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Open AccessArticle The Venom Repertoire of Conus gloriamaris (Chemnitz, 1777), the Glory of the Sea

by Samuel D. Robinson, Qing Li, Aiping Lu, Pradip K. Bandyopadhyay, Mark Yandell, Baldomero M. Olivera and Helena Safavi-Hemami

Mar. Drugs 2017, 15(5), 145; doi:10.3390/md15050145

Received: 21 April 2017 / Revised: 15 May 2017 / Accepted: 17 May 2017 / Published: 20 May 2017

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Abstract

The marine cone snail Conus gloriamaris is an iconic species. For over two centuries, its shell was one of the most prized and valuable natural history objects in the world. Today, cone snails have attracted attention for their remarkable venom components. Many conotoxins

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The marine cone snail Conus gloriamaris is an iconic species. For over two centuries, its shell was one of the most prized and valuable natural history objects in the world. Today, cone snails have attracted attention for their remarkable venom components. Many conotoxins are proving valuable as research tools, drug leads, and drugs. In this article, we present the venom gland transcriptome of C. gloriamaris, revealing this species’ conotoxin repertoire. More than 100 conotoxin sequences were identified, representing a valuable resource for future drug discovery efforts. Full article

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Open AccessReview Molecular Simulations of Disulfide-Rich Venom Peptides with Ion Channels and Membranes

by Evelyne Deplazes

Molecules 2017, 22(3), 362; doi:10.3390/molecules22030362

Received: 8 February 2017 / Revised: 23 February 2017 / Accepted: 24 February 2017 / Published: 27 February 2017

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Abstract

Disulfide-rich peptides isolated from the venom of arthropods and marine animals are a rich source of potent and selective modulators of ion channels. This makes these peptides valuable lead molecules for the development of new drugs to treat neurological disorders. Consequently, much effort

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Disulfide-rich peptides isolated from the venom of arthropods and marine animals are a rich source of potent and selective modulators of ion channels. This makes these peptides valuable lead molecules for the development of new drugs to treat neurological disorders. Consequently, much effort goes into understanding their mechanism of action. This paper presents an overview of how molecular simulations have been used to study the interactions of disulfide-rich venom peptides with ion channels and membranes. The review is focused on the use of docking, molecular dynamics simulations, and free energy calculations to (i) predict the structure of peptide-channel complexes; (ii) calculate binding free energies including the effect of peptide modifications; and (iii) study the membrane-binding properties of disulfide-rich venom peptides. The review concludes with a summary and outlook. Full article

(This article belongs to the Special Issue Biomolecular Simulations)

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Open AccessArticle Bioactivity of Natural and Engineered Antimicrobial Peptides from Venom of the Scorpions Urodacus yaschenkoi and U. manicatus

by Karen Luna-Ramirez, Miray Tonk, Mohammad Rahnamaeian and Andreas Vilcinskas

Toxins 2017, 9(1), 22; doi:10.3390/toxins9010022

Received: 26 November 2016 / Revised: 26 December 2016 / Accepted: 29 December 2016 / Published: 6 January 2017

Abstract

The spread of multidrug-resistant human pathogens has drawn attention towards antimicrobial peptides (AMPs), which are major players in the innate immune systems of many organisms, including vertebrates, invertebrates, plants and microbes. Scorpion venom is an abundant source of novel and potent AMPs. Here,

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The spread of multidrug-resistant human pathogens has drawn attention towards antimicrobial peptides (AMPs), which are major players in the innate immune systems of many organisms, including vertebrates, invertebrates, plants and microbes. Scorpion venom is an abundant source of novel and potent AMPs. Here, we investigated natural and engineered AMPs from the scorpions Urodacus yaschenkoi and U. manicatus to determine their antimicrobial spectra as well as their hemolytic/cytotoxic activity. None of the AMPs were active against fungi, but many of them were active at low concentrations (0.25–30 µM) against seven different bacteria. Hemolytic and cytotoxic activities were determined using pig erythrocytes and baby hamster kidney cells, respectively. The amino acid substitutions in the engineered AMPs did not inhibit cytotoxicity, but reduced hemolysis and therefore increased the therapeutic indices. The phylogenetic analysis of scorpion AMPs revealed they are closely related and the GXK motif is highly conserved. The engineered scorpion AMPs offer a promising alternative for the treatment of multidrug-resistant bacterial infections and could be modified further to reduce their hemolytic/cytotoxic activity. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Impact of Bee Venom Enzymes on Diseases and Immune Responses

by Md. Sakib Hossen, Ummay Mahfuza Shapla, Siew Hua Gan and Md. Ibrahim Khalil

Molecules 2017, 22(1), 25; doi:10.3390/molecules22010025

Received: 3 December 2016 / Revised: 20 December 2016 / Accepted: 22 December 2016 / Published: 27 December 2016

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Abstract

Bee venom (BV) is used to treat many diseases and exhibits anti-inflammatory, anti-bacterial, antimutagenic, radioprotective, anti-nociceptive immunity promoting, hepatocyte protective and anti-cancer activity. According to the literature, BV contains several enzymes, including phospholipase A2 (PLA2), phospholipase B, hyaluronidase, acid phosphatase and α-glucosidase. Recent

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Bee venom (BV) is used to treat many diseases and exhibits anti-inflammatory, anti-bacterial, antimutagenic, radioprotective, anti-nociceptive immunity promoting, hepatocyte protective and anti-cancer activity. According to the literature, BV contains several enzymes, including phospholipase A2 (PLA2), phospholipase B, hyaluronidase, acid phosphatase and α-glucosidase. Recent studies have also reported the detection of different classes of enzymes in BV, including esterases, proteases and peptidases, protease inhibitors and other important enzymes involved in carbohydrate metabolism. Nevertheless, the physiochemical properties and functions of each enzyme class and their mechanisms remain unclear. Various pharmacotherapeutic effects of some of the BV enzymes have been reported in several studies. At present, ongoing research aims to characterize each enzyme and elucidate their specific biological roles. This review gathers all the current knowledge on BV enzymes and their specific mechanisms in regulating various immune responses and physiological changes to provide a basis for future therapies for various diseases. Full article

(This article belongs to the Special Issue Bioactive Natural Peptides As A Pipeline For Therapeutics)

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Open AccessArticle Anticonvulsant Effects of Fractions Isolated from Dinoponera quadriceps (Kempt) Ant Venom (Formicidae: Ponerinae)

by Diana Aline Morais Ferreira Nôga, Luiz Eduardo Mateus Brandão, Fernanda Carvalho Cagni, Delano Silva, Dina Lilia Oliveira de Azevedo, Arrilton Araújo, Wagner Ferreira dos Santos, Antonio Miranda, Regina Helena da Silva and Alessandra Mussi Ribeiro

Toxins 2017, 9(1), 5; doi:10.3390/toxins9010005

Received: 23 May 2016 / Revised: 24 October 2016 / Accepted: 1 November 2016 / Published: 23 December 2016

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Abstract

Natural products, sources of new pharmacological substances, have large chemical diversity and architectural complexity. In this context, some toxins obtained from invertebrate venoms have anticonvulsant effects. Epilepsy is a neurological disorder that affects about 65 million people worldwide, and approximately 30% of cases

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Natural products, sources of new pharmacological substances, have large chemical diversity and architectural complexity. In this context, some toxins obtained from invertebrate venoms have anticonvulsant effects. Epilepsy is a neurological disorder that affects about 65 million people worldwide, and approximately 30% of cases are resistant to pharmacological treatment. Previous studies from our group show that the denatured venom of the ant Dinoponera quadriceps (Kempt) protects mice against bicuculline (BIC)-induced seizures and death. The aim of this study was to investigate the anticonvulsant activity of compounds isolated from D. quadriceps venom against seizures induced by BIC in mice. Crude venom was fractionated by high-performance liquid chromatography (HPLC) resulting in six fractions referred to as DqTx1–DqTx6. A liquid chromatography-mass spectrometry (LC/MS) analysis revealed a major 431 Da compound in fractions DqTx1 and DqTx2. Fractions DqTx3 and DqTx4 showed a compound of 2451 Da and DqTx5 revealed a 2436 Da compound. Furthermore, the DqTx6 fraction exhibited a major component with a molecular weight of 13,196 Da. Each fraction (1 mg/mL) was microinjected into the lateral ventricle of mice, and the animals were observed in an open field. We did not observe behavioral alterations when the fractions were given alone. Conversely, when the fractions were microinjected 20 min prior to the administration of BIC (21.6 nM), DqTx1, DqTx4, and DqTx6 fractions increased the latency for onset of tonic-clonic seizures. Moreover, all fractions, except DqTx5, increased latency to death. The more relevant result was obtained with the DqTx6 fraction, which protected 62.5% of the animals against tonic-clonic seizures. Furthermore, this fraction protected 100% of the animals from seizure episodes followed by death. Taken together, these findings indicate that compounds from ant venom might be a potential source of new anticonvulsants molecules. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Age-Related Modulations of AQP4 and Caveolin-1 in the Hippocampus Predispose the Toxic Effect of Phoneutria nigriventer Spider Venom

by Edilene S. Soares, Leila M. Stávale, Monique C. P. Mendonça, Andressa Coope and Maria Alice da Cruz-Höfling

Int. J. Mol. Sci. 2016, 17(11), 1462; doi:10.3390/ijms17111462

Received: 23 June 2016 / Revised: 1 August 2016 / Accepted: 22 August 2016 / Published: 23 November 2016

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Abstract

We have previously demonstrated that Phoneutria nigriventer venom (PNV) causes blood–brain barrier (BBB) breakdown, swelling of astrocytes end-feet and fluid permeation into brain interstitium in rats. Caveolae and water channels respond to BBB alterations by co-participation in shear stress response and edema formation/resolution.

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We have previously demonstrated that Phoneutria nigriventer venom (PNV) causes blood–brain barrier (BBB) breakdown, swelling of astrocytes end-feet and fluid permeation into brain interstitium in rats. Caveolae and water channels respond to BBB alterations by co-participation in shear stress response and edema formation/resolution. Herein, we showed post-natal developmental-related changes of two BBB-associated transporter proteins: the endothelial caveolin-1 (Cav-1), the major scaffolding protein from caveolae frame, and the astroglial aquaporin-4 (AQP4), the main water channel protein expressed in astrocytic peri-vascular end-feet processes, in the hippocampus of rats intraperitoneally-administered PNV. Western blotting protein levels; immunohistochemistry (IHC) protein distribution in CA1, CA2, and CA3 subfields; and gene expression by Real Time-Polymerase Chain Reaction (qPCR) were assessed in post-natal Day 14 (P14) and 8–10-week-old rats over critical periods of envenomation. The intensity and duration of the toxic manifestations indicate P14 neonate rats more vulnerable to PNV than adults. Histologically, the capillaries of P14 and 8–10-week-old rats treated with PNV showed perivascular edema, while controls did not. The intensity of the toxic manifestations in P14 decreases temporally (2 > 5 > 24 h), while inversely the expression of AQP4 and Cav-1 peaked at 24 h when clinically PNV-treated animals do not differ from saline controls. IHC of AQP4 revealed that hippocampal CA1 showed the least expression at 2 h when toxic manifestation was maximal. Subfield IHC quantification revealed that in P14 rats Cav-1 peaked at 24 h when toxic manifestations were absent, whereas in 8–10-week-old rats Cav-1 peaked at 2 h when toxic signs were highest, and progressively attenuated such increases until 24 h, remaining though significantly above baseline. Considering astrocyte-endothelial physical and functional interactions, we hypothesize that age-related modulations of AQP4 and Cav-1 might be linked both to changes in functional properties of astrocytes during post-natal development and in the BBB breakdown induced by the venom of P. nigriventer. Full article

