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Open AccessArticle Venomics of Remipede Crustaceans Reveals Novel Peptide Diversity and Illuminates the Venom’s Biological Role

by Björn M. von Reumont, Eivind A. B. Undheim, Robin-Tobias Jauss and Ronald A. Jenner

Toxins 2017, 9(8), 234; doi:10.3390/toxins9080234

Received: 27 June 2017 / Accepted: 24 July 2017 / Published: 26 July 2017

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Abstract

We report the first integrated proteomic and transcriptomic investigation of a crustacean venom. Remipede crustaceans are the venomous sister group of hexapods, and the venom glands of the remipede Xibalbanus tulumensis express a considerably more complex cocktail of proteins and peptides than previously

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We report the first integrated proteomic and transcriptomic investigation of a crustacean venom. Remipede crustaceans are the venomous sister group of hexapods, and the venom glands of the remipede Xibalbanus tulumensis express a considerably more complex cocktail of proteins and peptides than previously thought. We identified 32 venom protein families, including 13 novel peptide families that we name xibalbins, four of which lack similarities to any known structural class. Our proteomic data confirm the presence in the venom of 19 of the 32 families. The most highly expressed venom components are serine peptidases, chitinase and six of the xibalbins. The xibalbins represent Inhibitory Cystine Knot peptides (ICK), a double ICK peptide, peptides with a putative Cystine-stabilized α-helix/β-sheet motif, a peptide similar to hairpin-like β-sheet forming antimicrobial peptides, two peptides related to different hormone families, and four peptides with unique structural motifs. Remipede venom components represent the full range of evolutionary recruitment frequencies, from families that have been recruited into many animal venoms (serine peptidases, ICKs), to those having a very narrow taxonomic range (double ICKs), to those unique for remipedes. We discuss the most highly expressed venom components to shed light on their possible functional significance in the predatory and defensive use of remipede venom, and to provide testable ideas for any future bioactivity studies. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessFeature PaperArticle Third Generation Antivenomics: Pushing the Limits of the In Vitro Preclinical Assessment of Antivenoms

by Davinia Pla, Yania Rodríguez and Juan J. Calvete

Toxins 2017, 9(5), 158; doi:10.3390/toxins9050158

Received: 20 April 2017 / Revised: 5 May 2017 / Accepted: 5 May 2017 / Published: 10 May 2017

Abstract

Second generation antivenomics is a translational venomics approach designed to complement in vivo preclinical neutralization assays. It provides qualitative and quantitative information on the set of homologous and heterologous venom proteins presenting antivenom-recognized epitopes and those exhibiting impaired immunoreactivity. In a situation of

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Second generation antivenomics is a translational venomics approach designed to complement in vivo preclinical neutralization assays. It provides qualitative and quantitative information on the set of homologous and heterologous venom proteins presenting antivenom-recognized epitopes and those exhibiting impaired immunoreactivity. In a situation of worrying antivenom shortage in many tropical and sub-tropical regions with high snakebite mortality and morbidity rates, such knowledge has the potential to facilitate the optimal deployment of currently existing antivenoms and to aid in the rational design of novel broad specificity antidotes. The aim of the present work was to expand the analytical capability of the immunoaffinity second-generation antivenomics platform, endowing it with the ability to determine the maximal binding capacity of an antivenom toward the different toxins present in a venom, and to quantify the fraction of venom-specific antibodies present in a given antivenom. The application of this new platform, termed third generation (3G) antivenomics, in the preclinical evaluation of antivenoms is illustrated in this paper for the case of antivenom EchiTAb-Plus-ICP^® reactivity towards the toxins of homologous (B. arietans) and heterologous (N. melanoleuca) venoms. Full article

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

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Open AccessFeature PaperReview Antivenom for Neuromuscular Paralysis Resulting From Snake Envenoming

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

Toxins 2017, 9(4), 143; doi:10.3390/toxins9040143

Received: 22 March 2017 / Revised: 11 April 2017 / Accepted: 13 April 2017 / Published: 19 April 2017

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Abstract

Antivenom therapy is currently the standard practice for treating neuromuscular dysfunction in snake envenoming. We reviewed the clinical and experimental evidence-base for the efficacy and effectiveness of antivenom in snakebite neurotoxicity. The main site of snake neurotoxins is the neuromuscular junction, and the

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Antivenom therapy is currently the standard practice for treating neuromuscular dysfunction in snake envenoming. We reviewed the clinical and experimental evidence-base for the efficacy and effectiveness of antivenom in snakebite neurotoxicity. The main site of snake neurotoxins is the neuromuscular junction, and the majority are either: (1) pre-synaptic neurotoxins irreversibly damaging the presynaptic terminal; or (2) post-synaptic neurotoxins that bind to the nicotinic acetylcholine receptor. Pre-clinical tests of antivenom efficacy for neurotoxicity include rodent lethality tests, which are problematic, and in vitro pharmacological tests such as nerve-muscle preparation studies, that appear to provide more clinically meaningful information. We searched MEDLINE (from 1946) and EMBASE (from 1947) until March 2017 for clinical studies. The search yielded no randomised placebo-controlled trials of antivenom for neuromuscular dysfunction. There were several randomised and non-randomised comparative trials that compared two or more doses of the same or different antivenom, and numerous cohort studies and case reports. The majority of studies available had deficiencies including poor case definition, poor study design, small sample size or no objective measures of paralysis. A number of studies demonstrated the efficacy of antivenom in human envenoming by clearing circulating venom. Studies of snakes with primarily pre-synaptic neurotoxins, such as kraits (Bungarus spp.) and taipans (Oxyuranus spp.) suggest that antivenom does not reverse established neurotoxicity, but early administration may be associated with decreased severity or prevent neurotoxicity. Small studies of snakes with mainly post-synaptic neurotoxins, including some cobra species (Naja spp.), provide preliminary evidence that neurotoxicity may be reversed with antivenom, but placebo controlled studies with objective outcome measures are required to confirm this. Full article

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

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Open AccessArticle Cubozoan Sting-Site Seawater Rinse, Scraping, and Ice Can Increase Venom Load: Upending Current First Aid Recommendations

by Angel Anne Yanagihara and Christie L. Wilcox

Toxins 2017, 9(3), 105; doi:10.3390/toxins9030105

Received: 3 February 2017 / Revised: 9 March 2017 / Accepted: 13 March 2017 / Published: 15 March 2017

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Abstract

Cnidarian envenomations are the leading cause of severe and lethal human sting injuries from marine life. The total amount of venom discharged into sting-site tissues, sometimes referred to as “venom load”, has been previously shown to correlate with tentacle contact length and sequelae

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Cnidarian envenomations are the leading cause of severe and lethal human sting injuries from marine life. The total amount of venom discharged into sting-site tissues, sometimes referred to as “venom load”, has been previously shown to correlate with tentacle contact length and sequelae severity. Since <1% of cnidae discharge upon initial tentacle contact, effective and safe removal of adherent tentacles is of paramount importance in the management of life-threatening cubozoan stings. We evaluated whether common rinse solutions or scraping increased venom load as measured in a direct functional assay of venom activity (hemolysis). Scraping significantly increased hemolysis by increasing cnidae discharge. For Alatina alata, increases did not occur if the tentacles were first doused with vinegar or if heat was applied. However, in Chironex fleckeri, vinegar dousing and heat treatment were less effective, and the best outcomes occurred with the use of venom-inhibiting technologies (Sting No More^® products). Seawater rinsing, considered a “no-harm” alternative, significantly increased venom load. The application of ice severely exacerbated A. alata stings, but had a less pronounced effect on C. fleckeri stings, while heat application markedly reduced hemolysis for both species. Our results do not support scraping or seawater rinsing to remove adherent tentacles. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle The Cardiovascular and Neurotoxic Effects of the Venoms of Six Bony and Cartilaginous Fish Species

by Han Han, Kate Baumann, Nicholas R. Casewell, Syed A. Ali, James Dobson, Ivan Koludarov, Jordan Debono, Scott C. Cutmore, Niwanthi W. Rajapakse, Timothy N. W. Jackson, Rob Jones, Wayne C. Hodgson, Bryan G. Fry and Sanjaya Kuruppu

Toxins 2017, 9(2), 67; doi:10.3390/toxins9020067

Received: 15 September 2016 / Accepted: 3 February 2017 / Published: 16 February 2017

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Abstract

Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii

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Fish venoms are often poorly studied, in part due to the difficulty in obtaining, extracting, and storing them. In this study, we characterize the cardiovascular and neurotoxic effects of the venoms from the following six species of fish: the cartilaginous stingrays Neotrygon kuhlii and Himantura toshi, and the bony fish Platycephalus fucus, Girella tricuspidata, Mugil cephalus, and Dentex tumifrons. All venoms (10–100 μg/kg, i.v.), except G. tricuspidata and P. fuscus, induced a biphasic response on mean arterial pressure (MAP) in the anesthetised rat. P. fucus venom exhibited a hypotensive response, while venom from G. tricuspidata displayed a single depressor response. All venoms induced cardiovascular collapse at 200 μg/kg, i.v. The in vitro neurotoxic effects of venom were examined using the chick biventer cervicis nerve‐muscle (CBCNM) preparation. N. kuhlii, H. toshi, and P. fucus venoms caused concentration‐dependent inhibition of indirect twitches in the CBCNM preparation. These three venoms also inhibited responses to exogenous acetylcholine (ACh) and carbachol (CCh), but not potassium chloride (KCl), indicating a post‐synaptic mode of action. Venom from G. tricuspidata, M. cephalus, and D. tumifrons had no significant effect on indirect twitches or agonist responses in the CBCNM. Our results demonstrate that envenoming by these species of fish may result in moderate cardiovascular and/or neurotoxic effects. Future studies aimed at identifying the molecules responsible for these effects could uncover potentially novel lead compounds for future pharmaceuticals, in addition to generating new knowledge about the evolutionary relationships between venomous animals. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Detection of Naja atra Cardiotoxin Using Adenosine-Based Molecular Beacon

by Yi-Jun Shi, Ying-Jung Chen, Wan-Ping Hu and Long-Sen Chang

Toxins 2017, 9(1), 24; doi:10.3390/toxins9010024

Received: 29 October 2016 / Revised: 2 January 2017 / Accepted: 4 January 2017 / Published: 7 January 2017

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Abstract

This study presents an adenosine (A)-based molecular beacon (MB) for selective detection of Naja atra cardiotoxin (CTX) that functions by utilizing the competitive binding between CTX and the poly(A) stem of MB to coralyne. The 5′- and 3′-end of MB were labeled with

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This study presents an adenosine (A)-based molecular beacon (MB) for selective detection of Naja atra cardiotoxin (CTX) that functions by utilizing the competitive binding between CTX and the poly(A) stem of MB to coralyne. The 5′- and 3′-end of MB were labeled with a reporter fluorophore and a non-fluorescent quencher, respectively. Coralyne induced formation of the stem-loop MB structure through A₂-coralyne-A₂ coordination, causing fluorescence signal turn-off due to fluorescence resonance energy transfer between the fluorophore and quencher. CTX3 could bind to coralyne. Moreover, CTX3 alone induced the folding of MB structure and quenching of MB fluorescence. Unlike that of snake venom α-neurotoxins, the fluorescence signal of coralyne-MB complexes produced a bell-shaped concentration-dependent curve in the presence of CTX3 and CTX isotoxins; a turn-on fluorescence signal was noted when CTX concentration was ≤80 nM, while a turn-off fluorescence signal was noted with a further increase in toxin concentrations. The fluorescence signal of coralyne-MB complexes yielded a bell-shaped curve in response to varying concentrations of N. atra crude venom but not those of Bungarus multicinctus and Protobothrops mucrosquamatus venoms. Moreover, N. nigricollis venom also functioned as N. atra venom to yield a bell-shaped concentration-dependent curve of MB fluorescence signal, again supporting that the hairpin-shaped MB could detect crude venoms containing CTXs. Taken together, our data validate that a platform composed of coralyne-induced stem-loop MB structure selectively detects CTXs. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Venom Gland Transcriptomic and Proteomic Analyses of the Enigmatic Scorpion Superstitionia donensis (Scorpiones: Superstitioniidae), with Insights on the Evolution of Its Venom Components

by Carlos E. Santibáñez-López, Jimena I. Cid-Uribe, Cesar V. F. Batista, Ernesto Ortiz and Lourival D. Possani

