to the Special Issue Marine Peptides and Their Mimetics)

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Open AccessReview Jellyfish Stings and Their Management: A Review

by Luca Cegolon, William C. Heymann, John H. Lange and Giuseppe Mastrangelo

Mar. Drugs 2013, 11(2), 523-550; doi:10.3390/md11020523

Received: 28 November 2012 / Revised: 22 December 2012 / Accepted: 25 January 2013 / Published: 22 February 2013

Abstract

Jellyfish (cnidarians) have a worldwide distribution. Despite most being harmless, some species may cause local and also systemic reactions. Treatment of jellyfish envenomation is directed at: alleviating the local effects of venom, preventing further nematocyst discharges and controlling systemic reactions, including shock. In

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Jellyfish (cnidarians) have a worldwide distribution. Despite most being harmless, some species may cause local and also systemic reactions. Treatment of jellyfish envenomation is directed at: alleviating the local effects of venom, preventing further nematocyst discharges and controlling systemic reactions, including shock. In severe cases, the most important step is stabilizing and maintaining vital functions. With some differences between species, there seems to be evidence and consensus on oral/topical analgesics, hot water and ice packs as effective painkillers and on 30 s application of domestic vinegar (4%–6% acetic acid) to prevent further discharge of unfired nematocysts remaining on the skin. Conversely, alcohol, methylated spirits and fresh water should be carefully avoided, since they could massively discharge nematocysts; pressure immobilization bandaging should also be avoided, as laboratory studies show that it stimulates additional venom discharge from nematocysts. Most treatment approaches are presently founded on relatively weak evidence; therefore, further research (especially randomized clinical trials) is strongly recommended. Dissemination of appropriate treatment modalities should be deployed to better inform and educate those at risk. Adequate signage should be placed at beaches to notify tourists of the jellyfish risk. Swimmers in risky areas should wear protective equipment. Full article

(This article belongs to the Special Issue Marine Neurotoxins)

Open AccessArticle Vixapatin (VP12), a C-Type Lectin-Protein from Vipera xantina palestinae Venom: Characterization as a Novel Anti-angiogenic Compound

by Tatjana Momic, Gadi Cohen, Reuven Reich, Franziska T. Arlinghaus, Johannes A. Eble, Cezary Marcinkiewicz and Philip Lazarovici

Toxins 2012, 4(10), 862-877; doi:10.3390/toxins4100862

Received: 30 August 2012 / Revised: 29 September 2012 / Accepted: 8 October 2012 / Published: 18 October 2012

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Abstract

A C-type lectin-like protein (CTL), originally identified as VP12 and lately named Vixapatin, was isolated and characterized from Israeli viper Vipera xantina palestinae snake venom. This CTL was characterized as a selective α2β1 integrin inhibitor with anti-melanoma metastatic activity. The major aim of

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A C-type lectin-like protein (CTL), originally identified as VP12 and lately named Vixapatin, was isolated and characterized from Israeli viper Vipera xantina palestinae snake venom. This CTL was characterized as a selective α2β1 integrin inhibitor with anti-melanoma metastatic activity. The major aim of the present study was to prove the possibility that this protein is also a potent novel anti-angiogenic compound. Using an adhesion assay, we demonstrated that Vixapatin selectively and potently inhibited the α2 mediated adhesion of K562 over-expressing cells, with IC₅₀ of 3 nM. 3 nM Vixapatin blocked proliferation of human dermal microvascular endothelial cells (HDMEC); 25 nM inhibited collagen I induced migration of human fibrosarcoma HT-1080 cells; and 50 nM rat C6 glioma and human breast carcinoma MDA-MB-231 cells. 1 µM Vixapatin reduced HDMEC tube formation by 75% in a Matrigel assay. Furthermore, 1 µM Vixapatin decreased by 70% bFGF-induced physiological angiogenesis, and by 94% C6 glioma-induced pathological angiogenesis, in shell-less embryonic quail chorioallantoic membrane assay. Vixapatin’s ability to inhibit all steps of the angiogenesis process suggest that it is a novel pharmacological tool for studying α2β1 integrin mediated angiogenesis and a lead compound for the development of a novel anti-angiogenic/angiostatic/anti-cancer drug. Full article

(This article belongs to the Special Issue Novel Properties of Well-Characterized Toxins)

Open AccessArticle Molecular Analysis of the Interaction of the Snake Venom Rhodocytin with the Platelet Receptor CLEC-2

by Aleksandra A. Watson and Christopher A. O’Callaghan

Toxins 2011, 3(8), 991-1003; doi:10.3390/toxins3080991

Received: 6 July 2011 / Revised: 21 July 2011 / Accepted: 8 August 2011 / Published: 10 August 2011