(This article belongs to the Special Issue Aquaporin)

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Open AccessArticle Bee Venom Inhibits Porphyromonas gingivalis Lipopolysaccharides-Induced Pro-Inflammatory Cytokines through Suppression of NF-κB and AP-1 Signaling Pathways

by Woon-Hae Kim, Hyun-Jin An, Jung-Yeon Kim, Mi-Gyeong Gwon, Hyemin Gu, Jae-Bok Park, Woo Jung Sung, Yong-Chul Kwon, Kyung-Duck Park, Sang Mi Han and Kwan-Kyu Park

Molecules 2016, 21(11), 1508; doi:10.3390/molecules21111508

Received: 26 September 2016 / Revised: 28 October 2016 / Accepted: 4 November 2016 / Published: 10 November 2016

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Abstract

Periodontitis is a chronic inflammatory disease that leads to destruction of tooth supporting tissues. Porphyromonas gingivalis (P. gingivalis), especially its lipopolysaccharides (LPS), is one of major pathogens that cause periodontitis. Bee venom (BV) has been widely used as a traditional medicine

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Periodontitis is a chronic inflammatory disease that leads to destruction of tooth supporting tissues. Porphyromonas gingivalis (P. gingivalis), especially its lipopolysaccharides (LPS), is one of major pathogens that cause periodontitis. Bee venom (BV) has been widely used as a traditional medicine for various diseases. Previous studies have demonstrated the anti-inflammatory, anti-bacterial effects of BV. However, a direct role and cellular mechanism of BV on periodontitis-like human keratinocytes have not been explored. Therefore, we investigated the anti-inflammatory mechanism of BV against P. gingivalis LPS (PgLPS)-induced HaCaT human keratinocyte cell line. The anti-inflammatory effect of BV was demonstrated by various molecular biological methods. The results showed that PgLPS increased the expression of Toll-like receptor (TLR)-4 and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and interferon (IFN)-γ. In addition, PgLPS induced activation of the signaling pathways of inflammatory cytokines-related transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). BV effectively inhibited those pro-inflammatory cytokines through suppression of NF-κB and AP-1 signaling pathways. These results suggest that administration of BV attenuates PgLPS-induced inflammatory responses. Furthermore, BV may be a useful treatment to anti-inflammatory therapy for periodontitis. Full article

(This article belongs to the Section Natural Products)

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Open AccessReview A Comprehensive View of the Structural and Functional Alterations of Extracellular Matrix by Snake Venom Metalloproteinases (SVMPs): Novel Perspectives on the Pathophysiology of Envenoming

by José María Gutiérrez, Teresa Escalante, Alexandra Rucavado, Cristina Herrera and Jay W. Fox

Toxins 2016, 8(10), 304; doi:10.3390/toxins8100304

Received: 16 September 2016 / Accepted: 14 October 2016 / Published: 22 October 2016

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Abstract

Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics

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Snake venom metalloproteinases (SVMPs) affect the extracellular matrix (ECM) in multiple and complex ways. Previously, the combination of various methodological platforms, including electron microscopy, histochemistry, immunohistochemistry, and Western blot, has allowed a partial understanding of such complex pathology. In recent years, the proteomics analysis of exudates collected in the vicinity of tissues affected by SVMPs has provided novel and exciting information on SVMP-induced ECM alterations. The presence of fragments of an array of ECM proteins, including those of the basement membrane, has revealed a complex pathological scenario caused by the direct action of SVMPs. In addition, the time-course analysis of these changes has underscored that degradation of some fibrillar collagens is likely to depend on the action of endogenous proteinases, such as matrix metalloproteinases (MMPs), synthesized as a consequence of the inflammatory process. The action of SVMPs on the ECM also results in the release of ECM-derived biologically-active peptides that exert diverse actions in the tissue, some of which might be associated with reparative events or with further tissue damage. The study of the effects of SVMP on the ECM is an open field of research which may bring a renewed understanding of snake venom-induced pathology. Full article

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

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Open AccessArticle Cross-Neutralisation of In Vitro Neurotoxicity of Asian and Australian Snake Neurotoxins and Venoms by Different Antivenoms

by Anjana Silva, Wayne C. Hodgson and Geoffrey K. Isbister

Toxins 2016, 8(10), 302; doi:10.3390/toxins8100302

Received: 10 August 2016 / Revised: 22 September 2016 / Accepted: 1 October 2016 / Published: 18 October 2016

Abstract

There is limited information on the cross-neutralisation of neurotoxic venoms with antivenoms. Cross-neutralisation of the in vitro neurotoxicity of four Asian and four Australian snake venoms, four post-synaptic neurotoxins (α-bungarotoxin, α-elapitoxin-Nk2a, α-elapitoxin-Ppr1 and α-scutoxin; 100 nM) and one pre-synaptic neurotoxin (taipoxin; 100 nM)

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There is limited information on the cross-neutralisation of neurotoxic venoms with antivenoms. Cross-neutralisation of the in vitro neurotoxicity of four Asian and four Australian snake venoms, four post-synaptic neurotoxins (α-bungarotoxin, α-elapitoxin-Nk2a, α-elapitoxin-Ppr1 and α-scutoxin; 100 nM) and one pre-synaptic neurotoxin (taipoxin; 100 nM) was studied with five antivenoms: Thai cobra antivenom (TCAV), death adder antivenom (DAAV), Thai neuro polyvalent antivenom (TNPAV), Indian Polyvalent antivenom (IPAV) and Australian polyvalent antivenom (APAV). The chick biventer cervicis nerve-muscle preparation was used for this study. Antivenom was added to the organ bath 20 min prior to venom. Pre- and post-synaptic neurotoxicity of Bungarus caeruleus and Bungarus fasciatus venoms was neutralised by all antivenoms except TCAV, which did not neutralise pre-synaptic activity. Post-synaptic neurotoxicity of Ophiophagus hannah was neutralised by all antivenoms, and Naja kaouthia by all antivenoms except IPAV. Pre- and post-synaptic neurotoxicity of Notechis scutatus was neutralised by all antivenoms, except TCAV, which only partially neutralised pre-synaptic activity. Pre- and post-synaptic neurotoxicity of Oxyuranus scutellatus was neutralised by TNPAV and APAV, but TCAV and IPAV only neutralised post-synaptic neurotoxicity. Post-synaptic neurotoxicity of Acanthophis antarcticus was neutralised by all antivenoms except IPAV. Pseudonaja textillis post-synaptic neurotoxicity was only neutralised by APAV. The α-neurotoxins were neutralised by TNPAV and APAV, and taipoxin by all antivenoms except IPAV. Antivenoms raised against venoms with post-synaptic neurotoxic activity (TCAV) cross-neutralised the post-synaptic activity of multiple snake venoms. Antivenoms raised against pre- and post-synaptic neurotoxic venoms (TNPAV, IPAV, APAV) cross-neutralised both activities of Asian and Australian venoms. While acknowledging the limitations of adding antivenom prior to venom in an in vitro preparation, cross-neutralization of neurotoxicity means that antivenoms from one region may be effective in other regions which do not have effective antivenoms. TCAV only neutralized post-synaptic neurotoxicity and is potentially useful in distinguishing pre-synaptic and post-synaptic effects in the chick biventer cervicis preparation. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Novel Catalytically-Inactive PII Metalloproteinases from a Viperid Snake Venom with Substitutions in the Canonical Zinc-Binding Motif

by Erika Camacho, Libia Sanz, Teresa Escalante, Alicia Pérez, Fabián Villalta, Bruno Lomonte, Ana Gisele C. Neves-Ferreira, Andrés Feoli, Juan J. Calvete, José María Gutiérrez and Alexandra Rucavado

Toxins 2016, 8(10), 292; doi:10.3390/toxins8100292

Received: 12 September 2016 / Revised: 28 September 2016 / Accepted: 30 September 2016 / Published: 12 October 2016

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Abstract

Snake venom metalloproteinases (SVMPs) play key biological roles in prey immobilization and digestion. The majority of these activities depend on the hydrolysis of relevant protein substrates in the tissues. Hereby, we describe several isoforms and a cDNA clone sequence, corresponding to PII SVMP

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Snake venom metalloproteinases (SVMPs) play key biological roles in prey immobilization and digestion. The majority of these activities depend on the hydrolysis of relevant protein substrates in the tissues. Hereby, we describe several isoforms and a cDNA clone sequence, corresponding to PII SVMP homologues from the venom of the Central American pit viper Bothriechis lateralis, which have modifications in the residues of the canonical sequence of the zinc-binding motif HEXXHXXGXXH. As a consequence, the proteolytic activity of the isolated proteins was undetectable when tested on azocasein and gelatin. These PII isoforms comprise metalloproteinase and disintegrin domains in the mature protein, thus belonging to the subclass PIIb of SVMPs. PII SVMP homologues were devoid of hemorrhagic and in vitro coagulant activities, effects attributed to the enzymatic activity of SVMPs, but induced a mild edema. One of the isoforms presents the characteristic RGD sequence in the disintegrin domain and inhibits ADP- and collagen-induced platelet aggregation. Catalytically-inactive SVMP homologues may have been hitherto missed in the characterization of snake venoms. The presence of such enzymatically-inactive homologues in snake venoms and their possible toxic and adaptive roles deserve further investigation. Full article

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

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Open AccessReview Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges

by Viviane A. Bastos, Francisco Gomes-Neto, Jonas Perales, Ana Gisele C. Neves-Ferreira and Richard H. Valente

Toxins 2016, 8(9), 250; doi:10.3390/toxins8090250

Received: 18 June 2016 / Revised: 11 August 2016 / Accepted: 15 August 2016 / Published: 26 August 2016

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Abstract

The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera

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The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using “gold-standard” methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted. Full article

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

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Open AccessFeature PaperArticle Insights into the Evolution of a Snake Venom Multi-Gene Family from the Genomic Organization of Echis ocellatus SVMP Genes

by Libia Sanz and Juan J. Calvete

Toxins 2016, 8(7), 216; doi:10.3390/toxins8070216

Received: 12 June 2016 / Revised: 29 June 2016 / Accepted: 6 July 2016 / Published: 12 July 2016

Abstract

The molecular events underlying the evolution of the Snake Venom Metalloproteinase (SVMP) family from an A Disintegrin And Metalloproteinase (ADAM) ancestor remain poorly understood. Comparative genomics may provide decisive information to reconstruct the evolutionary history of this multi-locus toxin family. Here, we report

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The molecular events underlying the evolution of the Snake Venom Metalloproteinase (SVMP) family from an A Disintegrin And Metalloproteinase (ADAM) ancestor remain poorly understood. Comparative genomics may provide decisive information to reconstruct the evolutionary history of this multi-locus toxin family. Here, we report the genomic organization of Echis ocellatus genes encoding SVMPs from the PII and PI classes. Comparisons between them and between these genes and the genomic structures of Anolis carolinensis ADAM28 and E. ocellatus PIII-SVMP EOC00089 suggest that insertions and deletions of intronic regions played key roles along the evolutionary pathway that shaped the current diversity within the multi-locus SVMP gene family. In particular, our data suggest that emergence of EOC00028-like PI-SVMP from an ancestral PII(e/d)-type SVMP involved splicing site mutations that abolished both the 3′ splice AG acceptor site of intron 12* and the 5′ splice GT donor site of intron 13*, and resulted in the intronization of exon 13* and the consequent destruction of the structural integrity of the PII-SVMP characteristic disintegrin domain. Full article