Toxins 2016, 8(12), 367; doi:10.3390/toxins8120367

Received: 25 October 2016 / Revised: 28 November 2016 / Accepted: 1 December 2016 / Published: 9 December 2016

Abstract

Venom gland transcriptomic and proteomic analyses have improved our knowledge on the diversity of the heterogeneous components present in scorpion venoms. However, most of these studies have focused on species from the family Buthidae. To gain insights into the molecular diversity of the

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Venom gland transcriptomic and proteomic analyses have improved our knowledge on the diversity of the heterogeneous components present in scorpion venoms. However, most of these studies have focused on species from the family Buthidae. To gain insights into the molecular diversity of the venom components of scorpions belonging to the family Superstitioniidae, one of the neglected scorpion families, we performed a transcriptomic and proteomic analyses for the species Superstitionia donensis. The total mRNA extracted from the venom glands of two specimens was subjected to massive sequencing by the Illumina protocol, and a total of 219,073 transcripts were generated. We annotated 135 transcripts putatively coding for peptides with identity to known venom components available from different protein databases. Fresh venom collected by electrostimulation was analyzed by LC-MS/MS allowing the identification of 26 distinct components with sequences matching counterparts from the transcriptomic analysis. In addition, the phylogenetic affinities of the found putative calcins, scorpines, La1-like peptides and potassium channel κ toxins were analyzed. The first three components are often reported as ubiquitous in the venom of different families of scorpions. Our results suggest that, at least calcins and scorpines, could be used as molecular markers in phylogenetic studies of scorpion venoms. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle Viperid Envenomation Wound Exudate Contributes to Increased Vascular Permeability via a DAMPs/TLR-4 Mediated Pathway

by Alexandra Rucavado, Carolina A. Nicolau, Teresa Escalante, Junho Kim, Cristina Herrera, José María Gutiérrez and Jay W. Fox

Toxins 2016, 8(12), 349; doi:10.3390/toxins8120349

Received: 4 October 2016 / Revised: 15 November 2016 / Accepted: 17 November 2016 / Published: 24 November 2016

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Abstract

Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate

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Viperid snakebite envenomation is characterized by inflammatory events including increase in vascular permeability. A copious exudate is generated in tissue injected with venom, whose proteomics analysis has provided insights into the mechanisms of venom-induced tissue damage. Hereby it is reported that wound exudate itself has the ability to induce increase in vascular permeability in the skin of mice. Proteomics analysis of exudate revealed the presence of cytokines and chemokines, together with abundant damage associated molecular pattern molecules (DAMPs) resulting from both proteolysis of extracellular matrix and cellular lysis. Moreover, significant differences in the amounts of cytokines/chemokines and DAMPs were detected between exudates collected 1 h and 24 h after envenomation, thus highlighting a complex temporal dynamic in the composition of exudate. Pretreatment of mice with Eritoran, an antagonist of Toll-like receptor 4 (TLR4), significantly reduced the exudate-induced increase in vascular permeability, thus suggesting that DAMPs might be acting through this receptor. It is hypothesized that an “Envenomation-induced DAMPs cycle of tissue damage” may be operating in viperid snakebite envenomation through which venom-induced tissue damage generates a variety of DAMPs which may further expand tissue alterations. Full article

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

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Open AccessArticle Proteomic Characterization and Comparison of Malaysian Tropidolaemus wagleri and Cryptelytrops purpureomaculatus Venom Using Shotgun-Proteomics

by Syafiq Asnawi Zainal Abidin, Pathmanathan Rajadurai, Md Ezharul Hoque Chowdhury, Muhamad Rusdi Ahmad Rusmili, Iekhsan Othman and Rakesh Naidu

Toxins 2016, 8(10), 299; doi:10.3390/toxins8100299

Received: 19 May 2016 / Revised: 11 October 2016 / Accepted: 11 October 2016 / Published: 18 October 2016

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Abstract

Tropidolaemus wagleri and Cryptelytrops purpureomaculatus are venomous pit viper species commonly found in Malaysia. Tandem mass spectrometry analysis of the crude venoms has detected different proteins in T. wagleri and C. purpureomaculatus. They were classified into 13 venom protein families consisting of

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Tropidolaemus wagleri and Cryptelytrops purpureomaculatus are venomous pit viper species commonly found in Malaysia. Tandem mass spectrometry analysis of the crude venoms has detected different proteins in T. wagleri and C. purpureomaculatus. They were classified into 13 venom protein families consisting of enzymatic and nonenzymatic proteins. Enzymatic families detected in T. wagleri and C. purpureomaculatus venom were snake venom metalloproteinase, phospholipase A₂, ʟ-amino acid oxidase, serine proteases, 5′-nucleotidase, phosphodiesterase, and phospholipase B. In addition, glutaminyl cyclotransferase was detected in C. purpureomaculatus. C-type lectin-like proteins were common nonenzymatic components in both species. Waglerin was present and unique to T. wagleri—it was not in C. purpureomaculatus venom. In contrast, cysteine-rich secretory protein, bradykinin-potentiating peptide, and C-type natriuretic peptide were present in C. purpureomaculatus venom. Composition of the venom proteome of T. wagleri and C. purpureomaculatus provides useful information to guide production of effective antivenom and identification of proteins with potential therapeutic applications. Full article

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

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Open AccessCommunication Varespladib (LY315920) Appears to Be a Potent, Broad-Spectrum, Inhibitor of Snake Venom Phospholipase A2 and a Possible Pre-Referral Treatment for Envenomation

by Matthew Lewin, Stephen Samuel, Janie Merkel and Philip Bickler

Toxins 2016, 8(9), 248; doi:10.3390/toxins8090248

Received: 17 June 2016 / Revised: 11 August 2016 / Accepted: 15 August 2016 / Published: 25 August 2016

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Abstract

Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because

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Snakebite remains a neglected medical problem of the developing world with up to 125,000 deaths each year despite more than a century of calls to improve snakebite prevention and care. An estimated 75% of fatalities from snakebite occur outside the hospital setting. Because phospholipase A2 (PLA2) activity is an important component of venom toxicity, we sought candidate PLA2 inhibitors by directly testing drugs. Surprisingly, varespladib and its orally bioavailable prodrug, methyl-varespladib showed high-level secretory PLA2 (sPLA2) inhibition at nanomolar and picomolar concentrations against 28 medically important snake venoms from six continents. In vivo proof-of-concept studies with varespladib had striking survival benefit against lethal doses of Micrurus fulvius and Vipera berus venom, and suppressed venom-induced sPLA2 activity in rats challenged with 100% lethal doses of M. fulvius venom. Rapid development and deployment of a broad-spectrum PLA2 inhibitor alone or in combination with other small molecule inhibitors of snake toxins (e.g., metalloproteases) could fill the critical therapeutic gap spanning pre-referral and hospital setting. Lower barriers for clinical testing of safety tested, repurposed small molecule therapeutics are a potentially economical and effective path forward to fill the pre-referral gap in the setting of snakebite. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Biotechnological Trends in Spider and Scorpion Antivenom Development

by Andreas Hougaard Laustsen, Mireia Solà, Emma Christine Jappe, Saioa Oscoz, Line Præst Lauridsen and Mikael Engmark

Toxins 2016, 8(8), 226; doi:10.3390/toxins8080226

Received: 14 June 2016 / Revised: 19 June 2016 / Accepted: 13 July 2016 / Published: 23 July 2016

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Abstract

Spiders and scorpions are notorious for their fearful dispositions and their ability to inject venom into prey and predators, causing symptoms such as necrosis, paralysis, and excruciating pain. Information on venom composition and the toxins present in these species is growing due to

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Spiders and scorpions are notorious for their fearful dispositions and their ability to inject venom into prey and predators, causing symptoms such as necrosis, paralysis, and excruciating pain. Information on venom composition and the toxins present in these species is growing due to an interest in using bioactive toxins from spiders and scorpions for drug discovery purposes and for solving crystal structures of membrane-embedded receptors. Additionally, the identification and isolation of a myriad of spider and scorpion toxins has allowed research within next generation antivenoms to progress at an increasingly faster pace. In this review, the current knowledge of spider and scorpion venoms is presented, followed by a discussion of all published biotechnological efforts within development of spider and scorpion antitoxins based on small molecules, antibodies and fragments thereof, and next generation immunization strategies. The increasing number of discovery and development efforts within this field may point towards an upcoming transition from serum-based antivenoms towards therapeutic solutions based on modern biotechnology. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessReview Colubrid Venom Composition: An -Omics Perspective

by Inácio L. M. Junqueira-de-Azevedo, Pollyanna F. Campos, Ana T. C. Ching and Stephen P. Mackessy

Toxins 2016, 8(8), 230; doi:10.3390/toxins8080230

Received: 7 June 2016 / Revised: 4 July 2016 / Accepted: 8 July 2016 / Published: 23 July 2016

Abstract

Snake venoms have been subjected to increasingly sensitive analyses for well over 100 years, but most research has been restricted to front-fanged snakes, which actually represent a relatively small proportion of extant species of advanced snakes. Because rear-fanged snakes are a diverse and

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Snake venoms have been subjected to increasingly sensitive analyses for well over 100 years, but most research has been restricted to front-fanged snakes, which actually represent a relatively small proportion of extant species of advanced snakes. Because rear-fanged snakes are a diverse and distinct radiation of the advanced snakes, understanding venom composition among “colubrids” is critical to understanding the evolution of venom among snakes. Here we review the state of knowledge concerning rear-fanged snake venom composition, emphasizing those toxins for which protein or transcript sequences are available. We have also added new transcriptome-based data on venoms of three species of rear-fanged snakes. Based on this compilation, it is apparent that several components, including cysteine-rich secretory proteins (CRiSPs), C-type lectins (CTLs), CTLs-like proteins and snake venom metalloproteinases (SVMPs), are broadly distributed among “colubrid” venoms, while others, notably three-finger toxins (3FTxs), appear nearly restricted to the Colubridae (sensu stricto). Some putative new toxins, such as snake venom matrix metalloproteinases, are in fact present in several colubrid venoms, while others are only transcribed, at lower levels. This work provides insights into the evolution of these toxin classes, but because only a small number of species have been explored, generalizations are still rather limited. It is likely that new venom protein families await discovery, particularly among those species with highly specialized diets. Full article

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

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Open AccessArticle Respiratory Effects of Sarafotoxins from the Venom of Different Atractaspis Genus Snake Species

by Stéphanie Malaquin, Sam Bayat, Osama Abou Arab, Gilles Mourier, Emmanuel Lorne, Saïd Kamel, Hervé Dupont, Frédéric Ducancel and Yazine Mahjoub