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Abstract

The Malayan pit viper, Calloselasma rhodostoma, produces a potent venom toxin, rhodocytin (aggretin) which causes platelet aggregation. Rhodocytin is a ligand for the receptor CLEC-2 on the surface of platelets. The interaction of these two molecules initiates a signaling pathway which results

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The Malayan pit viper, Calloselasma rhodostoma, produces a potent venom toxin, rhodocytin (aggretin) which causes platelet aggregation. Rhodocytin is a ligand for the receptor CLEC-2 on the surface of platelets. The interaction of these two molecules initiates a signaling pathway which results in platelet activation and aggregation. We have previously solved the crystal structures of CLEC-2 and of rhodocytin, and have proposed models by which tetrameric rhodocytin may interact with either two monomers of CLEC-2, or with one or two copies of dimeric CLEC-2. In the current study we use a range of approaches to analyze the molecular interfaces and dynamics involved in the models of the interaction of rhodocytin with either one or two copies of dimeric CLEC-2, and their implications for clustering of CLEC-2 on the platelet surface. Full article

(This article belongs to the Special Issue Snake Venoms)

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Open AccessReview ADAM-15 Disintegrin-Like Domain Structure and Function

by Dong Lu, Mike Scully, Vijay Kakkar and Xinjie Lu

Toxins 2010, 2(10), 2411-2427; doi:10.3390/toxins2102411

Received: 30 August 2010 / Revised: 13 October 2010 / Accepted: 18 October 2010 / Published: 19 October 2010

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Abstract

The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in

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The ADAM (a disintegrin-like and metalloproteinase) proteins are a family of transmembrane cell-surface proteins with important functions in adhesion and proteolytic processing in all animals. Human ADAM-15 is the only member of the ADAM family with the integrin binding motif Arg-Gly-Asp (RGD) in its disintegrin-like domain. This motif is also found in most snake venom disintegrins and other disintegrin-like proteins. This unique RGD motif within ADAM-15 serves as an integrin ligand binding site, through which it plays a pivotal role in interacting with integrin receptors, a large family of heterodimeric transmembrane glycoproteins. This manuscript will present a review of the RGD-containing disintegrin-like domain structures and the structural features responsible for their activity as antagonists of integrin function in relation to the canonical RGD template. Full article

(This article belongs to the Special Issue Disintegrins: Structure-Function and Translational Potential)

Open AccessArticle In Vitro Antiophidian Properties of Dipteryx alata Vogel Bark Extracts

by Virgínia Sbrugnera Nazato, Leandro Rubem-Mauro, Nathalia Aparecida Gatto Vieira, Dimas Dos Santos Rocha, Junior, Magali Glauzer Silva, Patricia Santos Lopes, Cháriston André Dal-Belo, Jose Carlos Cogo, Marcio Galdino Dos Santos, Maria Alice Da Cruz-Höfling and Yoko Oshima-Franco

Molecules 2010, 15(9), 5956-5970; doi:10.3390/molecules15095956

Received: 9 July 2010 / Revised: 18 August 2010 / Accepted: 25 August 2010 / Published: 30 August 2010

Cited by 16 | Viewed by 9266 | PDF Full-text (356 KB)

Abstract

Extracts from Dipteryx alata bark obtained with different solvents (hexane, dichloromethane, ethyl acetate and methanol) were mixed in vitro with Bothrops jararacussu (Bjssu, 40 μg/mL) and Crotalus durissus terrificus (Cdt, 15 μg/mL) snake venoms, and applied to a mouse phrenic nerve-diaphragm preparation to

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Extracts from Dipteryx alata bark obtained with different solvents (hexane, dichloromethane, ethyl acetate and methanol) were mixed in vitro with Bothrops jararacussu (Bjssu, 40 μg/mL) and Crotalus durissus terrificus (Cdt, 15 μg/mL) snake venoms, and applied to a mouse phrenic nerve-diaphragm preparation to evaluate the possible neutralization of venom effects. Cdt venom neurotoxic effect was not inhibited by any of the extracts, while the neurotoxic and myotoxic actions of Bjssu venom were decreased by the methanolic extract. This inhibition appears to be augmented by tannins. Dichloromethane bark extract inhibited ~40% of Bjssu venom effects and delayed blockade induced by Cdt. The methodology used to determine which extract was active allows inferring that: (i) phenolic acids and flavonoids contained in the methanolic extract plus tannins were responsible mostly for neutralization of Bjssu effects; (ii) terpenoids from the dichloromethane extract may participate in the anti-Cdt and anti-Bjssu venom effects; (iii) a given extract could not inhibit venoms from different species even if those belong to the same family, so it is improper to generalize a certain plant as antiophidian; (iv) different polarity extracts do not present the same inhibitory capability, thus demonstrating the need for characterizing both venom pharmacology and the phytochemistry of medicinal plant compounds Full article