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

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Open AccessArticle Lebein, a Snake Venom Disintegrin, Induces Apoptosis in Human Melanoma Cells

by Manel B. Hammouda, María F. Montenegro, Luis Sánchez-del-Campo, Ons Zakraoui, Zohra Aloui, Ichrak Riahi-Chebbi, Habib Karoui, José Neptuno Rodríguez-López and Khadija Essafi-Benkhadir

Toxins 2016, 8(7), 206; doi:10.3390/toxins8070206

Received: 4 May 2016 / Revised: 22 June 2016 / Accepted: 1 July 2016 / Published: 5 July 2016

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Abstract

Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that

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Melanoma, the most threatening form of skin cancer, has a very poor prognosis and is characterized by its very invasive and chemoresistant properties. Despite the recent promising news from the field of immunotherapy, there is an urgent need for new therapeutic approaches that are free of resistance mechanisms and side effects. Anti-neoplasic properties have been highlighted for different disintegrins from snake venom including Lebein; however, the exact effect of Lebein on melanoma has not yet been defined. In this study, we showed that Lebein blocks melanoma cell proliferation and induces a more differentiated phenotype with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and microphthalmia-associated transcription factor (MITF) overexpression. Melanoma cells became detached but were less invasive with upregulation of E-cadherin after Lebein exposure. Lebein induced a caspase-independent apoptotic program with apoptosis inducing factor (AIF), BCL-2-associated X protein (BAX) and Bim overexpression together with downregulation of B-cell lymphoma-2 (BCL-2). It generated a distinct response in reactive oxygen species (ROS) generation and p53 levels depending on the p53 cell line status (wild type or mutant). Therefore, we propose Lebein as a new candidate for development of potential therapies for melanoma. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessFeature PaperReview Processing of Snake Venom Metalloproteinases: Generation of Toxin Diversity and Enzyme Inactivation

by Ana M. Moura-da-Silva, Michelle T. Almeida, José A. Portes-Junior, Carolina A. Nicolau, Francisco Gomes-Neto and Richard H. Valente

Toxins 2016, 8(6), 183; doi:10.3390/toxins8060183

Received: 4 May 2016 / Revised: 27 May 2016 / Accepted: 3 June 2016 / Published: 9 June 2016

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Abstract

Snake venom metalloproteinases (SVMPs) are abundant in the venoms of vipers and rattlesnakes, playing important roles for the snake adaptation to different environments, and are related to most of the pathological effects of these venoms in human victims. The effectiveness of SVMPs is

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Snake venom metalloproteinases (SVMPs) are abundant in the venoms of vipers and rattlesnakes, playing important roles for the snake adaptation to different environments, and are related to most of the pathological effects of these venoms in human victims. The effectiveness of SVMPs is greatly due to their functional diversity, targeting important physiological proteins or receptors in different tissues and in the coagulation system. Functional diversity is often related to the genetic diversification of the snake venom. In this review, we discuss some published evidence that posit that processing and post-translational modifications are great contributors for the generation of functional diversity and for maintaining latency or inactivation of enzymes belonging to this relevant family of venom toxins. Full article

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

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Open AccessArticle The Acaricidal Activity of Venom from the Jellyfish Nemopilema nomurai against the Carmine Spider Mite Tetranychus cinnabarinus

by Huahua Yu, Yang Yue, Xiangli Dong, Rongfeng Li and Pengcheng Li

Toxins 2016, 8(6), 179; doi:10.3390/toxins8060179

Received: 14 April 2016 / Revised: 24 May 2016 / Accepted: 31 May 2016 / Published: 9 June 2016

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Abstract

The carmine spider mite Tetranychus cinnabarinus (T. cinnabarinus) is a common polyphagous pest that attacks crops, vegetables, flowers, and so on. It is necessary to find lead compounds for developing novel, powerful, and environmentally-friendly acaricides as an alternative approach to controlling

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The carmine spider mite Tetranychus cinnabarinus (T. cinnabarinus) is a common polyphagous pest that attacks crops, vegetables, flowers, and so on. It is necessary to find lead compounds for developing novel, powerful, and environmentally-friendly acaricides as an alternative approach to controlling the carmine spider mite because of the serious resistance and residual agrochemicals in the environment. In addition, the study on the acaricidal activities of marine bioactive substances is comparatively deficient. In the present study, the acaricidal activity of venom (NnFV) from the jellyfish Nemopilema nomurai against the carmine spider mite T. cinnabarinus was determined for the first time. The venom had contact toxicity, and the 24-h LC₅₀-value was 29.1 μg/mL. The mite body wall was affected by the venom, with the mite body having no luster and being seriously shrunken after 24 h. T. cinnabarinus was a potential target pest of NnFV, which had potential as a type of natural bioacaricide. The repellent activity and systemic toxicity of the venom against T. cinnabarinus were also studied. However, NnFV had no repellent activity and systemic toxicity against T. cinnabarinus. Full article

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

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Open AccessArticle Molecular Characterization of Three Novel Phospholipase A₂ Proteins from the Venom of Atheris chlorechis, Atheris nitschei and Atheris squamigera

by He Wang, Xiaole Chen, Mei Zhou, Lei Wang, Tianbao Chen and Chris Shaw

Toxins 2016, 8(6), 168; doi:10.3390/toxins8060168

Received: 24 February 2016 / Revised: 12 May 2016 / Accepted: 20 May 2016 / Published: 1 June 2016

Abstract

Secretory phospholipase A₂ (sPLA₂) is known as a major component of snake venoms and displays higher-order catalytic hydrolysis functions as well as a wide range of pathological effects. Atheris is not a notoriously dangerous genus of snakes although there are

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Secretory phospholipase A₂ (sPLA₂) is known as a major component of snake venoms and displays higher-order catalytic hydrolysis functions as well as a wide range of pathological effects. Atheris is not a notoriously dangerous genus of snakes although there are some reports of fatal cases after envenomation due to the effects of coagulation disturbances and hemorrhaging. Molecular characterization of Atheris venom enzymes is incomplete and there are only a few reports in the literature. Here, we report, for the first time, the cloning and characterization of three novel cDNAs encoding phospholipase A₂ precursors (one each) from the venoms of the Western bush viper (Atheris chlorechis), the Great Lakes bush viper (Atheris nitschei) and the Variable bush viper (Atheris squamigera), using a “shotgun cloning” strategy. Open-reading frames of respective cloned cDNAs contained putative 16 residue signal peptides and mature proteins composed of 121 to 123 amino acid residues. Alignment of mature protein sequences revealed high degrees of structural conservation and identity with Group II venom PLA₂ proteins from other taxa within the Viperidae. Reverse-phase High Performance Liquid Chromatography (HPLC) profiles of these three snake venoms were obtained separately and chromatographic fractions were assessed for phospholipase activity using an egg yolk suspension assay. The molecular masses of mature proteins were all identified as approximately 14 kDa. Mass spectrometric analyses of the fractionated oligopeptides arising from tryptic digestion of intact venom proteins, was performed for further structural characterization. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview ADAM and ADAMTS Family Proteins and Snake Venom Metalloproteinases: A Structural Overview

by Soichi Takeda

Toxins 2016, 8(5), 155; doi:10.3390/toxins8050155

Received: 8 April 2016 / Revised: 2 May 2016 / Accepted: 4 May 2016 / Published: 17 May 2016

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Abstract

A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major

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A disintegrin and metalloproteinase (ADAM) family proteins constitute a major class of membrane-anchored multidomain proteinases that are responsible for the shedding of cell-surface protein ectodomains, including the latent forms of growth factors, cytokines, receptors and other molecules. Snake venom metalloproteinases (SVMPs) are major components in most viper venoms. SVMPs are primarily responsible for hemorrhagic activity and may also interfere with the hemostatic system in envenomed animals. SVMPs are phylogenetically most closely related to ADAMs and, together with ADAMs and related ADAM with thrombospondin motifs (ADAMTS) family proteinases, constitute adamalysins/reprolysins or the M12B clan (MEROPS database) of metalloproteinases. Although the catalytic domain structure is topologically similar to that of other metalloproteinases such as matrix metalloproteinases, the M12B proteinases have a modular structure with multiple non-catalytic ancillary domains that are not found in other proteinases. Notably, crystallographic studies revealed that, in addition to the conserved metalloproteinase domain, M12B members share a hallmark cysteine-rich domain designated as the “ADAM_CR” domain. Despite their name, ADAMTSs lack disintegrin-like structures and instead comprise two ADAM_CR domains. This review highlights the current state of our knowledge on the three-dimensional structures of M12B proteinases, focusing on their unique domains that may collaboratively participate in directing these proteinases to specific substrates. Full article

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

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Open AccessReview Anti-Inflammatory Applications of Melittin, a Major Component of Bee Venom: Detailed Mechanism of Action and Adverse Effects

by Gihyun Lee and Hyunsu Bae

Molecules 2016, 21(5), 616; doi:10.3390/molecules21050616

Received: 10 March 2016 / Revised: 18 April 2016 / Accepted: 9 May 2016 / Published: 11 May 2016

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Abstract

Inflammation is a pervasive phenomenon triggered by the innate and adaptive immune systems to maintain homeostasis. The phenomenon normally leads to recovery from infection and healing, but when not properly phased, inflammation may cause immune disorders. Bee venom is a toxin that bees

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Inflammation is a pervasive phenomenon triggered by the innate and adaptive immune systems to maintain homeostasis. The phenomenon normally leads to recovery from infection and healing, but when not properly phased, inflammation may cause immune disorders. Bee venom is a toxin that bees use for their protection from enemies. However, for centuries it has been used in the Orient as an anti-inflammatory medicine for the treatment of chronic inflammatory diseases. Bee venom and its major component, melittin, are potential means of reducing excessive immune responses and provide new alternatives for the control of inflammatory diseases. Recent experimental studies show that the biological functions of melittin could be applied for therapeutic use in vitro and in vivo. Reports verifying the therapeutic effects of melittin are accumulating in the literature, but the cellular mechanism(s) of the anti-inflammatory effects of melittin are not fully elucidated. In the present study, we review the current knowledge on the therapeutic effects of melittin and its detailed mechanisms of action against several inflammatory diseases including skin inflammation, neuroinflammation, atherosclerosis, arthritis and liver inflammation, its adverse effects as well as future prospects regarding the use of melittin. Full article

(This article belongs to the Special Issue Natural Toxins)

Open AccessArticle Regulatory T Cells Contribute to the Inhibition of Radiation-Induced Acute Lung Inflammation via Bee Venom Phospholipase A₂ in Mice

by Dasom Shin, Gihyun Lee, Sung-Hwa Sohn, Soojin Park, Kyung-Hwa Jung, Ji Min Lee, Jieun Yang, Jaeho Cho and Hyunsu Bae

Toxins 2016, 8(5), 131; doi:10.3390/toxins8050131

Received: 10 March 2016 / Revised: 23 April 2016 / Accepted: 26 April 2016 / Published: 30 April 2016

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Abstract

Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A₂ (bvPLA₂) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is