Toxins 2016, 8(7), 215; doi:10.3390/toxins8070215

Received: 10 May 2016 / Revised: 23 June 2016 / Accepted: 4 July 2016 / Published: 11 July 2016

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Abstract

Sarafotoxins (SRTX) are endothelin-like peptides extracted from the venom of snakes belonging to the Atractaspididae family. A recent in vivo study on anesthetized and ventilated animals showed that sarafotoxin-b (SRTX-b), extracted from the venom of Atractaspis engaddensis, decreases cardiac output by inducing

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Sarafotoxins (SRTX) are endothelin-like peptides extracted from the venom of snakes belonging to the Atractaspididae family. A recent in vivo study on anesthetized and ventilated animals showed that sarafotoxin-b (SRTX-b), extracted from the venom of Atractaspis engaddensis, decreases cardiac output by inducing left ventricular dysfunction while sarafotoxin-m (SRTX-m), extracted from the venom of Atractaspis microlepidota microlepidota, induces right ventricular dysfunction with increased airway pressure. The aim of the present experimental study was to compare the respiratory effects of SRTX-m and SRTX-b. Male Wistar rats were anesthetized, tracheotomized and mechanically ventilated. They received either a 1 LD₅₀ IV bolus of SRTX-b (n = 5) or 1 LD₅₀ of SRTX-m (n = 5). The low-frequency forced oscillation technique was used to measure respiratory impedance. Airway resistance (Raw), parenchymal damping (G) and elastance (H) were determined from impedance data, before and 5 min after SRTX injection. SRTX-m and SRTX-b injections induced acute hypoxia and metabolic acidosis with an increased anion gap. Both toxins markedly increased Raw, G and H, but with a much greater effect of SRTX-b on H, which may have been due to pulmonary edema in addition to bronchoconstriction. Therefore, despite their structural analogy, these two toxins exert different effects on respiratory function. These results emphasize the role of the C-terminal extension in the in vivo effect of these toxins. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Tempo and Mode of the Evolution of Venom and Poison in Tetrapods

by Richard J. Harris and Kevin Arbuckle

Toxins 2016, 8(7), 193; doi:10.3390/toxins8070193

Received: 27 April 2016 / Revised: 7 June 2016 / Accepted: 14 June 2016 / Published: 23 June 2016

Abstract

Toxic weaponry in the form of venom and poison has evolved in most groups of animals, including all four major lineages of tetrapods. Moreover, the evolution of such traits has been linked to several key aspects of the biology of toxic animals including

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Toxic weaponry in the form of venom and poison has evolved in most groups of animals, including all four major lineages of tetrapods. Moreover, the evolution of such traits has been linked to several key aspects of the biology of toxic animals including life-history and diversification. Despite this, attempts to investigate the macroevolutionary patterns underlying such weaponry are lacking. In this study we analyse patterns of venom and poison evolution across reptiles, amphibians, mammals, and birds using a suite of phylogenetic comparative methods. We find that each major lineage has a characteristic pattern of trait evolution, but mammals and reptiles evolve under a surprisingly similar regime, whilst that of amphibians appears to be particularly distinct and highly contrasting compared to other groups. Our results also suggest that the mechanism of toxin acquisition may be an important distinction in such evolutionary patterns; the evolution of biosynthesis is far less dynamic than that of sequestration of toxins from the diet. Finally, contrary to the situation in amphibians, other tetrapod groups show an association between the evolution of toxic weaponry and higher diversification rates. Taken together, our study provides the first broad-scale analysis of macroevolutionary patterns of venom and poison throughout tetrapods. Full article

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

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Open AccessArticle Venomic Analysis of the Poorly Studied Desert Coral Snake, Micrurus tschudii tschudii, Supports the 3FTx/PLA₂ Dichotomy across Micrurus Venoms

by Libia Sanz, Davinia Pla, Alicia Pérez, Yania Rodríguez, Alfonso Zavaleta, Maria Salas, Bruno Lomonte and Juan J. Calvete

Toxins 2016, 8(6), 178; doi:10.3390/toxins8060178

Received: 23 March 2016 / Revised: 17 May 2016 / Accepted: 1 June 2016 / Published: 7 June 2016

Abstract

The venom proteome of the poorly studied desert coral snake Micrurus tschudii tschudii was unveiled using a venomic approach, which identified ≥38 proteins belonging to only four snake venom protein families. The three-finger toxins (3FTxs) constitute, both in number of isoforms (~30) and

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The venom proteome of the poorly studied desert coral snake Micrurus tschudii tschudii was unveiled using a venomic approach, which identified ≥38 proteins belonging to only four snake venom protein families. The three-finger toxins (3FTxs) constitute, both in number of isoforms (~30) and total abundance (93.6% of the venom proteome), the major protein family of the desert coral snake venom. Phospholipases A₂ (PLA₂s; seven isoforms, 4.1% of the venom proteome), 1–3 Kunitz-type proteins (1.6%), and 1–2 l-amino acid oxidases (LAO, 0.7%) complete the toxin arsenal of M. t. tschudii. Our results add to the growing evidence that the occurrence of two divergent venom phenotypes, i.e., 3FTx- and PLA₂-predominant venom proteomes, may constitute a general trend across the cladogenesis of Micrurus. The occurrence of a similar pattern of venom phenotypic variability among true sea snake (Hydrophiinae) venoms suggests that the 3FTx/PLA₂ dichotomy may be widely distributed among Elapidae venoms. Full article

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

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Open AccessArticle Analysis of Protein Composition and Bioactivity of Neoponera villosa Venom (Hymenoptera: Formicidae)

by Wallace Felipe Blohem Pessoa, Ludimilla Carvalho Cerqueira Silva, Leila de Oliveira Dias, Jacques Hubert Charles Delabie, Helena Costa and Carla Cristina Romano

Int. J. Mol. Sci. 2016, 17(4), 513; doi:10.3390/ijms17040513

Received: 24 February 2016 / Revised: 23 March 2016 / Accepted: 30 March 2016 / Published: 21 April 2016

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Abstract

Ants cause a series of accidents involving humans. Such accidents generate different reactions in the body, ranging from a mild irritation at the bite site to anaphylactic shock, and these reactions depend on the mechanism of action of the venom. The study of

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Ants cause a series of accidents involving humans. Such accidents generate different reactions in the body, ranging from a mild irritation at the bite site to anaphylactic shock, and these reactions depend on the mechanism of action of the venom. The study of animal venom is a science known as venomics. Through venomics, the composition of the venom of several ant species has already been characterized and their biological activities described. Thus, the aim of this study was to evaluate the protein composition and biological activities (hemolytic and immunostimulatory) of the venom of Neoponera villosa (N. villosa), an ant widely distributed in South America. The protein composition was evaluated by proteomic techniques, such as two-dimensional electrophoresis. To assess the biological activity, hemolysis assay was carried out and cytokines were quantified after exposure of macrophages to the venom. The venom of N. villosa has a profile composed of 145 proteins, including structural and metabolic components (e.g., tubulin and ATPase), allergenic and immunomodulatory proteins (arginine kinase and heat shock proteins (HSPs)), protective proteins of venom (superoxide dismutase (SOD) and catalase) and tissue degradation proteins (hyaluronidase and phospholipase A2). The venom was able to induce hemolysis in human erythrocytes and also induced release of both pro-inflammatory cytokines, as the anti-inflammatory cytokine release by murine macrophages. These results allow better understanding of the composition and complexity of N. villosa venom in the human body, as well as the possible mechanisms of action after the bite. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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Open AccessFeature PaperReview From Mollusks to Medicine: A Venomics Approach for the Discovery and Characterization of Therapeutics from Terebridae Peptide Toxins

by Aida Verdes, Prachi Anand, Juliette Gorson, Stephen Jannetti, Patrick Kelly, Abba Leffler, Danny Simpson, Girish Ramrattan and Mandë Holford

Toxins 2016, 8(4), 117; doi:10.3390/toxins8040117

Received: 3 March 2016 / Revised: 6 April 2016 / Accepted: 7 April 2016 / Published: 19 April 2016

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Abstract

Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this

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Animal venoms comprise a diversity of peptide toxins that manipulate molecular targets such as ion channels and receptors, making venom peptides attractive candidates for the development of therapeutics to benefit human health. However, identifying bioactive venom peptides remains a significant challenge. In this review we describe our particular venomics strategy for the discovery, characterization, and optimization of Terebridae venom peptides, teretoxins. Our strategy reflects the scientific path from mollusks to medicine in an integrative sequential approach with the following steps: (1) delimitation of venomous Terebridae lineages through taxonomic and phylogenetic analyses; (2) identification and classification of putative teretoxins through omics methodologies, including genomics, transcriptomics, and proteomics; (3) chemical and recombinant synthesis of promising peptide toxins; (4) structural characterization through experimental and computational methods; (5) determination of teretoxin bioactivity and molecular function through biological assays and computational modeling; (6) optimization of peptide toxin affinity and selectivity to molecular target; and (7) development of strategies for effective delivery of venom peptide therapeutics. While our research focuses on terebrids, the venomics approach outlined here can be applied to the discovery and characterization of peptide toxins from any venomous taxa. Full article

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

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Open AccessReview Venoms of Heteropteran Insects: A Treasure Trove of Diverse Pharmacological Toolkits

by Andrew A. Walker, Christiane Weirauch, Bryan G. Fry and Glenn F. King

Toxins 2016, 8(2), 43; doi:10.3390/toxins8020043

Received: 21 December 2015 / Revised: 25 January 2016 / Accepted: 26 January 2016 / Published: 12 February 2016

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Abstract

The piercing-sucking mouthparts of the true bugs (Insecta: Hemiptera: Heteroptera) have allowed diversification from a plant-feeding ancestor into a wide range of trophic strategies that include predation and blood-feeding. Crucial to the success of each of these strategies is the injection of venom.