Open AccessReview Mediterranean Jellyfish Venoms: A Review on Scyphomedusae

by Gian Luigi Mariottini and Luigi Pane

Mar. Drugs 2010, 8(4), 1122-1152; doi:10.3390/md8041122

Received: 10 February 2010 / Revised: 15 March 2010 / Accepted: 30 March 2010 / Published: 4 April 2010

Cited by 62 | Viewed by 8532 | PDF Full-text (381 KB) | HTML Full-text | XML Full-text

Abstract

The production of natural toxins is an interesting aspect, which characterizes the physiology and the ecology of a number of marine species that use them for defence/offence purposes. Cnidarians are of particular concern from this point of view; their venoms are contained in

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The production of natural toxins is an interesting aspect, which characterizes the physiology and the ecology of a number of marine species that use them for defence/offence purposes. Cnidarians are of particular concern from this point of view; their venoms are contained in specialized structures–the nematocysts–which, after mechanical or chemical stimulation, inject the venom in the prey or in the attacker. Cnidarian stinging is a serious health problem for humans in the zones where extremely venomous jellyfish or anemones are common, such as in temperate and tropical oceanic waters and particularly along several Pacific coasts, and severe cases of envenomation, including also lethal cases mainly induced by cubomedusae, were reported. On the contrary, in the Mediterranean region the problem of jellyfish stings is quite modest, even though they can have anyhow an impact on public health and be of importance from the ecological and economic point of view owing to the implications on ecosystems and on some human activities such as tourism, bathing and fishing. This paper reviews the knowledge about the various aspects related to the occurrence and the stinging of the Mediterranean scyphozoan jellyfish as well as the activity of their venoms. Full article

(This article belongs to the Special Issue Marine Biotoxins: Novel Issues about Old Compounds)

Open AccessReview Behavioral and Chemical Ecology of Marine Organisms with Respect to Tetrodotoxin

by Becky L. Williams

Mar. Drugs 2010, 8(3), 381-398; doi:10.3390/md8030381

Received: 4 February 2010 / Revised: 24 February 2010 / Accepted: 25 February 2010 / Published: 26 February 2010

Cited by 46 | Viewed by 8037 | PDF Full-text (151 KB) | HTML Full-text | XML Full-text

Abstract

The behavioral and chemical ecology of marine organisms that possess tetrodotoxin (TTX) has not been comprehensively reviewed in one work to date. The evidence for TTX as an antipredator defense, as venom, as a sex pheromone, and as an attractant for TTX-sequestering organisms

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The behavioral and chemical ecology of marine organisms that possess tetrodotoxin (TTX) has not been comprehensively reviewed in one work to date. The evidence for TTX as an antipredator defense, as venom, as a sex pheromone, and as an attractant for TTX-sequestering organisms is discussed. Little is known about the adaptive value of TTX in microbial producers; thus, I focus on what is known about metazoans that are purported to accumulate TTX through diet or symbioses. Much of what has been proposed is inferred based on the anatomical distribution of TTX. Direct empirical tests of these hypotheses are absent in most cases. Full article

(This article belongs to the Special Issue Tetrodotoxin 2011)

Open AccessReview Bothrops lanceolatus Bites: Guidelines for Severity Assessment and Emergent Management

by Dabor Resiere, Bruno Mégarbane, Ruddy Valentino, Hossein Mehdaoui and Laurent Thomas

Toxins 2010, 2(1), 163-173; doi:10.3390/toxins2010163

Received: 6 December 2009 / Revised: 13 January 2010 / Accepted: 19 January 2010 / Published: 22 January 2010

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Abstract

Approximately 20–30 declared snakebite cases occurin Martinique each year. Bothrops lanceolatus, a member of the Crotalidae family, is considered to be the only involved snake. B. lanceolatus, commonly named “Fer-de-Lance”, is endemic and only found on this Caribbean island. Envenomation local