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Bee venom has long been used to treat various inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Previously, we reported that bee venom phospholipase A₂ (bvPLA₂) has an anti-inflammatory effect through the induction of regulatory T cells. Radiotherapy is a common anti-cancer method, but often causes adverse effects, such as inflammation. This study was conducted to evaluate the protective effects of bvPLA₂ in radiation-induced acute lung inflammation. Mice were focally irradiated with 75 Gy of X-rays in the lung and administered bvPLA₂ six times after radiation. To evaluate the level of inflammation, the number of immune cells, mRNA level of inflammatory cytokine, and histological changes in the lung were measured. BvPLA₂ treatment reduced the accumulation of immune cells, such as macrophages, neutrophils, lymphocytes, and eosinophils. In addition, bvPLA₂ treatment decreased inflammasome-, chemokine-, cytokine- and fibrosis-related genes’ mRNA expression. The histological results also demonstrated the attenuating effect of bvPLA₂ on radiation-induced lung inflammation. Furthermore, regulatory T cell depletion abolished the therapeutic effects of bvPLA₂ in radiation-induced pneumonitis, implicating the anti-inflammatory effects of bvPLA₂ are dependent upon regulatory T cells. These results support the therapeutic potential of bvPLA₂ in radiation pneumonitis and fibrosis treatments. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle The Spider Venom Peptide Lycosin-II Has Potent Antimicrobial Activity against Clinically Isolated Bacteria

by Yongjun Wang, Ling Wang, Huali Yang, Haoliang Xiao, Athar Farooq, Zhonghua Liu, Min Hu and Xiaoliu Shi

Toxins 2016, 8(5), 119; doi:10.3390/toxins8050119

Received: 2 February 2016 / Revised: 5 April 2016 / Accepted: 6 April 2016 / Published: 26 April 2016

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Abstract

Antimicrobial peptides have been accepted as excellent candidates for developing novel antibiotics against drug-resistant bacteria. Recent studies indicate that spider venoms are the source for the identification of novel antimicrobial peptides. In the present study, we isolated and characterized an antibacterial peptide named

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Antimicrobial peptides have been accepted as excellent candidates for developing novel antibiotics against drug-resistant bacteria. Recent studies indicate that spider venoms are the source for the identification of novel antimicrobial peptides. In the present study, we isolated and characterized an antibacterial peptide named lycosin-II from the venom of the spider Lycosa singoriensis. It contains 21 amino acid residue lacking cysteine residues and forms a typical linear amphipathic and cationic α-helical conformation. Lycosin-II displays potent bacteriostatic effect on the tested drug-resistant bacterial strains isolated from hospital patients, including multidrug-resistant A. baumannii, which has presented a huge challenge for the infection therapy. The inhibitory ability of lycosin-II might derive from its binding to cell membrane, because Mg²⁺ could compete with the binding sites to reduce the bacteriostatic potency of lycosin-II. Our data suggest that lycosin-II might be a lead in the development of novel antibiotics for curing drug-resistant bacterial infections. Full article

(This article belongs to the Special Issue Arthropod Venoms)

Open AccessArticle Effect of Bee Venom and Its Fractions on the Release of Pro-Inflammatory Cytokines in PMA-Differentiated U937 Cells Co-Stimulated with LPS

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

Vaccines 2016, 4(2), 11; doi:10.3390/vaccines4020011

Received: 2 March 2016 / Revised: 12 April 2016 / Accepted: 13 April 2016 / Published: 19 April 2016

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Abstract

The venom of Apis mellifera (honey bee) has been reported to play a role in immunotherapy, but existing evidence to support its immuno-modulatory claims is insufficient. Four fractions from whole bee venom (BV) were separated using medium pressure liquid chromatography. Their ability to

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The venom of Apis mellifera (honey bee) has been reported to play a role in immunotherapy, but existing evidence to support its immuno-modulatory claims is insufficient. Four fractions from whole bee venom (BV) were separated using medium pressure liquid chromatography. Their ability to induce the production of cytokines TNFα, IL-1β and IL-6 in phorbol-12-myristate-13-acetate (PMA)-treated U937 cells was assessed. The levels of the three cytokines produced by stimulation with the four fractions and crude BV without LPS were not significantly different from negative control values. However, co-stimulation of the cells with LPS and Fraction 4 (F-4) induced a 1.6-fold increase in TNF-α level (p < 0.05) compared to LPS alone. Likewise, LPS-induced IL-1β production was significantly synergised in the presence of F-1 (nine-fold), F-2 (six-fold), F-3 (four-fold) and F-4 (two-fold) fractions, but was only slightly enhanced with crude BV (1.5-fold) relative to LPS. Furthermore, the LPS-stimulated production of IL-6 was not significantly increased in cells co-treated with F-2 and F-3, but the organic fraction (F-4) showed an inhibitory effect (p < 0.05) on IL-6 production. The latter was elucidated by NMR spectroscopy and found to contain(Z)-9-eicosen-1-ol. The effects observed with the purified BV fractions were more marked than those obtained with the crude sample. Full article

Open AccessArticle MP-V1 from the Venom of Social Wasp Vespula vulgaris Is a de Novo Type of Mastoparan that Displays Superior Antimicrobial Activities

by Yangseon Kim, Minky Son, Eun-Young Noh, Soonok Kim, Changmu Kim, Joo-Hong Yeo, Chanin Park, Keun Woo Lee and Woo Young Bang

Molecules 2016, 21(4), 512; doi:10.3390/molecules21040512

Received: 30 January 2016 / Revised: 19 March 2016 / Accepted: 12 April 2016 / Published: 19 April 2016

Abstract

Mastoparans from the venom of social wasps have attracted considerable attention as effective antibiotic candidates. In this study, mastoparan V1 (MP-V1) from Vespula vulgaris was first disclosed to have a peptide amino acid sequence distinct from typical mastoparans and its biochemical properties and

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Mastoparans from the venom of social wasps have attracted considerable attention as effective antibiotic candidates. In this study, mastoparan V1 (MP-V1) from Vespula vulgaris was first disclosed to have a peptide amino acid sequence distinct from typical mastoparans and its biochemical properties and antimicrobial effects were compared with those of typical mastoparans MP-L, -X(V) and -B. Circular dichroism (CD) spectroscopy revealed that MP-V1 and -X(V) form more stable α-helical conformations in lipid membrane-like environments than MP-L and -B. In parallel, these two also showed more effective antimicrobial activities against the pathogens than did MP-L and -B. Although MP-V1 had a less stable α-helical conformation than MP-X(V), it showed stronger antimicrobial effects against Streptococcus mutans and Salmonella enterica than MP-X(V). In the meantime, analysis of hemolytic activity revealed a range of doses (~50 μM) that exhibited little potent cytotoxicity on human erythrocytes. Finally, the atypical MP-V1 peptide amino acid sequence provided important clues to understanding its antimicrobial mechanism from a structural perspective. Therefore, it has been concluded that MP-V1 is a de novo type of mastoparan with superior antimicrobial activities against both pathogenic bacteria and fungi, which may be useful in developing multipurpose antimicrobial drugs against infectious diseases. Full article

(This article belongs to the Special Issue Natural Toxins)

Open AccessFeature PaperArticle δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats

by Bruna Luiza Emerich, Renata C. M. Ferreira, Marta N. Cordeiro, Márcia Helena Borges, Adriano M. C. Pimenta, Suely G. Figueiredo, Igor Dimitri G. Duarte and Maria Elena de Lima

Toxins 2016, 8(4), 106; doi:10.3390/toxins8040106

Received: 29 January 2016 / Revised: 17 March 2016 / Accepted: 5 April 2016 / Published: 12 April 2016

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Abstract

PnTx4(6-1), henceforth renamed δ-Ctenitoxin-Pn1a (δ-CNTX-Pn1a), a peptide from Phoneutria nigriventer spider venom, initially described as an insect toxin, binds to site 3 of sodium channels in nerve cord synaptosomes and slows down sodium current inactivation in isolated axons in cockroaches (Periplaneta americana

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PnTx4(6-1), henceforth renamed δ-Ctenitoxin-Pn1a (δ-CNTX-Pn1a), a peptide from Phoneutria nigriventer spider venom, initially described as an insect toxin, binds to site 3 of sodium channels in nerve cord synaptosomes and slows down sodium current inactivation in isolated axons in cockroaches (Periplaneta americana). δ-CNTX-Pn1a does not cause any apparent toxicity to mice, when intracerebroventricularly injected (30 μg). In this study, we evaluated the antinociceptive effect of δ-CNTX-Pn1a in three animal pain models and investigated its mechanism of action in acute pain. In the inflammatory pain model, induced by carrageenan, δ-CNTX-Pn1a restored the nociceptive threshold of rats, when intraplantarly injected, 2 h and 30 min after carrageenan administration. Concerning the neuropathic pain model, δ-CNTX-Pn1a, when intrathecally administered, reversed the hyperalgesia evoked by sciatic nerve constriction. In the acute pain model, induced by prostaglandin E₂, intrathecal administration of δ-CNTX-Pn1a caused a dose-dependent antinociceptive effect. Using antagonists of the receptors, we showed that the antinociceptive effect of δ-CNTX-Pn1a involves both the cannabinoid system, through CB₁ receptors, and the opioid system, through μ and δ receptors. Our data show, for the first time, that δ-Ctenitoxin-Pn1a is able to induce antinociception in inflammatory, neuropathic and acute pain models. Full article

(This article belongs to the Special Issue Arthropod Venoms)

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Open AccessReview Hemorrhage Caused by Snake Venom Metalloproteinases: A Journey of Discovery and Understanding

by José María Gutiérrez, Teresa Escalante, Alexandra Rucavado and Cristina Herrera

Toxins 2016, 8(4), 93; doi:10.3390/toxins8040093

Received: 7 March 2016 / Revised: 15 March 2016 / Accepted: 18 March 2016 / Published: 26 March 2016

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Abstract

The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main

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The historical development of discoveries and conceptual frames for understanding the hemorrhagic activity induced by viperid snake venoms and by hemorrhagic metalloproteinases (SVMPs) present in these venoms is reviewed. Histological and ultrastructural tools allowed the identification of the capillary network as the main site of action of SVMPs. After years of debate, biochemical developments demonstrated that all hemorrhagic toxins in viperid venoms are zinc-dependent metalloproteinases. Hemorrhagic SVMPs act by initially hydrolyzing key substrates at the basement membrane (BM) of capillaries. This degradation results in the weakening of the mechanical stability of the capillary wall, which becomes distended owing of the action of the hemodynamic biophysical forces operating in the circulation. As a consequence, the capillary wall is disrupted and extravasation occurs. SVMPs do not induce rapid toxicity to endothelial cells, and the pathological effects described in these cells in vivo result from the mechanical action of these hemodynamic forces. Experimental evidence suggests that degradation of type IV collagen, and perhaps also perlecan, is the key event in the onset of microvessel damage. It is necessary to study this phenomenon from a holistic, systemic perspective in which the action of other venom components is also taken into consideration. Full article

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

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Open AccessArticle A New Indole Alkaloid from the Toad Venom of Bufo bufo gargarizans

by Ying-Hui Dai, Bo Shen, Ming-Yu Xia, An-Dong Wang, Yu-Lin Chen, Dong-Chun Liu and Dong Wang

Molecules 2016, 21(3), 349; doi:10.3390/molecules21030349

Received: 23 January 2016 / Revised: 4 March 2016 / Accepted: 8 March 2016 / Published: 16 March 2016

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Abstract

A new indole alkaloid named bufobutarginine (1), along with three known bufotenines, namely, serotonin (2), bufotenidine (3), and bufotenine (4), were isolated from the water extract of toad venom. Their structures were elucidated by spectral methods. This is the first time that arginine

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A new indole alkaloid named bufobutarginine (1), along with three known bufotenines, namely, serotonin (2), bufotenidine (3), and bufotenine (4), were isolated from the water extract of toad venom. Their structures were elucidated by spectral methods. This is the first time that arginine has been found to be involved in the biosynthesis of bufotenines in parotid of toad. The cytotoxic activities of these compounds have been assayed against A375 and A549 cell lines by the MTT method; however, they showed no cytotoxic activities. Full article