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The piercing-sucking mouthparts of the true bugs (Insecta: Hemiptera: Heteroptera) have allowed diversification from a plant-feeding ancestor into a wide range of trophic strategies that include predation and blood-feeding. Crucial to the success of each of these strategies is the injection of venom. Here we review the current state of knowledge with regard to heteropteran venoms. Predaceous species produce venoms that induce rapid paralysis and liquefaction. These venoms are powerfully insecticidal, and may cause paralysis or death when injected into vertebrates. Disulfide-rich peptides, bioactive phospholipids, small molecules such as N,N-dimethylaniline and 1,2,5-trithiepane, and toxic enzymes such as phospholipase A₂, have been reported in predatory venoms. However, the detailed composition and molecular targets of predatory venoms are largely unknown. In contrast, recent research into blood-feeding heteropterans has revealed the structure and function of many protein and non-protein components that facilitate acquisition of blood meals. Blood-feeding venoms lack paralytic or liquefying activity but instead are cocktails of pharmacological modulators that disable the host haemostatic systems simultaneously at multiple points. The multiple ways venom is used by heteropterans suggests that further study will reveal heteropteran venom components with a wide range of bioactivities that may be recruited for use as bioinsecticides, human therapeutics, and pharmacological tools. Full article

(This article belongs to the Special Issue Arthropod Venoms)

Open AccessFeature PaperReview The Biochemical Toxin Arsenal from Ant Venoms

by Axel Touchard, Samira R. Aili, Eduardo Gonçalves Paterson Fox, Pierre Escoubas, Jérôme Orivel, Graham M. Nicholson and Alain Dejean

Toxins 2016, 8(1), 30; doi:10.3390/toxins8010030

Received: 22 December 2015 / Revised: 7 January 2016 / Accepted: 8 January 2016 / Published: 20 January 2016

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Abstract

Ants (Formicidae) represent a taxonomically diverse group of hymenopterans with over 13,000 extant species, the majority of which inject or spray secretions from a venom gland. The evolutionary success of ants is mostly due to their unique eusociality that has permitted them to

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Ants (Formicidae) represent a taxonomically diverse group of hymenopterans with over 13,000 extant species, the majority of which inject or spray secretions from a venom gland. The evolutionary success of ants is mostly due to their unique eusociality that has permitted them to develop complex collaborative strategies, partly involving their venom secretions, to defend their nest against predators, microbial pathogens, ant competitors, and to hunt prey. Activities of ant venom include paralytic, cytolytic, haemolytic, allergenic, pro-inflammatory, insecticidal, antimicrobial, and pain-producing pharmacologic activities, while non-toxic functions include roles in chemical communication involving trail and sex pheromones, deterrents, and aggregators. While these diverse activities in ant venoms have until now been largely understudied due to the small venom yield from ants, modern analytical and venomic techniques are beginning to reveal the diversity of toxin structure and function. As such, ant venoms are distinct from other venomous animals, not only rich in linear, dimeric and disulfide-bonded peptides and bioactive proteins, but also other volatile and non-volatile compounds such as alkaloids and hydrocarbons. The present review details the unique structures and pharmacologies of known ant venom proteinaceous and alkaloidal toxins and their potential as a source of novel bioinsecticides and therapeutic agents. Full article

(This article belongs to the Special Issue Arthropod Venoms)

Open AccessFeature PaperArticle Snake Venomics and Antivenomics of Bothrops diporus, a Medically Important Pitviper in Northeastern Argentina

by Carolina Gay, Libia Sanz, Juan J. Calvete and Davinia Pla

Toxins 2016, 8(1), 9; doi:10.3390/toxins8010009

Received: 17 November 2015 / Revised: 17 December 2015 / Accepted: 17 December 2015 / Published: 25 December 2015

Abstract

Snake species within genus Bothrops are responsible for more than 80% of the snakebites occurring in South America. The species that cause most envenomings in Argentina, B. diporus, is widely distributed throughout the country, but principally found in the Northeast, the region

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Snake species within genus Bothrops are responsible for more than 80% of the snakebites occurring in South America. The species that cause most envenomings in Argentina, B. diporus, is widely distributed throughout the country, but principally found in the Northeast, the region with the highest rates of snakebites. The venom proteome of this medically relevant snake was unveiled using a venomic approach. It comprises toxins belonging to fourteen protein families, being dominated by PI- and PIII-SVMPs, PLA₂ molecules, BPP-like peptides, L-amino acid oxidase and serine proteinases. This toxin profile largely explains the characteristic pathophysiological effects of bothropic snakebites observed in patients envenomed by B. diporus. Antivenomic analysis of the SAB antivenom (Instituto Vital Brazil) against the venom of B. diporus showed that this pentabothropic antivenom efficiently recognized all the venom proteins and exhibited poor affinity towards the small peptide (BPPs and tripeptide inhibitors of PIII-SVMPs) components of the venom. Full article

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

Open AccessReview Scorpions from Mexico: From Species Diversity to Venom Complexity

by Carlos E. Santibáñez-López, Oscar F. Francke, Carolina Ureta and Lourival D. Possani

Toxins 2016, 8(1), 2; doi:10.3390/toxins8010002

Received: 28 October 2015 / Revised: 25 November 2015 / Accepted: 9 December 2015 / Published: 24 December 2015

Abstract

Scorpions are among the oldest terrestrial arthropods, which are distributed worldwide, except for Antarctica and some Pacific islands. Scorpion envenomation represents a public health problem in several parts of the world. Mexico harbors the highest diversity of scorpions in the world, including some

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Scorpions are among the oldest terrestrial arthropods, which are distributed worldwide, except for Antarctica and some Pacific islands. Scorpion envenomation represents a public health problem in several parts of the world. Mexico harbors the highest diversity of scorpions in the world, including some of the world’s medically important scorpion species. The systematics and diversity of Mexican scorpion fauna has not been revised in the past decade; and due to recent and exhaustive collection efforts as part of different ongoing major revisionary systematic projects, our understanding of this diversity has changed compared with previous assessments. Given the presence of several medically important scorpion species, the study of their venom in the country is also important. In the present contribution, the diversity of scorpion species in Mexico is revised and updated based on several new systematic contributions; 281 different species are recorded. Commentaries on recent venomic, ecological and behavioral studies of Mexican scorpions are also provided. A list containing the most important peptides identified from 16 different species is included. A graphical representation of the different types of components found in these venoms is also revised. A map with hotspots showing the current knowledge on scorpion distribution and areas explored in Mexico is also provided. Full article

(This article belongs to the Special Issue Arthropod Venoms)

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Open AccessReview Recent Advances in Research on Widow Spider Venoms and Toxins

by Shuai Yan and Xianchun Wang

Toxins 2015, 7(12), 5055-5067; doi:10.3390/toxins7124862

Received: 2 August 2015 / Revised: 2 November 2015 / Accepted: 16 November 2015 / Published: 27 November 2015

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Abstract

Widow spiders have received much attention due to the frequently reported human and animal injures caused by them. Elucidation of the molecular composition and action mechanism of the venoms and toxins has vast implications in the treatment of latrodectism and in the neurobiology

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Widow spiders have received much attention due to the frequently reported human and animal injures caused by them. Elucidation of the molecular composition and action mechanism of the venoms and toxins has vast implications in the treatment of latrodectism and in the neurobiology and pharmaceutical research. In recent years, the studies of the widow spider venoms and the venom toxins, particularly the α-latrotoxin, have achieved many new advances; however, the mechanism of action of the venom toxins has not been completely clear. The widow spider is different from many other venomous animals in that it has toxic components not only in the venom glands but also in other parts of the adult spider body, newborn spiderlings, and even the eggs. More recently, the molecular basis for the toxicity outside the venom glands has been systematically investigated, with four proteinaceous toxic components being purified and preliminarily characterized, which has expanded our understanding of the widow spider toxins. This review presents a glance at the recent advances in the study on the venoms and toxins from the Latrodectus species. Full article

(This article belongs to the Special Issue Arthropod Venoms)

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Open AccessArticle Effect of Venom from the Jellyfish Nemopilema nomurai on the Silkworm Bombyx mori L.

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

Toxins 2015, 7(10), 3876-3886; doi:10.3390/toxins7103876

Received: 10 July 2015 / Revised: 12 September 2015 / Accepted: 17 September 2015 / Published: 24 September 2015

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Abstract

The silkworm Bombyx mori L. (B. mori) has a significant impact on the economy by producing more than 80% of the globally produced raw silk. The exposure of silkworm to pesticides may cause adverse effects on B. mori, such as

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The silkworm Bombyx mori L. (B. mori) has a significant impact on the economy by producing more than 80% of the globally produced raw silk. The exposure of silkworm to pesticides may cause adverse effects on B. mori, such as a reduction in the production and quality of silk. This study aims to assay the effect of venom from the jellyfish Nemopilema nomurai on growth, cuticle and acetylcholinesterase (AChE) activity of the silkworm B. mori by the leaf dipping method. The experimental results revealed that the four samples caused neither antifeeding nor a lethal effect on B. mori. The sample SFV inhibited B. mori growth after 6 days of treatment in a dose-dependent manner. The samples SFV, DSFV and Fr-1 inhibited the precipitation and synthesis of chitin in the cuticle after 12 and 14 days of treatment. In the case of the four samples, the AChE was significantly improved after 14 days of treatment. Full article

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

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Open AccessArticle Bee Venom Protects against Rotenone-Induced Cell Death in NSC34 Motor Neuron Cells

by So Young Jung, Kang-Woo Lee, Sun-Mi Choi and Eun Jin Yang

Toxins 2015, 7(9), 3715-3726; doi:10.3390/toxins7093715

Received: 8 July 2015 / Revised: 20 August 2015 / Accepted: 31 August 2015 / Published: 21 September 2015

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Abstract

Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine

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Rotenone, an inhibitor of mitochondrial complex I of the mitochondrial respiratory chain, is known to elevate mitochondrial reactive oxygen species and induce apoptosis via activation of the caspase-3 pathway. Bee venom (BV) extracted from honey bees has been widely used in oriental medicine and contains melittin, apamin, adolapin, mast cell-degranulating peptide, and phospholipase A₂. In this study, we tested the effects of BV on neuronal cell death by examining rotenone-induced mitochondrial dysfunction. NSC34 motor neuron cells were pretreated with 2.5 μg/mL BV and stimulated with 10 μM rotenone to induce cell toxicity. We assessed cell death by Western blotting using specific antibodies, such as phospho-ERK1/2, phospho-JNK, and cleaved capase-3 and performed an MTT assay for evaluation of cell death and mitochondria staining. Pretreatment with 2.5 μg/mL BV had a neuroprotective effect against 10 μM rotenone-induced cell death in NSC34 motor neuron cells. Pre-treatment with BV significantly enhanced cell viability and ameliorated mitochondrial impairment in rotenone-treated cellular model. Moreover, BV treatment inhibited the activation of JNK signaling and cleaved caspase-3 related to cell death and increased ERK phosphorylation involved in cell survival in rotenone-treated NSC34 motor neuron cells. Taken together, we suggest that BV treatment can be useful for protection of neurons against oxidative stress or neurotoxin-induced cell death. Full article

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

Open AccessArticle Partial Characterization of Venom from the Colombian Spider Phoneutria Boliviensis (Aranae:Ctenidae)

by Sebastian Estrada-Gomez, Leidy Johana Vargas Muñoz, Paula Lanchero and Cesar Segura Latorre

Toxins 2015, 7(8), 2872-2887; doi:10.3390/toxins7082872

Received: 1 April 2015 / Revised: 3 June 2015 / Accepted: 29 June 2015 / Published: 31 July 2015

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Abstract

We report on the first studies on the characterization of venom from Phoneutria boliviensis (Aranae:Ctenidae) (F. O. Pickard-Cambridge, 1897), done with Colombian species. After the electrostimulation extraction process, the venom showed physicochemical properties corresponding to a colorless and water-soluble liquid with a density

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We report on the first studies on the characterization of venom from Phoneutria boliviensis (Aranae:Ctenidae) (F. O. Pickard-Cambridge, 1897), done with Colombian species. After the electrostimulation extraction process, the venom showed physicochemical properties corresponding to a colorless and water-soluble liquid with a density of 0.86 mg/mL and 87% aqueous content. P. boliviensis venom and RP-HPLC fractions showed hemolytic activity and hydrolyzed the synthetic substrate 4-nitro-3-octanoyloxy-benzoic acid, indicating the presence of phospholipases A₂ enzymes. The electrophoretic profile showed an important protein content with molecular masses below 14 kDa, and differences between male and female protein content were also revealed. The RP-HPLC venom profile exposes differences between males and female content consistent with the electrophoretic profile. Five fractions collected from the RP-HPLC displayed significant larvicidal activity. Mass analysis indicates the presence of peptides ranging from 1047.71 to 3278.07 Da. Two peptides, Ctenitoxin-Pb48 and Ctenitoxin-Pb53, were partially identified using HPLC-nESI-MS/MS, which showed a high homology with other Ctenitoxins (family Tx3) from Phoneutria nigriventer, Phoneutria keyserlingi and Phoneutria reidyi affecting voltage-gated calcium receptors (Cav 1, 2.1, 2.2 and 2.3) and NMDA-glutamate receptors. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Bee Venom Acupuncture Augments Anti-Inflammation in the Peripheral Organs of hSOD1^G93A Transgenic Mice

by Sun-Hwa Lee, Sun-Mi Choi and Eun Jin Yang

Toxins 2015, 7(8), 2835-2844; doi:10.3390/toxins7082835

Received: 24 February 2015 / Accepted: 6 July 2015 / Published: 29 July 2015

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Abstract

Amyotrophic lateral sclerosis (ALS) includes progressively degenerated motor neurons in the brainstem, motor cortex, and spinal cord. Recent reports demonstrate the dysfunction of multiple organs, including the lungs, spleen, and liver, in ALS animals and patients. Bee venom acupuncture (BVA) has been used