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Approximately 20–30 declared snakebite cases occurin Martinique each year. Bothrops lanceolatus, a member of the Crotalidae family, is considered to be the only involved snake. B. lanceolatus, commonly named “Fer-de-Lance”, is endemic and only found on this Caribbean island. Envenomation local features include the presence of fang marks, swelling, pain, bleeding from punctures, and ecchymosis. Severe envenomation is associated with multiple systemic thromboses appearing within 48 h of the bite and resulting in cerebral, myocardial or pulmonary infarctions. Diagnosis requires first of all identification of the snake. Coagulation tests are helpful to identify thrombocytopenia or disseminated intravascular coagulation. A clinical score based on 4 grades is helpful to assess envonimation severity. A specific monovalent equine anti-venom (Bothrofav^®, Sanofi-Pasteur, France) to neutralize B. lanceolatus venom is available. Its early administration within 6h from the biting in case of progressive local injures, general signs or coagulation disturbances is effective to prevent severe thrombosis and coagulopathy. Its tolerance is considered to be good. Despite an increasing incidence of bites, no deaths have been recently attributed to B. lanceolatus in Martinique, probably due to the currently recommended strategy of early antivenom administration when required. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessArticle Isolation and Chemical Characterization of a Toxin Isolated from the Venom of the Sea Snake, Hydrophis torquatus aagardi

by Masaya Nagamizu, Yumiko Komori, Kei-ichi Uchiya, Toshiaki Nikai and Anthony T. Tu

Toxins 2009, 1(2), 162-172; doi:10.3390/toxins1020162

Received: 28 October 2009 / Revised: 2 December 2009 / Accepted: 7 December 2009 / Published: 8 December 2009

Cited by 2 | Viewed by 5271 | PDF Full-text (497 KB) | HTML Full-text | XML Full-text

Abstract

Sea snakes (family: Hydrophiidae) are serpents found in the coastal areas of the Indian and Pacific Oceans. There are two subfamilies in Hydrophiidae: Hydrophiinae and Laticaudinae. A toxin, aagardi toxin, was isolated from the venom of the Hydrophiinae snake, Hydrophis torquatus aagardi and

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Sea snakes (family: Hydrophiidae) are serpents found in the coastal areas of the Indian and Pacific Oceans. There are two subfamilies in Hydrophiidae: Hydrophiinae and Laticaudinae. A toxin, aagardi toxin, was isolated from the venom of the Hydrophiinae snake, Hydrophis torquatus aagardi and its chemical properties such as molecular weight, isoelectric point, importance of disulfide bonds, lack of enzymatic activity and amino acid sequence were determined. The amino acid sequence indicated a close relationship to the primary structure of other Hydrophiinae toxins and a significant difference from Laticaudinae toxins, confirming that primary toxin structure is closely related to sea snake phylogenecity. Full article

(This article belongs to the Special Issue Neurotoxins of Biological Origin)

Open AccessReview Conotoxins: Therapeutic Potential and Application

by Richard T. Layer and J. Michael McIntosh

Mar. Drugs 2006, 4(3), 119-142; doi:10.3390/md403119

Received: 30 November 2005 / Accepted: 8 March 2006 / Published: 6 April 2006

Cited by 16 | Viewed by 7289 | PDF Full-text (125 KB) | HTML Full-text | XML Full-text

Abstract

The pharmacological variety of conotoxins, diverse peptides found in the venoms of marine cone snails, is well recognized. Venoms from each of the estimated 500 species of cone snails contain 50 to 200 distinct biologically active peptides. Most conotoxins characterized to date target

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The pharmacological variety of conotoxins, diverse peptides found in the venoms of marine cone snails, is well recognized. Venoms from each of the estimated 500 species of cone snails contain 50 to 200 distinct biologically active peptides. Most conotoxins characterized to date target receptors and ion channels of excitable tissues, such as ligandgated nicotinic acetylcholine, N-methyl-D-aspartate, and type 3 serotonin receptors, as well as voltage-gated calcium, sodium, and potassium channels, and G-protein-coupled receptors including α-adrenergic, neurotensin, and vasopressin receptors, and the norepinephrine transporter. Several conotoxins have shown promise in preclinical models of pain, convulsive disorders, stroke, neuromuscular block, and cardioprotection. The pharmacological selectivity of the conotoxins, coupled with the safety and efficacy demonstrated in preclinical models, has led to their investigation as human therapeutic agents. In the following review, we will survey the pharmacology and therapeutic rationale of those conotoxins with potential clinical application, and discuss the unique challenges that each will face in the course of their transition from venom component to human therapeutic. Full article

(This article belongs to the Special Issue Marine Drugs and Ion Channels)

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