(This article belongs to the Section Natural Products)

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Open AccessArticle Characterization and Recombinant Expression of Terebrid Venom Peptide from Terebra guttata

by John Moon, Juliette Gorson, Mary Elizabeth Wright, Laurel Yee, Samer Khawaja, Hye Young Shin, Yasmine Karma, Rajeeva Lochan Musunri, Michelle Yun and Mande Holford

Toxins 2016, 8(3), 63; doi:10.3390/toxins8030063

Received: 1 January 2016 / Revised: 23 February 2016 / Accepted: 23 February 2016 / Published: 3 March 2016

Abstract

Venom peptides found in terebrid snails expand the toolbox of active compounds that can be applied to investigate cellular physiology and can be further developed as future therapeutics. However, unlike other predatory organisms, such as snakes, terebrids produce very small quantities of venom,

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Venom peptides found in terebrid snails expand the toolbox of active compounds that can be applied to investigate cellular physiology and can be further developed as future therapeutics. However, unlike other predatory organisms, such as snakes, terebrids produce very small quantities of venom, making it difficult to obtain sufficient amounts for biochemical characterization. Here, we describe the first recombinant expression and characterization of terebrid peptide, teretoxin Tgu6.1, from Terebra guttata. Tgu6.1 is a novel forty-four amino acid teretoxin peptide with a VI/VII cysteine framework (C–C–CC–C–C) similar to O, M and I conotoxin superfamilies. A ligation-independent cloning strategy with an ompT protease deficient strain of E. coli was employed to recombinantly produce Tgu6.1. Thioredoxin was introduced in the plasmid to combat disulfide folding and solubility issues. Specifically Histidine-6 tag and Ni-NTA affinity chromatography were applied as a purification method, and enterokinase was used as a specific cleavage protease to effectively produce high yields of folded Tgu6.1 without extra residues to the primary sequence. The recombinantly-expressed Tgu6.1 peptide was bioactive, displaying a paralytic effect when injected into a Nereis virens polychaete bioassay. The recombinant strategy described to express Tgu6.1 can be applied to produce high yields of other disulfide-rich peptides. Full article

(This article belongs to the Special Issue Venomics, Venom Proteomics and Venom Transcriptomics)

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Open AccessFeature PaperArticle Paulistine—The Functional Duality of a Wasp Venom Peptide Toxin

by Helen Andrade Arcuri, Paulo Cesar Gomes, Bibiana Monson de Souza, Nathalia Baptista Dias, Patrícia Brigatte, Rodrigo Guerino Stabeli and Mario Sergio Palma

Toxins 2016, 8(3), 61; doi:10.3390/toxins8030061

Received: 9 December 2015 / Revised: 12 February 2016 / Accepted: 22 February 2016 / Published: 29 February 2016

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Abstract

It has been reported that Paulistine in the venom of the wasp Polybia paulista co-exists as two different forms: an oxidized form presenting a compact structure due to the presence of a disulfide bridge, which causes inflammation through an apparent interaction with receptors

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It has been reported that Paulistine in the venom of the wasp Polybia paulista co-exists as two different forms: an oxidized form presenting a compact structure due to the presence of a disulfide bridge, which causes inflammation through an apparent interaction with receptors in the 5-lipoxygenase pathway, and a naturally reduced form (without the disulfide bridge) that exists in a linear conformation and which also causes hyperalgesia and acts in the cyclooxygenase type II pathway. The reduced peptide was acetamidomethylated (Acm-Paulistine) to stabilize this form, and it still maintained its typical inflammatory activity. Oxidized Paulistine docks onto PGHS2 (COX-2) molecules, blocking the access of oxygen to the heme group and inhibiting the inflammatory activity of Acm-Paulistine in the cyclooxygenase type II pathway. Docking simulations revealed that the site of the docking of Paulistine within the PGHS2 molecule is unusual among commercial inhibitors of the enzyme, with an affinity potentially much higher than those observed for traditional anti-inflammatory drugs. Therefore, Paulistine causes inflammatory activity at the level of the 5-lipooxygenase pathway and, in parallel, it competes with its reduced form in relation to the activation of the cyclooxygenase pathway. Thus, while the reduced Paulistine causes inflammation, its oxidized form is a potent inhibitor of this activity. Full article

(This article belongs to the Special Issue Arthropod Venoms)

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Open AccessArticle Combined Effects of Bee Venom Acupuncture and Morphine on Oxaliplatin-Induced Neuropathic Pain in Mice

by Woojin Kim, Min Joon Kim, Donghyun Go, Byung-Il Min, Heung Sik Na and Sun Kwang Kim

Toxins 2016, 8(2), 33; doi:10.3390/toxins8020033

Received: 2 December 2015 / Revised: 14 January 2016 / Accepted: 18 January 2016 / Published: 22 January 2016

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Abstract

Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat

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Oxaliplatin, a chemotherapeutic drug for colorectal cancer, induces severe peripheral neuropathy. Bee venom acupuncture (BVA) has been used to attenuate pain, and its effect is known to be mediated by spinal noradrenergic and serotonergic receptors. Morphine is a well-known opioid used to treat different types of pain. Here, we investigated whether treatment with a combination of these two agents has an additive effect on oxaliplatin-induced neuropathic pain in mice. To assess cold and mechanical allodynia, acetone and von Frey filament tests were used, respectively. Significant allodynia signs were observed three days after an oxaliplatin injection (6 mg/kg, i.p.). BVA (0.25, 1, and 2.5 mg/kg, s.c., ST36) or morphine (0.5, 2, and 5 mg/kg, i.p.) alone showed dose-dependent anti-allodynic effects. The combination of BVA and morphine at intermediate doses showed a greater and longer effect than either BVA or morphine alone at the highest dose. Intrathecal pretreatment with the opioidergic (naloxone, 20 μg) or 5-HT₃ (MDL-72222, 15 μg) receptor antagonist, but not with α₂-adrenergic (idazoxan, 10 μg) receptor antagonist, blocked this additive effect. Therefore, we suggest that the combination effect of BVA and morphine is mediated by spinal opioidergic and 5-HT₃ receptors and this combination has a robust and enduring analgesic action against oxaliplatin-induced neuropathic pain. Full article

(This article belongs to the Special Issue Arthropod Venoms)

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Open AccessArticle Preventive Effects of Bee Venom Derived Phospholipase A₂ on Oxaliplatin-Induced Neuropathic Pain in Mice

by Dongxing Li, Woojin Kim, Dasom Shin, Yongjae Jung, Hyunsu Bae and Sun Kwang Kim

Toxins 2016, 8(1), 27; doi:10.3390/toxins8010027

Received: 5 December 2015 / Revised: 12 January 2016 / Accepted: 14 January 2016 / Published: 19 January 2016

Abstract

Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A₂ (bvPLA₂) on oxaliplatin-induced neuropathic pain

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Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A₂ (bvPLA₂) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7–9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA₂ were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA₂ may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs. Full article

(This article belongs to the Special Issue Arthropod Venoms)

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Open AccessArticle Antibacterial Activity and Antibiotic-Enhancing Effects of Honeybee Venom against Methicillin-Resistant Staphylococcus aureus

by Sang Mi Han, Joung Min Kim, In Pyo Hong, Soon Ok Woo, Se Gun Kim, He Rye Jang and Sok Cheon Pak

Molecules 2016, 21(1), 79; doi:10.3390/molecules21010079

Received: 7 November 2015 / Revised: 4 January 2016 / Accepted: 8 January 2016 / Published: 12 January 2016

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Abstract

Methicillin-resistant Staphylococcus aureus (MRSA), along with other antibiotic resistant bacteria, has become a significant social and clinical problem. There is thus an urgent need to develop naturally bioactive compounds as alternatives to the few antibiotics that remain effective. Here we assessed the in

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Methicillin-resistant Staphylococcus aureus (MRSA), along with other antibiotic resistant bacteria, has become a significant social and clinical problem. There is thus an urgent need to develop naturally bioactive compounds as alternatives to the few antibiotics that remain effective. Here we assessed the in vitro activities of bee venom (BV), alone or in combination with ampicillin, penicillin, gentamicin or vancomycin, on growth of MRSA strains. The antimicrobial activity of BV against MRSA strains was investigated using minimum inhibitory concentrations (MIC), minimum bactericidal concentrations (MBC) and a time-kill assay. Expression of atl which encodes murein hydrolase, a peptidoglycan-degrading enzyme involved in cell separation, was measured by reverse transcription-polymerase chain reaction. The MICs of BV were 0.085 µg/mL and 0.11 µg/mL against MRSA CCARM 3366 and MRSA CCARM 3708, respectively. The MBC of BV against MRSA 3366 was 0.106 µg/mL and that against MRSA 3708 was 0.14 µg/mL. The bactericidal activity of BV corresponded to a decrease of at least 3 log CFU/g cells. The combination of BV with ampicillin or penicillin yielded an inhibitory concentration index ranging from 0.631 to 1.002, indicating a partial and indifferent synergistic effect. Compared to ampicillin or penicillin, both MRSA strains were more susceptible to the combination of BV with gentamicin or vancomycin. The expression of atl gene was increased in MRSA 3366 treated with BV. These results suggest that BV exhibited antibacterial activity and antibiotic-enhancing effects against MRSA strains. The atl gene was increased in MRSA exposed to BV, suggesting that cell division was interrupted. BV warrants further investigation as a natural antimicrobial agent and synergist of antibiotic activity. Full article

(This article belongs to the Special Issue Natural Toxins)

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Open AccessArticle Experimental Assays to Assess the Efficacy of Vinegar and Other Topical First-Aid Approaches on Cubozoan (Alatina alata) Tentacle Firing and Venom Toxicity

by Angel A. Yanagihara, Christie Wilcox, Rebecca King, Kikiana Hurwitz and Ann M. Castelfranco

Toxins 2016, 8(1), 19; doi:10.3390/toxins8010019

Received: 30 October 2015 / Revised: 28 December 2015 / Accepted: 4 January 2016 / Published: 11 January 2016

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Abstract

Despite the medical urgency presented by cubozoan envenomations, ineffective and contradictory first-aid management recommendations persist. A critical barrier to progress has been the lack of readily available and reproducible envenomation assays that (1) recapitulate live-tentacle stings; (2) allow quantitation and imaging of cnidae

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Despite the medical urgency presented by cubozoan envenomations, ineffective and contradictory first-aid management recommendations persist. A critical barrier to progress has been the lack of readily available and reproducible envenomation assays that (1) recapitulate live-tentacle stings; (2) allow quantitation and imaging of cnidae discharge; (3) allow primary quantitation of venom toxicity; and (4) employ rigorous controls. We report the implementation of an integrated array of three experimental approaches designed to meet the above-stated criteria. Mechanistically overlapping, yet distinct, the three approaches comprised (1) direct application of test solutions on live tentacles (termed tentacle solution assay, or TSA) with single image- and video-microscopy; (2) spontaneous stinging assay using freshly excised tentacles overlaid on substrate of live human red blood cells suspended in agarose (tentacle blood agarose assays, or TBAA); and (3) a “skin” covered adaptation of TBAA (tentacle skin blood agarose assay, or TSBAA). We report the use and results of these assays to evaluate the efficacy of topical first-aid approaches to inhibit tentacle firing and venom activity. TSA results included the potent stimulation of massive cnidae discharge by alcohols but only moderate induction by urine, freshwater, and “cola” (carbonated soft drink). Although vinegar, the 40-year field standard of first aid for the removal of adherent tentacles, completely inhibited cnidae firing in TSA and TSBAA ex vivo models, the most striking inhibition of both tentacle firing and subsequent venom-induced hemolysis was observed using newly-developed proprietary formulations (Sting No More™) containing copper gluconate, magnesium sulfate, and urea. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Bioactive Mimetics of Conotoxins and other Venom Peptides

by Peter J. Duggan and Kellie L. Tuck

Toxins 2015, 7(10), 4175-4198; doi:10.3390/toxins7104175

Received: 2 September 2015 / Accepted: 8 October 2015 / Published: 16 October 2015