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Amyotrophic lateral sclerosis (ALS) includes progressively degenerated motor neurons in the brainstem, motor cortex, and spinal cord. Recent reports demonstrate the dysfunction of multiple organs, including the lungs, spleen, and liver, in ALS animals and patients. Bee venom acupuncture (BVA) has been used for treating inflammatory diseases in Oriental Medicine. In a previous study, we demonstrated that BV prevented motor neuron death and increased anti-inflammation in the spinal cord of symptomatic hSOD1^G93A transgenic mice. In this study, we examined whether BVA’s effects depend on acupuncture point (ST36) in the organs, including the liver, spleen and kidney, of hSOD1^G93A transgenic mice. We found that BV treatment at ST36 reduces inflammation in the liver, spleen, and kidney compared with saline-treatment at ST36 and BV injected intraperitoneally in symptomatic hSOD1^G93A transgenic mice. Those findings suggest that BV treatment combined with acupuncture stimulation is more effective at reducing inflammation and increasing immune responses compared with only BV treatment, at least in an ALS animal model. Full article

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

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Open AccessArticle Repetitive Treatment with Diluted Bee Venom Attenuates the Induction of Below-Level Neuropathic Pain Behaviors in a Rat Spinal Cord Injury Model

by Suk-Yun Kang, Dae-Hyun Roh, Jung-Wan Choi, Yeonhee Ryu and Jang-Hern Lee

Toxins 2015, 7(7), 2571-2585; doi:10.3390/toxins7072571

Received: 11 May 2015 / Revised: 24 June 2015 / Accepted: 7 July 2015 / Published: 10 July 2015

Cited by 4 | Viewed by 1446 | PDF Full-text (331 KB) | HTML Full-text | XML Full-text

Abstract

The administration of diluted bee venom (DBV) into an acupuncture point has been utilized traditionally in Eastern medicine to treat chronic pain. We demonstrated previously that DBV has a potent anti-nociceptive efficacy in several rodent pain models. The present study was designed to

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The administration of diluted bee venom (DBV) into an acupuncture point has been utilized traditionally in Eastern medicine to treat chronic pain. We demonstrated previously that DBV has a potent anti-nociceptive efficacy in several rodent pain models. The present study was designed to examine the potential anti-nociceptive effect of repetitive DBV treatment in the development of below-level neuropathic pain in spinal cord injury (SCI) rats. DBV was applied into the Joksamli acupoint during the induction and maintenance phase following thoracic 13 (T13) spinal hemisection. We examined the effect of repetitive DBV stimulation on SCI-induced bilateral pain behaviors, glia expression and motor function recovery. Repetitive DBV stimulation during the induction period, but not the maintenance, suppressed pain behavior in the ipsilateral hind paw. Moreover, SCI-induced increase in spinal glia expression was also suppressed by repetitive DBV treatment in the ipsilateral dorsal spinal cord. Finally, DBV injection facilitated motor function recovery as indicated by the Basso–Beattie–Bresnahan rating score. These results indicate that the repetitive application of DBV during the induction phase not only decreased neuropathic pain behavior and glia expression, but also enhanced locomotor functional recovery after SCI. This study suggests that DBV acupuncture can be a potential clinical therapy for SCI management. Full article

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

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Open AccessArticle Analgesic Effects of Bee Venom Derived Phospholipase A₂ in a Mouse Model of Oxaliplatin-Induced Neuropathic Pain

by Dongxing Li, Younju Lee, Woojin Kim, Kyungjin Lee, Hyunsu Bae and Sun Kwang Kim

Toxins 2015, 7(7), 2422-2434; doi:10.3390/toxins7072422

Received: 15 May 2015 / Revised: 11 June 2015 / Accepted: 23 June 2015 / Published: 29 June 2015

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Abstract

A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various

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A single infusion of oxaliplatin, which is widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs that are triggered or aggravated when exposed to cold or mechanical stimuli. Bee Venom (BV) has been traditionally used in Korea to treat various pain symptoms. Our recent study demonstrated that BV alleviates oxaliplatin-induced cold allodynia in rats, via noradrenergic and serotonergic analgesic pathways. In this study, we have further investigated whether BV derived phospholipase A₂ (bvPLA₂) attenuates oxaliplatin-induced cold and mechanical allodynia in mice and its mechanism. The behavioral signs of cold and mechanical allodynia were evaluated by acetone and a von Frey hair test on the hind paw, respectively. The significant allodynia signs were observed from one day after an oxaliplatin injection (6 mg/kg, i.p.). Daily administration of bvPLA₂ (0.2 mg/kg, i.p.) for five consecutive days markedly attenuated cold and mechanical allodynia, which was more potent than the effect of BV (1 mg/kg, i.p.). The depletion of noradrenaline by an injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 50 mg/kg, i.p.) blocked the analgesic effect of bvPLA₂, whereas the depletion of serotonin by injecting DL-p-chlorophenylalanine (PCPA, 150 mg/kg, i.p.) for three successive days did not. Furthermore, idazoxan (α2-adrenegic receptor antagonist, 1 mg/kg, i.p.) completely blocked bvPLA₂-induced anti-allodynic action, whereas prazosin (α1-adrenegic antagonist, 10 mg/kg, i.p.) did not. These results suggest that bvPLA₂ treatment strongly alleviates oxaliplatin-induced acute cold and mechanical allodynia in mice through the activation of the noradrenergic system, via α2-adrenegic receptors, but not via the serotonergic system. Full article

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

Open AccessReview Therapeutic Effects of Bee Venom on Immunological and Neurological Diseases

by Deok-Sang Hwang, Sun Kwang Kim and Hyunsu Bae

Toxins 2015, 7(7), 2413-2421; doi:10.3390/toxins7072413

Received: 15 May 2015 / Revised: 16 May 2015 / Accepted: 24 June 2015 / Published: 29 June 2015

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Abstract

Bee Venom (BV) has long been used in Korea to relieve pain symptoms and to treat inflammatory diseases, such as rheumatoid arthritis. The underlying mechanisms of the anti-inflammatory and analgesic actions of BV have been proved to some extent. Additionally, recent clinical and

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Bee Venom (BV) has long been used in Korea to relieve pain symptoms and to treat inflammatory diseases, such as rheumatoid arthritis. The underlying mechanisms of the anti-inflammatory and analgesic actions of BV have been proved to some extent. Additionally, recent clinical and experimental studies have demonstrated that BV and BV-derived active components are applicable to a wide range of immunological and neurodegenerative diseases, including autoimmune diseases and Parkinson’s disease. These effects of BV are known to be mediated by modulating immune cells in the periphery, and glial cells and neurons in the central nervous system. This review will introduce the scientific evidence of the therapeutic effects of BV and its components on several immunological and neurological diseases, and describe their detailed mechanisms involved in regulating various immune responses and pathological changes in glia and neurons. Full article

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

Open AccessArticle Anti-Fibrotic Effect of Natural Toxin Bee Venom on Animal Model of Unilateral Ureteral Obstruction

by Hyun Jin An, Kyung Hyun Kim, Woo Ram Lee, Jung Yeon Kim, Sun Jae Lee, Sok Cheon Pak, Sang Mi Han and Kwan Kyu Park

Toxins 2015, 7(6), 1917-1928; doi:10.3390/toxins7061917

Received: 22 December 2014 / Revised: 27 April 2015 / Accepted: 1 May 2015 / Published: 29 May 2015

Cited by 2 | Viewed by 1422 | PDF Full-text (4328 KB) | HTML Full-text | XML Full-text

Abstract

Progressive renal fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Bee venom (BV) has been widely used as a traditional medicine for various diseases. However, the precise mechanism of BV in ameliorating the renal fibrosis is

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Progressive renal fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Bee venom (BV) has been widely used as a traditional medicine for various diseases. However, the precise mechanism of BV in ameliorating the renal fibrosis is not fully understood. To investigate the therapeutic effects of BV against unilateral ureteral obstruction (UUO)-induced renal fibrosis, BV was given intraperitoneally after ureteral ligation. At seven days after UUO surgery, the kidney tissues were collected for protein analysis and histologic examination. Histological observation revealed that UUO induced a considerable increase in the number of infiltrated inflammatory cells. However, BV treatment markedly reduced these reactions compared with untreated UUO mice. The expression levels of TNF-α and IL-1β were significantly reduced in BV treated mice compared with UUO mice. In addition, treatment with BV significantly inhibited TGF-β1 and fibronectin expression in UUO mice. Moreover, the expression of α-SMA was markedly withdrawn after treatment with BV. These findings suggest that BV attenuates renal fibrosis and reduces inflammatory responses by suppression of multiple growth factor-mediated pro-fibrotic genes. In conclusion, BV may be a useful therapeutic agent for the prevention of fibrosis that characterizes progression of chronic kidney disease. Full article

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

Open AccessArticle Honeybee (Apis mellifera) Venom Reinforces Viral Clearance during the Early Stage of Infection with Porcine Reproductive and Respiratory Syndrome Virus through the Up-Regulation of Th1-Specific Immune Responses

by Jin-A Lee, Yun-Mi Kim, Pung-Mi Hyun, Jong-Woon Jeon, Jin-Kyu Park, Guk-Hyun Suh, Bock-Gie Jung and Bong-Joo Lee

Toxins 2015, 7(5), 1837-1853; doi:10.3390/toxins7051837

Received: 9 February 2015 / Revised: 15 May 2015 / Accepted: 18 May 2015 / Published: 22 May 2015

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Abstract

Porcine reproductive and respiratory syndrome (PRRS) is a chronic and immunosuppressive viral disease that is responsible for substantial economic losses for the swine industry. Honeybee venom (HBV) is known to possess several beneficial biological properties, particularly, immunomodulatory effects. Therefore, this study aimed at

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Porcine reproductive and respiratory syndrome (PRRS) is a chronic and immunosuppressive viral disease that is responsible for substantial economic losses for the swine industry. Honeybee venom (HBV) is known to possess several beneficial biological properties, particularly, immunomodulatory effects. Therefore, this study aimed at evaluating the effects of HBV on the immune response and viral clearance during the early stage of infection with porcine reproductive and respiratory syndrome virus (PRRSV) in pigs. HBV was administered via three routes of nasal, neck, and rectal and then the pigs were inoculated with PRRSV intranasally. The CD4⁺/CD8⁺ cell ratio and levels of interferon (IFN)-γ and interleukin (IL)-12 were significantly increased in the HBV-administered healthy pigs via nasal and rectal administration. In experimentally PRRSV-challenged pigs with virus, the viral genome load in the serum, lung, bronchial lymph nodes and tonsil was significantly decreased, as was the severity of interstitial pneumonia, in the nasal and rectal administration group. Furthermore, the levels of Th1 cytokines (IFN-γ and IL-12) were significantly increased, along with up-regulation of pro-inflammatory cytokines (TNF-α and IL-1β) with HBV administration. Thus, HBV administration—especially via the nasal or rectal route—could be a suitable strategy for immune enhancement and prevention of PRRSV infection in pigs. Full article