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Abstract

Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and

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Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties. Full article

(This article belongs to the Special Issue Conotoxins: Novel Pharmacologies for Nervous System Disorders)

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Open AccessArticle Preformulation Studies of Bee Venom for the Preparation of Bee Venom-Loaded PLGA Particles

by Min-Ho Park, Ju-Heon Kim, Jong-Woon Jeon, Jin-Kyu Park, Bong-Joo Lee, Guk-Hyun Suh and Cheong-Weon Cho

Molecules 2015, 20(8), 15072-15083; doi:10.3390/molecules200815072

Received: 21 June 2015 / Revised: 4 August 2015 / Accepted: 5 August 2015 / Published: 18 August 2015

Cited by 3 | Viewed by 1343 | PDF Full-text (1647 KB) | HTML Full-text | XML Full-text

Abstract

It is known that allergic people was potentially vulnerable to bee venom (BV), which can induce an anaphylactic shock, eventually leading to death. Up until recently, this kind of allergy was treated only by venom immunotherapy (VIT) and its efficacy has been recognized

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It is known that allergic people was potentially vulnerable to bee venom (BV), which can induce an anaphylactic shock, eventually leading to death. Up until recently, this kind of allergy was treated only by venom immunotherapy (VIT) and its efficacy has been recognized worldwide. This treatment is practiced by subcutaneous injections that gradually increase the doses of the allergen. This is inconvenient for patients due to frequent injections. Poly (D,L-lactide-co-glycolide) (PLGA) has been broadly studied as a carrier for drug delivery systems (DDS) of proteins and peptides. PLGA particles usually induce a sustained release. In this study, the physicochemical properties of BV were examined prior to the preparation of BV-loaded PLGA nanoparticles NPs). The content of melittin, the main component of BV, was 53.3%. When protected from the light BV was stable at 4 °C in distilled water, during 8 weeks. BV-loaded PLGA particles were prepared using dichloromethane as the most suitable organic solvent and two min of ultrasonic emulsification time. This study has characterized the physicochemical properties of BV for the preparation BV-loaded PLGA NPs in order to design and optimize a suitable sustained release system in the future. Full article

(This article belongs to the Section Medicinal Chemistry)

Open AccessArticle Three Peptide Modulators of the Human Voltage-Gated Sodium Channel 1.7, an Important Analgesic Target, from the Venom of an Australian Tarantula

by Chun Yuen Chow, Ben Cristofori-Armstrong, Eivind A. B. Undheim, Glenn F. King and Lachlan D. Rash

Toxins 2015, 7(7), 2494-2513; doi:10.3390/toxins7072494

Received: 15 April 2015 / Revised: 19 June 2015 / Accepted: 24 June 2015 / Published: 30 June 2015

Abstract

Voltage-gated sodium (Na_V) channels are responsible for propagating action potentials in excitable cells. Na_V1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom

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Voltage-gated sodium (Na_V) channels are responsible for propagating action potentials in excitable cells. Na_V1.7 plays a crucial role in the human pain signalling pathway and it is an important therapeutic target for treatment of chronic pain. Numerous spider venom peptides have been shown to modulate the activity of Na_V channels and these peptides represent a rich source of research tools and therapeutic lead molecules. The aim of this study was to determine the diversity of Na_V1.7-active peptides in the venom of an Australian Phlogius sp. tarantula and to characterise their potency and subtype selectivity. We isolated three novel peptides, μ-TRTX-Phlo1a, -Phlo1b and -Phlo2a, that inhibit human Na_V1.7 (hNa_V1.7). Phlo1a and Phlo1b are 35-residue peptides that differ by one amino acid and belong in NaSpTx family 2. The partial sequence of Phlo2a revealed extensive similarity with ProTx-II from NaSpTx family 3. Phlo1a and Phlo1b inhibit hNa_V1.7 with IC₅₀ values of 459 and 360 nM, respectively, with only minor inhibitory activity on rat Na_V1.2 and hNa_V1.5. Although similarly potent at hNa_V1.7 (IC₅₀ 333 nM), Phlo2a was less selective, as it also potently inhibited rNa_V1.2 and hNa_V1.5. All three peptides cause a depolarising shift in the voltage-dependence of hNa_V1.7 activation. Full article

(This article belongs to the Special Issue Selected Papers from the 5th Venoms to Drugs Meeting)

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Open AccessReview Venom Proteins from Parasitoid Wasps and Their Biological Functions

by Sébastien J. M. Moreau and Sassan Asgari

Toxins 2015, 7(7), 2385-2412; doi:10.3390/toxins7072385

Received: 20 May 2015 / Revised: 16 June 2015 / Accepted: 16 June 2015 / Published: 26 June 2015

Cited by 17 | Viewed by 1321 | PDF Full-text (573 KB) | HTML Full-text | XML Full-text

Abstract

Parasitoid wasps are valuable biological control agents that suppress their host populations. Factors introduced by the female wasp at parasitization play significant roles in facilitating successful development of the parasitoid larva either inside (endoparasitoid) or outside (ectoparasitoid) the host. Wasp venoms consist of

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Parasitoid wasps are valuable biological control agents that suppress their host populations. Factors introduced by the female wasp at parasitization play significant roles in facilitating successful development of the parasitoid larva either inside (endoparasitoid) or outside (ectoparasitoid) the host. Wasp venoms consist of a complex cocktail of proteinacious and non-proteinacious components that may offer agrichemicals as well as pharmaceutical components to improve pest management or health related disorders. Undesirably, the constituents of only a small number of wasp venoms are known. In this article, we review the latest research on venom from parasitoid wasps with an emphasis on their biological function, applications and new approaches used in venom studies. Full article

(This article belongs to the Special Issue Bee and Wasp Venoms: Biological Characteristics and Therapeutic Application) Printed Edition available

Open AccessArticle A Severe Accident Caused by an Ocellate River Stingray (Potamotrygon motoro) in Central Brazil: How Well Do We Really Understand Stingray Venom Chemistry, Envenomation, and Therapeutics?

by Nelson Jorge da Silva, Jr., Kalley Ricardo Clementino Ferreira, Raimundo Nonato Leite Pinto and Steven Douglas Aird

Toxins 2015, 7(6), 2272-2288; doi:10.3390/toxins7062272

Received: 13 May 2015 / Revised: 29 May 2015 / Accepted: 30 May 2015 / Published: 18 June 2015

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Abstract

Freshwater stingrays cause many serious human injuries, but identification of the offending species is uncommon. The present case involved a large freshwater stingray, Potamotrygon motoro (Chondrichthyes: Potamotrygonidae), in the Araguaia River in Tocantins, Brazil. Appropriate first aid was administered within ~15 min, except

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Freshwater stingrays cause many serious human injuries, but identification of the offending species is uncommon. The present case involved a large freshwater stingray, Potamotrygon motoro (Chondrichthyes: Potamotrygonidae), in the Araguaia River in Tocantins, Brazil. Appropriate first aid was administered within ~15 min, except that an ice pack was applied. Analgesics provided no pain relief, although hot compresses did. Ciprofloxacin therapy commenced after ~18 h and continued seven days. Then antibiotic was suspended; however, after two more days and additional tests, cephalosporin therapy was initiated, and proved successful. Pain worsened despite increasingly powerful analgesics, until debridement of the wound was performed after one month. The wound finally closed ~70 days after the accident, but the patient continued to have problems wearing shoes even eight months later. Chemistry and pharmacology of Potamotrygon venom and mucus, and clinical management of freshwater stingray envenomations are reviewed in light of the present case. Bacterial infections of stingray puncture wounds may account for more long-term morbidity than stingray venom. Simultaneous prophylactic use of multiple antibiotics is recommended for all but the most superficial stingray wounds. Distinguishing relative contributions of venom, mucus, and bacteria will require careful genomic and transcriptomic investigations of stingray tissues and contaminating bacteria. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Sulfated Galactan from Palisada flagellifera Inhibits Toxic Effects of Lachesis muta Snake Venom

by Ana Cláudia Rodrigues da Silva, Luciana Garcia Ferreira, Maria Eugênia Rabello Duarte, Miguel Daniel Noseda, Eladio Flores Sanchez and André Lopes Fuly

Mar. Drugs 2015, 13(6), 3761-3775; doi:10.3390/md13063761

Received: 8 April 2015 / Revised: 20 May 2015 / Accepted: 25 May 2015 / Published: 11 June 2015

Cited by 2 | Viewed by 1153 | PDF Full-text (639 KB) | HTML Full-text | XML Full-text

Abstract

In Brazil, snakebites are a public health problem and accidents caused by Lachesis muta have the highest mortality index. Envenomation by L. muta is characterized by systemic (hypotension, bleeding and renal failure) and local effects (necrosis, pain and edema). The treatment to reverse

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In Brazil, snakebites are a public health problem and accidents caused by Lachesis muta have the highest mortality index. Envenomation by L. muta is characterized by systemic (hypotension, bleeding and renal failure) and local effects (necrosis, pain and edema). The treatment to reverse the evolution of all the toxic effects is performed by injection of antivenom. However, such therapy does not effectively neutralize tissue damage or any other local effect, since in most cases victims delay seeking appropriate medical care. In this way, alternative therapies are in demand, and molecules from natural sources have been exhaustively tested. In this paper, we analyzed the inhibitory effect of a sulfated galactan obtained from the red seaweed Palisada flagellifera against some toxic activities of L. muta venom. Incubation of sulfated galactan with venom resulted in inhibition of hemolysis, coagulation, proteolysis, edema and hemorrhage. Neutralization of hemorrhage was also observed when the galactan was administered after or before the venom injection; thus mimicking a real in vivo situation. Moreover, the galactan blocked the edema caused by a phospholipase A₂ isolated from the same venom. Therefore, the galactan from P. flagellifera may represent a promising tool to treat envenomation by L. muta as a coadjuvant for the conventional antivenom. Full article

(This article belongs to the Special Issue Marine Secondary Metabolites)

Open AccessArticle AaeAP1 and AaeAP2: Novel Antimicrobial Peptides from the Venom of the Scorpion, Androctonus aeneas: Structural Characterisation, Molecular Cloning of Biosynthetic Precursor-Encoding cDNAs and Engineering of Analogues with Enhanced Antimicrobial and Anticancer Activities

by Qiang Du, Xiaojuan Hou, Lei Wang, Yingqi Zhang, Xinping Xi, Hui Wang, Mei Zhou, Jinao Duan, Minjie Wei, Tianbao Chen and Chris Shaw

Toxins 2015, 7(2), 219-237; doi:10.3390/toxins7020219

Received: 6 December 2014 / Accepted: 19 January 2015 / Published: 23 January 2015

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Abstract

The main functions of the abundant polypeptide toxins present in scorpion venoms are the debilitation of arthropod prey or defence against predators. These effects are achieved mainly through the blocking of an array of ion channel types within the membranes of excitable cells.

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The main functions of the abundant polypeptide toxins present in scorpion venoms are the debilitation of arthropod prey or defence against predators. These effects are achieved mainly through the blocking of an array of ion channel types within the membranes of excitable cells. However, while these ion channel-blocking toxins are tightly-folded by multiple disulphide bridges between cysteine residues, there are additional groups of peptides in the venoms that are devoid of cysteine residues. These non-disulphide bridged peptides are the subject of much research interest, and among these are peptides that exhibit antimicrobial activity. Here, we describe two novel non-disulphide-bridged antimicrobial peptides that are present in the venom of the North African scorpion, Androctonus aeneas. The cDNAs encoding the biosynthetic precursors of both peptides were cloned from a venom-derived cDNA library using 3'- and 5'-RACE strategies. Both translated precursors contained open-reading frames of 74 amino acid residues, each encoding one copy of a putative novel nonadecapeptide, whose primary structures were FLFSLIPSVIAGLVSAIRN and FLFSLIPSAIAGLVSAIRN, respectively. Both peptides were C-terminally amidated. Synthetic versions of each natural peptide displayed broad-spectrum antimicrobial activities, but were devoid of antiproliferative activity against human cancer cell lines. However, synthetic analogues of each peptide, engineered for enhanced cationicity and amphipathicity, exhibited increases in antimicrobial potency and acquired antiproliferative activity against a range of human cancer cell lines. These data clearly illustrate the potential that natural peptide templates provide towards the design of synthetic analogues for therapeutic exploitation. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Neuromuscular Activity of Micrurus laticollaris (Squamata: Elapidae) Venom in Vitro

by Alejandro Carbajal-Saucedo, Rafael Stuani Floriano, Cháriston André Dal Belo, Alejandro Olvera-Rodríguez, Alejandro Alagón and Léa Rodrigues-Simioni

Toxins 2014, 6(1), 359-370; doi:10.3390/toxins6010359

Received: 25 October 2013 / Revised: 20 December 2013 / Accepted: 30 December 2013 / Published: 17 January 2014

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Abstract

In this work, we have examined the neuromuscular activity of Micrurus laticollaris (Mexican coral snake) venom (MLV) in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations, the MLV induced an irreversible concentration- and time-dependent (1–30 µg/mL) neuromuscular blockade, with 50% blockade occurring

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In this work, we have examined the neuromuscular activity of Micrurus laticollaris (Mexican coral snake) venom (MLV) in vertebrate isolated nerve-muscle preparations. In chick biventer cervicis preparations, the MLV induced an irreversible concentration- and time-dependent (1–30 µg/mL) neuromuscular blockade, with 50% blockade occurring between 8 and 30 min. Muscle contractures evoked by exogenous acetylcholine were completely abolished by MLV, whereas those of KCl were also significantly altered (86% ± 11%, 53% ± 11%, 89% ± 5% and 89% ± 7% for one, three, 10 and 30 µg of venom/mL, respectively; n = 4; p < 0.05). In mouse phrenic nerve-diaphragm preparations, MLV (1–10 µg/mL) promoted a slight increase in the amplitude of twitch-tension (3 µg/mL), followed by neuromuscular blockade (n = 4); the highest concentration caused complete inhibition of the twitches (time for 50% blockade = 26 ± 3 min), without exhibiting a previous neuromuscular facilitation. The venom (3 µg/mL) induced a biphasic modulation in the frequency of miniature end-plate potentials (MEPPs)/min, causing a significant increase after 15 min, followed by a decrease after 60 min (from 17 ± 1.4 (basal) to 28 ± 2.5 (t₁₅) and 12 ± 2 (t₆₀)). The membrane resting potential of mouse diaphragm preparations pre-exposed or not to d-tubocurarine (5 µg/mL) was also significantly less negative with MLV (10 µg/mL). Together, these results indicate that M. laticollaris venom induces neuromuscular blockade by a combination of pre- and post-synaptic activities. Full article

Open AccessArticle Three-Fingered RAVERs: Rapid Accumulation of Variations in Exposed Residues of Snake Venom Toxins

by Kartik Sunagar, Timothy N. W. Jackson, Eivind A. B. Undheim, Syed. A. Ali, Agostinho Antunes and Bryan G. Fry

Toxins 2013, 5(11), 2172-2208; doi:10.3390/toxins5112172

Received: 2 October 2013 / Revised: 8 November 2013 / Accepted: 11 November 2013 / Published: 18 November 2013

Abstract

Three-finger toxins (3FTx) represent one of the most abundantly secreted and potently toxic components of colubrid (Colubridae), elapid (Elapidae) and psammophid (Psammophiinae subfamily of the Lamprophidae) snake venom arsenal. Despite their conserved structural similarity, they perform a diversity of biological functions. Although they

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Three-finger toxins (3FTx) represent one of the most abundantly secreted and potently toxic components of colubrid (Colubridae), elapid (Elapidae) and psammophid (Psammophiinae subfamily of the Lamprophidae) snake venom arsenal. Despite their conserved structural similarity, they perform a diversity of biological functions. Although they are theorised to undergo adaptive evolution, the underlying diversification mechanisms remain elusive. Here, we report the molecular evolution of different 3FTx functional forms and show that positively selected point mutations have driven the rapid evolution and diversification of 3FTx. These diversification events not only correlate with the evolution of advanced venom delivery systems (VDS) in Caenophidia, but in particular the explosive diversification of the clade subsequent to the evolution of a high pressure, hollow-fanged VDS in elapids, highlighting the significant role of these toxins in the evolution of advanced snakes. We show that Type I, II and III α-neurotoxins have evolved with extreme rapidity under the influence of positive selection. We also show that novel Oxyuranus/Pseudonaja Type II forms lacking the apotypic loop-2 stabilising cysteine doublet characteristic of Type II forms are not phylogenetically basal in relation to other Type IIs as previously thought, but are the result of secondary loss of these apotypic cysteines on at least three separate occasions. Not all 3FTxs have evolved rapidly: κ-neurotoxins, which form non-covalently associated heterodimers, have experienced a relatively weaker influence of diversifying selection; while cytotoxic 3FTx, with their functional sites, dispersed over 40% of the molecular surface, have been extremely constrained by negative selection. We show that the a previous theory of 3FTx molecular evolution (termed ASSET) is evolutionarily implausible and cannot account for the considerable variation observed in very short segments of 3FTx. Instead, we propose a theory of Rapid Accumulation of Variations in Exposed Residues (RAVER) to illustrate the significance of point mutations, guided by focal mutagenesis and positive selection in the evolution and diversification of 3FTx. Full article

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

Open AccessArticle Atractaspis aterrima Toxins: The First Insight into the Molecular Evolution of Venom in Side-Stabbers

by Yves Terrat, Kartik Sunagar, Bryan G. Fry, Timothy N. W. Jackson, Holger Scheib, Rudy Fourmy, Marion Verdenaud, Guillaume Blanchet, Agostinho Antunes and Frederic Ducancel

Toxins 2013, 5(11), 1948-1964; doi:10.3390/toxins5111948

Received: 17 September 2013 / Revised: 19 October 2013 / Accepted: 22 October 2013 / Published: 28 October 2013

Abstract

Although snake venoms have been the subject of intense research, primarily because of their tremendous potential as a bioresource for design and development of therapeutic compounds, some specific groups of snakes, such as the genus Atractaspis, have been completely neglected. To date

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Although snake venoms have been the subject of intense research, primarily because of their tremendous potential as a bioresource for design and development of therapeutic compounds, some specific groups of snakes, such as the genus Atractaspis, have been completely neglected. To date only limited number of toxins, such as sarafotoxins have been well characterized from this lineage. In order to investigate the molecular diversity of venom from Atractaspis aterrima—the slender burrowing asp, we utilized a high-throughput transcriptomic approach completed with an original bioinformatics analysis pipeline. Surprisingly, we found that Sarafotoxins do not constitute the major ingredient of the transcriptomic cocktail; rather a large number of previously well-characterized snake venom-components were identified. Notably, we recovered a large diversity of three-finger toxins (3FTxs), which were found to have evolved under the significant influence of positive selection. From the normalized and non-normalized transcriptome libraries, we were able to evaluate the relative abundance of the different toxin groups, uncover rare transcripts, and gain new insight into the transcriptomic machinery. In addition to previously characterized toxin families, we were able to detect numerous highly-transcribed compounds that possess all the key features of venom-components and may constitute new classes of toxins. Full article

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

Open AccessArticle In Vitro Antiplasmodial Activity of Phospholipases A₂ and a Phospholipase Homologue Isolated from the Venom of the Snake Bothrops asper

by Juan Carlos Quintana Castillo, Leidy Johana Vargas, Cesar Segura, José María Gutiérrez and Juan Carlos Alarcón Pérez

Toxins 2012, 4(12), 1500-1516; doi:10.3390/toxins4121500

Received: 2 November 2012 / Revised: 23 November 2012 / Accepted: 30 November 2012 / Published: 14 December 2012

Cited by 7 | Viewed by 1991 | PDF Full-text (1639 KB) | HTML Full-text | XML Full-text

Abstract

The antimicrobial and antiparasite activity of phospholipase A₂ (PLA₂) from snakes and bees has been extensively explored. We studied the antiplasmodial effect of the whole venom of the snake Bothrops asper and of two fractions purified by ion-exchange chromatography: one

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The antimicrobial and antiparasite activity of phospholipase A₂ (PLA₂) from snakes and bees has been extensively explored. We studied the antiplasmodial effect of the whole venom of the snake Bothrops asper and of two fractions purified by ion-exchange chromatography: one containing catalytically-active phospholipases A₂ (PLA₂) (fraction V) and another containing a PLA₂ homologue devoid of enzymatic activity (fraction VI). The antiplasmodial effect was assessed on in vitro cultures of Plasmodium falciparum. The whole venom of B. asper, as well as its fractions V and VI, were active against the parasite at 0.13 ± 0.01 µg/mL, 1.42 ± 0.56 µg/mL and 22.89 ± 1.22 µg/mL, respectively. Differences in the cytotoxic activity on peripheral blood mononuclear cells between the whole venom and fractions V and VI were observed, fraction V showing higher toxicity than total venom and fraction VI. Regarding toxicity in mice, the whole venom showed the highest lethal effect in comparison to fractions V and VI. These results suggest that B. asper PLA₂ and its homologue have antiplasmodial potential. Full article

(This article belongs to the Special Issue Toxins as Therapeutics)

Open AccessReview Spider-Venom Peptides as Bioinsecticides

by Monique J. Windley, Volker Herzig, Sławomir A. Dziemborowicz, Margaret C. Hardy, Glenn F. King and Graham M. Nicholson

Toxins 2012, 4(3), 191-227; doi:10.3390/toxins4030191

Received: 31 January 2012 / Revised: 7 March 2012 / Accepted: 15 March 2012 / Published: 22 March 2012

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Abstract

Over 10,000 arthropod species are currently considered to be pest organisms. They are estimated to contribute to the destruction of ~14% of the world’s annual crop production and transmit many pathogens. Presently, arthropod pests of agricultural and health significance are controlled predominantly through

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Over 10,000 arthropod species are currently considered to be pest organisms. They are estimated to contribute to the destruction of ~14% of the world’s annual crop production and transmit many pathogens. Presently, arthropod pests of agricultural and health significance are controlled predominantly through the use of chemical insecticides. Unfortunately, the widespread use of these agrochemicals has resulted in genetic selection pressure that has led to the development of insecticide-resistant arthropods, as well as concerns over human health and the environment. Bioinsecticides represent a new generation of insecticides that utilise organisms or their derivatives (e.g., transgenic plants, recombinant baculoviruses, toxin-fusion proteins and peptidomimetics) and show promise as environmentally-friendly alternatives to conventional agrochemicals. Spider-venom peptides are now being investigated as potential sources of bioinsecticides. With an estimated 100,000 species, spiders are one of the most successful arthropod predators. Their venom has proven to be a rich source of hyperstable insecticidal mini-proteins that cause insect paralysis or lethality through the modulation of ion channels, receptors and enzymes. Many newly characterized insecticidal spider toxins target novel sites in insects. Here we review the structure and pharmacology of these toxins and discuss the potential of this vast peptide library for the discovery of novel bioinsecticides. Full article