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

Open AccessReview Bioactive Components in Fish Venoms

by Rebekah Ziegman and Paul Alewood

Toxins 2015, 7(5), 1497-1531; doi:10.3390/toxins7051497

Received: 8 April 2015 / Revised: 21 April 2015 / Accepted: 23 April 2015 / Published: 30 April 2015

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Abstract

Animal venoms are widely recognized excellent resources for the discovery of novel drug leads and physiological tools. Most are comprised of a large number of components, of which the enzymes, small peptides, and proteins are studied for their important bioactivities. However, in spite

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Animal venoms are widely recognized excellent resources for the discovery of novel drug leads and physiological tools. Most are comprised of a large number of components, of which the enzymes, small peptides, and proteins are studied for their important bioactivities. However, in spite of there being over 2000 venomous fish species, piscine venoms have been relatively underrepresented in the literature thus far. Most studies have explored whole or partially fractioned venom, revealing broad pharmacology, which includes cardiovascular, neuromuscular, cytotoxic, inflammatory, and nociceptive activities. Several large proteinaceous toxins, such as stonustoxin, verrucotoxin, and Sp-CTx, have been isolated from scorpaenoid fish. These form pores in cell membranes, resulting in cell death and creating a cascade of reactions that result in many, but not all, of the physiological symptoms observed from envenomation. Additionally, Natterins, a novel family of toxins possessing kininogenase activity have been found in toadfish venom. A variety of smaller protein toxins, as well as a small number of peptides, enzymes, and non-proteinaceous molecules have also been isolated from a range of fish venoms, but most remain poorly characterized. Many other bioactive fish venom components remain to be discovered and investigated. These represent an untapped treasure of potentially useful molecules. Full article

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

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Open AccessArticle The Effects of Bee Venom Acupuncture on the Central Nervous System and Muscle in an Animal hSOD1^G93A Mutant

by MuDan Cai, Sun-Mi Choi and Eun Jin Yang

Toxins 2015, 7(3), 846-858; doi:10.3390/toxins7030846

Received: 26 November 2014 / Revised: 17 February 2015 / Accepted: 3 March 2015 / Published: 13 March 2015

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Abstract

Amyotrophic lateral sclerosis (ALS) is caused by the degeneration of lower and upper motor neurons, leading to muscle paralysis and respiratory failure. However, there is no effective drug or therapy to treat ALS. Complementary and alternative medicine (CAM), including acupuncture, pharmacopuncture, herbal medicine,

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Amyotrophic lateral sclerosis (ALS) is caused by the degeneration of lower and upper motor neurons, leading to muscle paralysis and respiratory failure. However, there is no effective drug or therapy to treat ALS. Complementary and alternative medicine (CAM), including acupuncture, pharmacopuncture, herbal medicine, and massage is popular due to the significant limitations of conventional therapy. Bee venom acupuncture (BVA), also known as one of pharmacopunctures, has been used in Oriental medicine to treat inflammatory diseases. The purpose of this study is to investigate the effect of BVA on the central nervous system (CNS) and muscle in symptomatic hSOD1^G93A transgenic mice, an animal model of ALS. Our findings show that BVA at ST36 enhanced motor function and decreased motor neuron death in the spinal cord compared to that observed in hSOD1^G93A transgenic mice injected intraperitoneally (i.p.) with BV. Furthermore, BV treatment at ST36 eliminated signaling downstream of inflammatory proteins such as TLR4 in the spinal cords of symptomatic hSOD1^G93A transgenic mice. However, i.p. treatment with BV reduced the levels of TNF-α and Bcl-2 expression in the muscle hSOD1^G93A transgenic mice. Taken together, our findings suggest that BV pharmacopuncture into certain acupoints may act as a chemical stimulant to activate those acupoints and subsequently engage the endogenous immune modulatory system in the CNS in an animal model of ALS. Full article

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

Open AccessArticle Immunological Cross-Reactivity and Neutralisation of European Viper Venoms with the Monospecific Vipera berus Antivenom ViperaTAb

by Nicholas R. Casewell, Ibrahim Al-Abdulla, David Smith, Ruth Coxon and John Landon

Toxins 2014, 6(8), 2471-2482; doi:10.3390/toxins6082471

Received: 12 June 2014 / Revised: 13 August 2014 / Accepted: 13 August 2014 / Published: 19 August 2014

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Abstract

Medically important cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. The mainstay of snakebite therapy is polyclonal antibody therapy, referred to as antivenom. Here we investigate the capability of the monospecific V. berus antivenom,

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Medically important cases of snakebite in Europe are predominately caused by European vipers of the genus Vipera. The mainstay of snakebite therapy is polyclonal antibody therapy, referred to as antivenom. Here we investigate the capability of the monospecific V. berus antivenom, ViperaTAb^®, to cross-react with, and neutralise lethality induced by, a variety of European vipers. Using ELISA and immunoblotting, we find that ViperaTAb^® antibodies recognise and bind to the majority of toxic components found in the venoms of the Vipera species tested at comparably high levels to those observed with V. berus. Using in vivo pre-clinical efficacy studies, we demonstrate that ViperaTAb^® effectively neutralises lethality induced by V. berus, V. aspis, V. ammodytes and V. latastei venoms and at much higher levels than those outlined by regulatory pharmacopoeial guidelines. Notably, venom neutralisation was found to be superior to (V. berus, V. aspis and V. latastei), or as equally effective as (V. ammodytes), the monospecific V. ammodytes “Zagreb antivenom”, which has long been successfully used for treating European snake envenomings. This study suggests that ViperaTAb^® may be a valuable therapeutic product for treating snakebite by a variety of European vipers found throughout the continent. Full article

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

Open AccessArticle Cancer Cell Growth Inhibitory Effect of Bee Venom via Increase of Death Receptor 3 Expression and Inactivation of NF-kappa B in NSCLC Cells

by Kyung Eun Choi, Chul Ju Hwang, Sun Mi Gu, Mi Hee Park, Joo Hwan Kim, Joo Ho Park, Young Jin Ahn, Ji Young Kim, Min Jong Song, Ho Sueb Song, Sang-Bae Han and Jin Tae Hong

Toxins 2014, 6(8), 2210-2228; doi:10.3390/toxins6082210

Received: 8 April 2014 / Revised: 16 June 2014 / Accepted: 18 July 2014 / Published: 25 July 2014

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Abstract

Our previous findings have demonstrated that bee venom (BV) has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well

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Our previous findings have demonstrated that bee venom (BV) has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB) activity assay. BV (1–5 μg/mL) inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax) was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF)-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Intraspecific Variation of Centruroides Edwardsii Venom from Two Regions of Colombia

by Sebastián Estrada-Gómez, Nelson Ivan Cupitra, Walter Murillo Arango and Leidy Johana Vargas Muñoz

Toxins 2014, 6(7), 2082-2096; doi:10.3390/toxins6072082

Received: 4 April 2014 / Revised: 20 May 2014 / Accepted: 6 June 2014 / Published: 14 July 2014

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Abstract

We report the first description studies, partial characterization, and intraspecific difference of Centruroides edwardsii, Gervais 1843, venom. C. edwardsii from two Colombian regions (Antioquia and Tolima) were evaluated. Both venoms showed hemolytic activity, possibly dependent of enzymatic active phospholipases, and neither coagulant

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We report the first description studies, partial characterization, and intraspecific difference of Centruroides edwardsii, Gervais 1843, venom. C. edwardsii from two Colombian regions (Antioquia and Tolima) were evaluated. Both venoms showed hemolytic activity, possibly dependent of enzymatic active phospholipases, and neither coagulant nor proteolytic activities were observed. Venom electrophoretic profile showed significant differences between C. edwardsii venom from both regions. A high concentration of proteins with molecular masses between 31 kDa and 97.4 kDa, and an important concentration close or below 14.4 kDa were detected. RP-HPLC retention times between 38.2 min and 42.1 min, showed bands close to 14.4 kDa, which may correspond to phospholipases. RP-HPLC venom profile showed a well conserved region in both venoms between 7 and 17 min, after this, significant differences were detected. From Tolima region venom, 50 well-defined peaks were detected, while in the Antioquia region venom, 55 well-defined peaks were detected. Larvicidal activity was only detected in the C. edwardsii venom from Antioquia. No antimicrobial activity was observed using complete venom or RP-HPLC collected fractions of both venoms. Lethally activity (carried out on female albino swiss mice) was detected at doses over 19.2 mg/kg of crude venom. Toxic effects included distress, excitability, eye irritation and secretions, hyperventilation, ataxia, paralysis, and salivation. Full article

(This article belongs to the Section Animal Venoms)

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Open AccessArticle In Vitro Toxic Effects of Puff Adder (Bitis arietans) Venom, and Their Neutralization by Antivenom

by Steven Fernandez, Wayne Hodgson, Janeyuth Chaisakul, Rachelle Kornhauser, Nicki Konstantakopoulos, Alexander Ian Smith and Sanjaya Kuruppu

Toxins 2014, 6(5), 1586-1597; doi:10.3390/toxins6051586

Received: 24 November 2013 / Revised: 6 April 2014 / Accepted: 4 May 2014 / Published: 19 May 2014

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Abstract

This study investigated the in vitro toxic effects of Bitis arietans venom and the ability of antivenom produced by the South African Institute of Medical Research (SAIMR) to neutralize these effects. The venom (50 µg/mL) reduced nerve-mediated twitches of the chick biventer muscle

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This study investigated the in vitro toxic effects of Bitis arietans venom and the ability of antivenom produced by the South African Institute of Medical Research (SAIMR) to neutralize these effects. The venom (50 µg/mL) reduced nerve-mediated twitches of the chick biventer muscle to 19% ± 2% of initial magnitude (n = 4) within 2 h. This inhibitory effect of the venom was significantly attenuated by prior incubation of tissues with SAIMR antivenom (0.864 µg/µL; 67% ± 4%; P < 0.05; n = 3–5, unpaired t-test). Addition of antivenom at t₅₀ failed to prevent further inhibition or reverse the inhibition of twitches and responses to agonists. The myotoxic action of the venom (50 µg/mL) was evidenced by a decrease in direct twitches (30% ± 6% of the initial twitch magnitude) and increase in baseline tension (by 0.7 ± 0.3 g within 3 h) of the chick biventer. Antivenom failed to block these effects. Antivenom however prevented the venom induced cytotoxic effects on L6 skeletal muscle cells. Venom induced a marginal but significant reduction in plasma clotting times at concentrations above 7.8 µg/100 µL of plasma, indicating poor procoagulant effects. In addition, the results of western immunoblotting indicate strong immunoreactivity with venom proteins, thus warranting further detailed studies on the neutralization of the effects of individual venom toxins by antivenom. Full article

(This article belongs to the Section Animal Venoms)

Open AccessArticle Ophiophagus hannah Venom: Proteome, Components Bound by Naja kaouthia Antivenin and Neutralization by N. kaouthia Neurotoxin-Specific Human ScFv

by Witchuda Danpaiboon, Onrapak Reamtong, Nitat Sookrung, Watee Seesuay, Yuwaporn Sakolvaree, Jeeraphong Thanongsaksrikul, Fonthip Dong-din-on, Potjanee Srimanote, Kanyarat Thueng-in and Wanpen Chaicumpa

Toxins 2014, 6(5), 1526-1558; doi:10.3390/toxins6051526

Received: 15 February 2014 / Revised: 20 April 2014 / Accepted: 5 May 2014 / Published: 13 May 2014

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Abstract

Venomous snakebites are an important health problem in tropical and subtropical countries. King cobra (Ophiophagus hannah) is the largest venomous snake found in South and Southeast Asia. In this study, the O. hannah venom proteome and the venom components cross-reactive to

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Venomous snakebites are an important health problem in tropical and subtropical countries. King cobra (Ophiophagus hannah) is the largest venomous snake found in South and Southeast Asia. In this study, the O. hannah venom proteome and the venom components cross-reactive to N. kaouthia monospecific antivenin were studied. O. hannah venom consisted of 14 different protein families, including three finger toxins, phospholipases, cysteine-rich secretory proteins, cobra venom factor, muscarinic toxin, L-amino acid oxidase, hypothetical proteins, low cysteine protein, phosphodiesterase, proteases, vespryn toxin, Kunitz, growth factor activators and others (coagulation factor, endonuclease, 5’-nucleotidase). N. kaouthia antivenin recognized several functionally different O. hannah venom proteins and mediated paratherapeutic efficacy by rescuing the O. hannah envenomed mice from lethality. An engineered human ScFv specific to N. kaouthia long neurotoxin (NkLN-HuScFv) cross-neutralized the O. hannah venom and extricated the O. hannah envenomed mice from death in a dose escalation manner. Homology modeling and molecular docking revealed that NkLN-HuScFv interacted with residues in loops 2 and 3 of the neurotoxins of both snake species, which are important for neuronal acetylcholine receptor binding. The data of this study are useful for snakebite treatment when and where the polyspecific antivenin is not available. Because the supply of horse-derived antivenin is limited and the preparation may cause some adverse effects in recipients, a cocktail of recombinant human ScFvs for various toxic venom components shared by different venomous snakes, exemplified by the in vitro produced NkLN-HuScFv in this study, should contribute to a possible future route for an improved alternative to the antivenins. Full article

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

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Open AccessArticle An Isoflavone from Dipteryx alata Vogel is Active against the in Vitro Neuromuscular Paralysis of Bothrops jararacussu Snake Venom and Bothropstoxin I, and Prevents Venom-Induced Myonecrosis

by Miriéle C. Ferraz, Edson H. Yoshida, Renata V.S. Tavares, José C. Cogo, Adélia C.O. Cintra, Cháriston A. Dal Belo, Luiz M. Franco, Márcio G. dos Santos, Flávia A. Resende, Eliana A. Varanda, Stephen Hyslop, Pilar Puebla, Arturo San Feliciano and Yoko Oshima-Franco

Molecules 2014, 19(5), 5790-5805; doi:10.3390/molecules19055790

Received: 10 March 2014 / Revised: 22 April 2014 / Accepted: 24 April 2014 / Published: 6 May 2014

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Abstract

Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of

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Snakebite is a neglected disease and serious health problem in Brazil, with most bites being caused by snakes of the genus Bothrops. Although serum therapy is the primary treatment for systemic envenomation, it is generally ineffective in neutralizing the local effects of these venoms. In this work, we examined the ability of 7,8,3'-trihydroxy-4'-methoxyisoflavone (TM), an isoflavone from Dipteryx alata, to neutralize the neurotoxicity (in mouse phrenic nerve-diaphragm preparations) and myotoxicity (assessed by light microscopy) of Bothrops jararacussu snake venom in vitro. The toxicity of TM was assessed using the Salmonella microsome assay (Ames test). Incubation with TM alone (200 μg/mL) did not alter the muscle twitch tension whereas incubation with venom (40 μg/mL) caused irreversible paralysis. Preincubation of TM (200 μg/mL) with venom attenuated the venom-induced neuromuscular blockade by 84% ± 5% (mean ± SEM; n = 4). The neuromuscular blockade caused by bothropstoxin-I (BthTX-I), the major myotoxic PLA₂ of this venom, was also attenuated by TM. Histological analysis of diaphragm muscle incubated with TM showed that most fibers were preserved (only 9.2% ± 1.7% were damaged; n = 4) compared to venom alone (50.3% ± 5.4% of fibers damaged; n = 3), and preincubation of TM with venom significantly attenuated the venom-induced damage (only 17% ± 3.4% of fibers damaged; n = 3; p < 0.05 compared to venom alone). TM showed no mutagenicity in the Ames test using Salmonella strains TA98 and TA97a with (+S9) and without (−S9) metabolic activation. These findings indicate that TM is a potentially useful compound for antagonizing the neuromuscular effects (neurotoxicity and myotoxicity) of B. jararacussu venom. Full article

(This article belongs to the Section Metabolites)

Open AccessReview Tracing Monotreme Venom Evolution in the Genomics Era

by Camilla M. Whittington and Katherine Belov

Toxins 2014, 6(4), 1260-1273; doi:10.3390/toxins6041260

Received: 28 January 2014 / Revised: 17 March 2014 / Accepted: 27 March 2014 / Published: 2 April 2014

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Abstract

The monotremes (platypuses and echidnas) represent one of only four extant venomous mammalian lineages. Until recently, monotreme venom was poorly understood. However, the availability of the platypus genome and increasingly sophisticated genomic tools has allowed us to characterize platypus toxins, and provides a

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The monotremes (platypuses and echidnas) represent one of only four extant venomous mammalian lineages. Until recently, monotreme venom was poorly understood. However, the availability of the platypus genome and increasingly sophisticated genomic tools has allowed us to characterize platypus toxins, and provides a means of reconstructing the evolutionary history of monotreme venom. Here we review the physiology of platypus and echidna crural (venom) systems as well as pharmacological and genomic studies of monotreme toxins. Further, we synthesize current ideas about the evolution of the venom system, which in the platypus is likely to have been retained from a venomous ancestor, whilst being lost in the echidnas. We also outline several research directions and outstanding questions that would be productive to address in future research. An improved characterization of mammalian venoms will not only yield new toxins with potential therapeutic uses, but will also aid in our understanding of the way that this unusual trait evolves. Full article

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

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Open AccessArticle Structure of N-Terminal Sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser of Aβ-Peptide with Phospholipase A₂ from Venom of Andaman Cobra Sub-Species Naja naja sagittifera at 2.0 Å Resolution

by Zeenat Mirza, Vikram Gopalakrishna Pillai and Wei-Zhu Zhong

Int. J. Mol. Sci. 2014, 15(3), 4221-4236; doi:10.3390/ijms15034221

Received: 16 January 2014 / Revised: 20 February 2014 / Accepted: 5 March 2014 / Published: 10 March 2014

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Abstract

Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂

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Alzheimer’s disease (AD) is one of the most significant social and health burdens of the present century. Plaques formed by extracellular deposits of amyloid β (Aβ) are the prime player of AD’s neuropathology. Studies have implicated the varied role of phospholipase A₂ (PLA₂) in brain where it contributes to neuronal growth and inflammatory response. Overall contour and chemical nature of the substrate-binding channel in the low molecular weight PLA₂s are similar. This study involves the reductionist fragment-based approach to understand the structure adopted by N-terminal fragment of Alzheimer’s Aβ peptide in its complex with PLA₂. In the current communication, we report the structure determined by X-ray crystallography of N-terminal sequence Asp-Ala-Glu-Phe-Arg-His-Asp-Ser (DAEFRHDS) of Aβ-peptide with a Group I PLA₂ purified from venom of Andaman Cobra sub-species Naja naja sagittifera at 2.0 Å resolution (Protein Data Bank (PDB) Code: 3JQ5). This is probably the first attempt to structurally establish interaction between amyloid-β peptide fragment and hydrophobic substrate binding site of PLA₂ involving H bond and van der Waals interactions. We speculate that higher affinity between Aβ and PLA₂ has the therapeutic potential of decreasing the Aβ–Aβ interaction, thereby reducing the amyloid aggregation and plaque formation in AD. Full article

(This article belongs to the Special Issue Molecular Science for Drug Development and Biomedicine) Printed Edition available

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Open AccessArticle Evolution Stings: The Origin and Diversification of Scorpion Toxin Peptide Scaffolds

by Kartik Sunagar, Eivind A. B. Undheim, Angelo H. C. Chan, Ivan Koludarov, Sergio A. Muñoz-Gómez, Agostinho Antunes and Bryan G. Fry

Toxins 2013, 5(12), 2456-2487; doi:10.3390/toxins5122456

Received: 21 November 2013 / Revised: 9 December 2013 / Accepted: 9 December 2013 / Published: 13 December 2013

Abstract

The episodic nature of natural selection and the accumulation of extreme sequence divergence in venom-encoding genes over long periods of evolutionary time can obscure the signature of positive Darwinian selection. Recognition of the true biocomplexity is further hampered by the limited taxon selection,

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The episodic nature of natural selection and the accumulation of extreme sequence divergence in venom-encoding genes over long periods of evolutionary time can obscure the signature of positive Darwinian selection. Recognition of the true biocomplexity is further hampered by the limited taxon selection, with easy to obtain or medically important species typically being the subject of intense venom research, relative to the actual taxonomical diversity in nature. This holds true for scorpions, which are one of the most ancient terrestrial venomous animal lineages. The family Buthidae that includes all the medically significant species has been intensely investigated around the globe, while almost completely ignoring the remaining non-buthid families. Australian scorpion lineages, for instance, have been completely neglected, with only a single scorpion species (Urodacus yaschenkoi) having its venom transcriptome sequenced. Hence, the lack of venom composition and toxin sequence information from an entire continent’s worth of scorpions has impeded our understanding of the molecular evolution of scorpion venom. The molecular origin, phylogenetic relationships and evolutionary histories of most scorpion toxin scaffolds remain enigmatic. In this study, we have sequenced venom gland transcriptomes of a wide taxonomical diversity of scorpions from Australia, including buthid and non-buthid representatives. Using state-of-art molecular evolutionary analyses, we show that a majority of CSα/β toxin scaffolds have experienced episodic influence of positive selection, while most non-CSα/β linear toxins evolve under the extreme influence of negative selection. For the first time, we have unraveled the molecular origin of the major scorpion toxin scaffolds, such as scorpion venom single von Willebrand factor C-domain peptides (SV-SVC), inhibitor cystine knot (ICK), disulphide-directed beta-hairpin (DDH), bradykinin potentiating peptides (BPP), linear non-disulphide bridged peptides and antimicrobial peptides (AMP). We have thus demonstrated that even neglected lineages of scorpions are a rich pool of novel biochemical components, which have evolved over millions of years to target specific ion channels in prey animals, and as a result, possess tremendous implications in therapeutics. Full article

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

Open AccessArticle Appraisal of Antiophidic Potential of Marine Sponges against Bothrops jararaca and Lachesis muta Venom

by Camila Nunes Faioli, Thaisa Francielle Souza Domingos, Eduardo Coriolano de Oliveira, Eládio Flores Sanchez, Suzi Ribeiro, Guilherme Muricy and Andre Lopes Fuly

Toxins 2013, 5(10), 1799-1813; doi:10.3390/toxins5101799

Received: 2 August 2013 / Revised: 8 October 2013 / Accepted: 11 October 2013 / Published: 17 October 2013