(This article belongs to the Special Issue Insecticidal Toxins)

Open AccessReview Pharmacological Aspects of Vipera xantina palestinae Venom

by Tatjana Momic, Franziska T. Arlinghaus, Hadar Arien-Zakay, Jeoshua Katzhendler, Johannes A. Eble, Cezary Marcinkiewicz and Philip Lazarovici

Toxins 2011, 3(11), 1420-1432; doi:10.3390/toxins3111420

Received: 14 September 2011 / Revised: 3 October 2011 / Accepted: 1 November 2011 / Published: 14 November 2011

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Abstract

In Israel, Vipera xantina palestinae (V.x.p.) is the most common venomous snake, accounting for several hundred cases of envenomation in humans and domestic animals every year, with a mortality rate of 0.5 to 2%. In this review we will briefly address

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In Israel, Vipera xantina palestinae (V.x.p.) is the most common venomous snake, accounting for several hundred cases of envenomation in humans and domestic animals every year, with a mortality rate of 0.5 to 2%. In this review we will briefly address the research developments relevant to our present understanding of the structure and function of V.x.p. venom with emphasis on venom disintegrins. Venom proteomics indicated the presence of four families of pharmacologically active compounds: (i) neurotoxins; (ii) hemorrhagins; (iii) angioneurin growth factors; and (iv) different types of integrin inhibitors. Viperistatin, a α1β1selective KTS disintegrin and VP12, a α2β1 selective C-type lectin were discovered. These snake venom proteins represent promising tools for research and development of novel collagen receptor selective drugs. These discoveries are also relevant for future improvement of antivenom therapy towards V.x.p. envenomation. Full article

(This article belongs to the Special Issue Snake Venoms)

Open AccessReview Brown Spider (Loxosceles genus) Venom Toxins: Tools for Biological Purposes

by Olga Meiri Chaim, Dilza Trevisan-Silva, Daniele Chaves-Moreira, Ana Carolina M. Wille, Valéria Pereira Ferrer, Fernando Hitomi Matsubara, Oldemir Carlos Mangili, Rafael Bertoni da Silveira, Luiza Helena Gremski, Waldemiro Gremski, Andrea Senff-Ribeiro and Silvio Sanches Veiga

Toxins 2011, 3(3), 309-344; doi:10.3390/toxins3030309

Received: 21 December 2010 / Revised: 26 February 2011 / Accepted: 17 March 2011 / Published: 22 March 2011

Cited by 41 | Viewed by 5485 | PDF Full-text (398 KB) | HTML Full-text | XML Full-text

Abstract

Venomous animals use their venoms as tools for defense or predation. These venoms are complex mixtures, mainly enriched of proteic toxins or peptides with several, and different, biological activities. In general, spider venom is rich in biologically active molecules that are useful in

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Venomous animals use their venoms as tools for defense or predation. These venoms are complex mixtures, mainly enriched of proteic toxins or peptides with several, and different, biological activities. In general, spider venom is rich in biologically active molecules that are useful in experimental protocols for pharmacology, biochemistry, cell biology and immunology, as well as putative tools for biotechnology and industries. Spider venoms have recently garnered much attention from several research groups worldwide. Brown spider (Loxosceles genus) venom is enriched in low molecular mass proteins (5–40 kDa). Although their venom is produced in minute volumes (a few microliters), and contain only tens of micrograms of protein, the use of techniques based on molecular biology and proteomic analysis has afforded rational projects in the area and permitted the discovery and identification of a great number of novel toxins. The brown spider phospholipase-D family is undoubtedly the most investigated and characterized, although other important toxins, such as low molecular mass insecticidal peptides, metalloproteases and hyaluronidases have also been identified and featured in literature. The molecular pathways of the action of these toxins have been reported and brought new insights in the field of biotechnology. Herein, we shall see how recent reports describing discoveries in the area of brown spider venom have expanded biotechnological uses of molecules identified in these venoms, with special emphasis on the construction of a cDNA library for venom glands, transcriptome analysis, proteomic projects, recombinant expression of different proteic toxins, and finally structural descriptions based on crystallography of toxins. Full article

(This article belongs to the Special Issue Spider Venoms)

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Open AccessReview Procoagulant Adaptation of a Blood Coagulation Prothrombinase-like Enzyme Complex in Australian Elapid Venom

by Mettine H.A. Bos and Rodney M. Camire

Toxins 2010, 2(6), 1554-1567; doi:10.3390/toxins2061554

Received: 30 March 2010 / Revised: 4 June 2010 / Accepted: 17 June 2010 / Published: 18 June 2010

Cited by 5 | Viewed by 4421 | PDF Full-text (756 KB) | HTML Full-text | XML Full-text

Abstract

The macromolecular enzyme complex prothrombinase serves an indispensable role in blood coagulation as it catalyzes the conversion of prothrombin to thrombin, a key regulatory enzyme in the formation of a blood clot. Interestingly, a virtually identical enzyme complex is found in the venom

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The macromolecular enzyme complex prothrombinase serves an indispensable role in blood coagulation as it catalyzes the conversion of prothrombin to thrombin, a key regulatory enzyme in the formation of a blood clot. Interestingly, a virtually identical enzyme complex is found in the venom of some Australian elapid snakes, which is composed of a cofactor factor Va-component and a serine protease factor Xa-like subunit. This review will provide an overview of the identification and characterization of the venom prothrombinase complex and will discuss the rationale for its powerful procoagulant nature responsible for the potent hemostatic toxicity of the elapid venom. Full article

(This article belongs to the Special Issue Protein Toxins as Proteases)

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Open AccessReview Venom Proteins of the Parasitoid Wasp Nasonia vitripennis: Recent Discovery of an Untapped Pharmacopee

by Ellen L. Danneels, David B. Rivers and Dirk C. De Graaf

Toxins 2010, 2(4), 494-516; doi:10.3390/toxins2040494

Received: 18 February 2010 / Revised: 22 March 2010 / Accepted: 24 March 2010 / Published: 30 March 2010

Cited by 45 | Viewed by 5605 | PDF Full-text (642 KB) | HTML Full-text | XML Full-text

Abstract

Adult females of Nasonia vitripennis inject a venomous mixture into its host flies prior to oviposition. Recently, the entire genome of this ectoparasitoid wasp was sequenced, enabling the identification of 79 venom proteins. The next challenge will be to unravel their specific functions,

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Adult females of Nasonia vitripennis inject a venomous mixture into its host flies prior to oviposition. Recently, the entire genome of this ectoparasitoid wasp was sequenced, enabling the identification of 79 venom proteins. The next challenge will be to unravel their specific functions, but based on homolog studies, some predictions already can be made. Parasitization has an enormous impact on hosts physiology of which five major effects are discussed in this review: the impact on immune responses, induction of developmental arrest, increases in lipid levels, apoptosis and nutrient releases. The value of deciphering this venom is also discussed. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessReview Inhibition of Hemorragic Snake Venom Components: Old and New Approaches

by Isabella Panfoli, Daniela Calzia, Silvia Ravera and Alessandro Morelli

Toxins 2010, 2(4), 417-427; doi:10.3390/toxins2040417

Received: 4 March 2010 / Revised: 22 March 2010 / Accepted: 23 March 2010 / Published: 25 March 2010

Cited by 13 | Viewed by 4781 | PDF Full-text (144 KB) | HTML Full-text | XML Full-text

Abstract

Snake venoms are complex toxin mixtures. Viperidae and Crotalidae venoms, which are hemotoxic, are responsible for most of the envenomations around the world. Administration of antivenins aimed at the neutralization of toxins in humans is prone to potential risks. Neutralization of snake venom

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Snake venoms are complex toxin mixtures. Viperidae and Crotalidae venoms, which are hemotoxic, are responsible for most of the envenomations around the world. Administration of antivenins aimed at the neutralization of toxins in humans is prone to potential risks. Neutralization of snake venom toxins has been achieved through different approaches: plant extracts have been utilized in etnomedicine. Direct electric current from low voltage showed neutralizing properties against venom phospholipase A2 and metalloproteases. This mini-review summarizes new achievements in venom key component inhibition. A deeper knowledge of alternative ways to inhibit venom toxins may provide supplemental treatments to serum therapy. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessReview Structure and Function of Snake Venom Proteins Affecting Platelet Plug Formation

by Taei Matsui, Jiharu Hamako and Koiti Titani

Toxins 2010, 2(1), 10-23; doi:10.3390/toxins2010010

Received: 1 December 2009 / Revised: 18 December 2009 / Accepted: 24 December 2009 / Published: 28 December 2009

Cited by 5 | Viewed by 6281 | PDF Full-text (2695 KB) | HTML Full-text | XML Full-text

Abstract

Many snake venom proteins have been isolated that affect platelet plug formation by interacting either with platelet integrins, membrane glycoprotein Ib (GPIb), or plasma von Willebrand factor (VWF). Among them, disintegrins purified from various snake venoms are strong inhibitors of platelet aggregation. Botrocetin

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Many snake venom proteins have been isolated that affect platelet plug formation by interacting either with platelet integrins, membrane glycoprotein Ib (GPIb), or plasma von Willebrand factor (VWF). Among them, disintegrins purified from various snake venoms are strong inhibitors of platelet aggregation. Botrocetin and bitiscetin derived from Bothrops jararaca and Bitis arietans venom, respectively, induce VWF-dependent platelet agglutination in vitro. Several GPIb-binding proteins have also been isolated from snake venoms. In this review, we focus on the structure and function of those snake venom proteins that influence platelet plug formation. These proteins are potentially useful as reagents for the sub-diagnosis of platelet disorder or von Willebrand disease, as well as for clinical and basic research of thrombosis and hemostasis. Full article

(This article belongs to the Special Issue Animal Venoms)

Open AccessArticle Molecular Docking Studies and Anti−Snake Venom Metalloproteinase Activity of Thai Mango Seed Kernel Extract

by Pimolpan Pithayanukul, Jiraporn Leanpolchareanchai and Patchreenart Saparpakorn

Molecules 2009, 14(9), 3198-3213; doi:10.3390/molecules14093198

Received: 10 August 2009 / Revised: 21 August 2009 / Accepted: 25 August 2009 / Published: 27 August 2009

Cited by 24 | Viewed by 7137 | PDF Full-text (1693 KB)

Abstract

Snakebite envenomations cause severe local tissue necrosis and the venom metalloproteinases are thought to be the key toxins involved. In this study, the ethanolic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle

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Snakebite envenomations cause severe local tissue necrosis and the venom metalloproteinases are thought to be the key toxins involved. In this study, the ethanolic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent and dose−dependent inhibitory effects on the caseinolytic and fibrinogenolytic activities of Malayan pit viper and Thai cobra venoms in in vitro tests. molecular docking studies revealed that the binding orientations of the phenolic principles were in the binding pockets of snake venom metalloproteinases (SVMPs). The phenolic principles could form hydrogen bonds with the three histidine residues in the conserved zinc−binding motif and could chelate the Zn²⁺ atom of the SVMPs, which could potentially result in inhibition of the venom enzymatic activities and thereby inhibit tissue necrosis. Full article

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