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Abstract

Snakebites are a health problem in many countries due to the high incidence of such accidents. Antivenom treatment has regularly been used for more than a century, however, this does not neutralize tissue damage and may even increase the severity and morbidity of

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Snakebites are a health problem in many countries due to the high incidence of such accidents. Antivenom treatment has regularly been used for more than a century, however, this does not neutralize tissue damage and may even increase the severity and morbidity of accidents. Thus, it has been relevant to search for new strategies to improve antiserum therapy, and a variety of molecules from natural sources with antiophidian properties have been reported. In this paper, we analyzed the ability of ten extracts from marine sponges (Amphimedon viridis, Aplysina fulva, Chondrosia collectrix, Desmapsamma anchorata, Dysidea etheria, Hymeniacidon heliophila, Mycale angulosa, Petromica citrina, Polymastia janeirensis, and Tedania ignis) to inhibit the effects caused by Bothrops jararaca and Lachesis muta venom. All sponge extracts inhibited proteolysis and hemolysis induced by both snake venoms, except H. heliophila, which failed to inhibit any biological activity. P. citrina inhibited lethality, hemorrhage, plasma clotting, and hemolysis induced by B. jararaca or L. muta. Moreover, other sponges inhibited hemorrhage induced only by B. jararaca. We conclude that Brazilian sponges may be a useful aid in the treatment of snakebites caused by L. muta and B. jararaca and therefore have potential for the discovery of molecules with antiophidian properties. Full article

Open AccessArticle Interactions of PLA₂-s from Vipera lebetina, Vipera berus berus and Naja naja oxiana Venom with Platelets, Bacterial and Cancer Cells

by Mari Samel, Heiki Vija, Imbi Kurvet, Kai Künnis-Beres, Katrin Trummal, Juhan Subbi, Anne Kahru and Jüri Siigur

Toxins 2013, 5(2), 203-223; doi:10.3390/toxins5020203

Received: 7 December 2012 / Revised: 16 January 2013 / Accepted: 17 January 2013 / Published: 24 January 2013

Abstract

Secretory phospholipasesA₂ (sPLA₂s) form a large family of structurally related enzymes widespread in nature. Herein, we studied the inhibitory effects of sPLA₂s from Vipera lebetina (VLPLA₂), Vipera berus berus (VBBPLA₂), and Naja naja oxiana

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Secretory phospholipasesA₂ (sPLA₂s) form a large family of structurally related enzymes widespread in nature. Herein, we studied the inhibitory effects of sPLA₂s from Vipera lebetina (VLPLA₂), Vipera berus berus (VBBPLA₂), and Naja naja oxiana (NNOPLA₂) venoms on (i) human platelets, (ii) four different bacterial strains (gram-negative Escherichia coli and Vibrio fischeri; gram-positive Staphylococcus aureus and Bacillus subtilis) and (iii) five types of cancer cells (PC-3, LNCaP, MCF-7, K-562 and B16-F10) in vitro. sPLA₂s inhibited collagen-induced platelet aggregation: VBBPLA₂ IC₅₀ = 0.054, VLPLA₂ IC₅₀ = 0.072, NNOPLA₂ IC₅₀ = 0.814 μM. p-Bromophenacylbromide-inhibited sPLA₂ had no inhibitory action on platelets. 36.17 μM VBBPLA₂completely inhibited the growth of gram-positive Bacillus subtilis whereas no growth inhibition was observed towards gram-negative Escherichia coli. The inhibitory action of sPLA₂s (~0.7 μM and ~7 μM) towards cancer cells depended on both venom and cell type. VBBPLA₂(7.2 μM) inhibited significantly the viability of K-562 cells and the cell death appeared apoptotic. The sPLA₂s exhibited no inhibitory effect towards LNCaP cells and some effect (8%–20%) towards other cells. Thus, already sub-μM concentrations of sPLA₂s inhibited collagen-induced platelet aggregation and from the current suite of studied svPLA₂s and test cells, VBBPLA₂ was the most growth inhibitory towards Bacillus subtilis and K-562 cells. Full article

Open AccessReview Exploiting the Nephrotoxic Effects of Venom from the Sea Anemone, Phyllodiscus semoni, to Create a Hemolytic Uremic Syndrome Model in the Rat

by Masashi Mizuno, Yasuhiko Ito and B. Paul Morgan

Mar. Drugs 2012, 10(7), 1582-1604; doi:10.3390/md10071582

Received: 31 May 2012 / Revised: 29 June 2012 / Accepted: 12 July 2012 / Published: 23 July 2012

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Abstract

In the natural world, there are many creatures with venoms that have interesting and varied activities. Although the sea anemone, a member of the phylum Coelenterata, has venom that it uses to capture and immobilise small fishes and shrimp and for protection

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In the natural world, there are many creatures with venoms that have interesting and varied activities. Although the sea anemone, a member of the phylum Coelenterata, has venom that it uses to capture and immobilise small fishes and shrimp and for protection from predators, most sea anemones are harmless to man. However, a few species are highly toxic; some have venoms containing neurotoxins, recently suggested as potential immune-modulators for therapeutic application in immune diseases. Phyllodiscus semoni is a highly toxic sea anemone; the venom has multiple effects, including lethality, hemolysis and renal injuries. We previously reported that venom extracted from Phyllodiscus semoni induced acute glomerular endothelial injuries in rats resembling hemolytic uremic syndrome (HUS), accompanied with complement dysregulation in glomeruli and suggested that the model might be useful for analyses of pathology and development of therapeutic approaches in HUS. In this mini-review, we describe in detail the venom-induced acute renal injuries in rat and summarize how the venom of Phyllodiscus semoni could have potential as a tool for analyses of complement activation and therapeutic interventions in HUS. Full article

(This article belongs to the Special Issue Sea Anemone Toxins)

Open AccessArticle Humanized-Single Domain Antibodies (VH/V_HH) that Bound Specifically to Naja kaouthia Phospholipase A2 and Neutralized the Enzymatic Activity

by Charnwit Chavanayarn, Jeeraphong Thanongsaksrikul, Kanyarat Thueng-in, Kunan Bangphoomi, Nitat Sookrung and Wanpen Chaicumpa

Toxins 2012, 4(7), 554-567; doi:10.3390/toxins4070554

Received: 19 June 2012 / Revised: 26 June 2012 / Accepted: 6 July 2012 / Published: 19 July 2012

Abstract

Naja kaouthia (monocled cobra) venom contains many isoforms of secreted phospholipase A2 (sPLA₂). The PLA₂ exerts several pharmacologic and toxic effects in the snake bitten subject, dependent or independent on the enzymatic activity. N. kaouthia venom appeared in two protein

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Naja kaouthia (monocled cobra) venom contains many isoforms of secreted phospholipase A2 (sPLA₂). The PLA₂ exerts several pharmacologic and toxic effects in the snake bitten subject, dependent or independent on the enzymatic activity. N. kaouthia venom appeared in two protein profiles, P3 and P5, after fractionating the venom by ion exchange column chromatography. In this study, phage clones displaying humanized-camel single domain antibodies (VH/V_HH) that bound specifically to the P3 and P5 were selected from a humanized-camel VH/V_HH phage display library. Two phagemid transfected E. coli clones (P3-1 and P3-3) produced humanized-V_HH, while another clone (P3-7) produced humanized-VH. At the optimal venom:antibody ratio, the VH/V_HH purified from the E. coli homogenates neutralized PLA₂ enzyme activity comparable to the horse immune serum against the N. kaouthia holo-venom. Homology modeling and molecular docking revealed that the VH/V_HH covered the areas around the PLA₂ catalytic groove and inserted their Complementarity Determining Regions (CDRs) into the enzymatic cleft. It is envisaged that the VH/V_HH would ameliorate/abrogate the principal toxicity of the venom PLA₂ (membrane phospholipid catabolism leading to cellular and subcellular membrane damage which consequently causes hemolysis, hemorrhage, and dermo-/myo-necrosis), if they were used for passive immunotherapy of the cobra bitten victim. The speculation needs further investigations. Full article

(This article belongs to the Special Issue Toxin-Antibody Interactions)

Open AccessArticle Recruitment of Glycosyl Hydrolase Proteins in a Cone Snail Venomous Arsenal: Further Insights into Biomolecular Features of Conus Venoms

by Aude Violette, Adrijana Leonardi, David Piquemal, Yves Terrat, Daniel Biass, Sébastien Dutertre, Florian Noguier, Frédéric Ducancel, Reto Stöcklin, Igor Križaj and Philippe Favreau

Mar. Drugs 2012, 10(2), 258-280; doi:10.3390/md10020258

Received: 25 November 2011 / Revised: 13 January 2012 / Accepted: 14 January 2012 / Published: 31 January 2012

Abstract

Cone snail venoms are considered an untapped reservoir of extremely diverse peptides, named conopeptides, displaying a wide array of pharmacological activities. We report here for the first time, the presence of high molecular weight compounds that participate in the envenomation cocktail used by

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Cone snail venoms are considered an untapped reservoir of extremely diverse peptides, named conopeptides, displaying a wide array of pharmacological activities. We report here for the first time, the presence of high molecular weight compounds that participate in the envenomation cocktail used by these marine snails. Using a combination of proteomic and transcriptomic approaches, we identified glycosyl hydrolase proteins, of the hyaluronidase type (Hyal), from the dissected and injectable venoms (“injectable venom” stands for the venom variety obtained by milking of the snails. This is in contrast to the “dissected venom”, which was obtained from dissected snails by extraction of the venom glands) of a fish-hunting cone snail, Conus consors (Pionoconus clade). The major Hyal isoform, Conohyal-Cn1, is expressed as a mixture of numerous glycosylated proteins in the 50 kDa molecular mass range, as observed in 2D gel and mass spectrometry analyses. Further proteomic analysis and venom duct mRNA sequencing allowed full sequence determination. Additionally, unambiguous segment location of at least three glycosylation sites could be determined, with glycans corresponding to multiple hexose (Hex) and N-acetylhexosamine (HexNAc) moieties. With respect to other known Hyals, Conohyal-Cn1 clearly belongs to the hydrolase-type of Hyals, with strictly conserved consensus catalytic donor and positioning residues. Potent biological activity of the native Conohyals could be confirmed in degrading hyaluronic acid. A similar Hyal sequence was also found in the venom duct transcriptome of C. adamsonii (Textilia clade), implying a possible widespread recruitment of this enzyme family in fish-hunting cone snail venoms. These results provide the first detailed Hyal sequence characterized from a cone snail venom, and to a larger extent in the Mollusca phylum, thus extending our knowledge on this protein family and its evolutionary selection in marine snail venoms. Full article

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Open AccessReview Spider-Venom Peptides as Therapeutics

by Natalie J. Saez, Sebastian Senff, Jonas E. Jensen, Sing Yan Er, Volker Herzig, Lachlan D. Rash and Glenn F. King

Toxins 2010, 2(12), 2851-2871; doi:10.3390/toxins2122851

Received: 16 November 2010 / Revised: 17 December 2010 / Accepted: 17 December 2010 / Published: 20 December 2010

Cited by 101 | Viewed by 6785 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text

Abstract

Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms

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Spiders are the most successful venomous animals and the most abundant terrestrial predators. Their remarkable success is due in large part to their ingenious exploitation of silk and the evolution of pharmacologically complex venoms that ensure rapid subjugation of prey. Most spider venoms are dominated by disulfide-rich peptides that typically have high affinity and specificity for particular subtypes of ion channels and receptors. Spider venoms are conservatively predicted to contain more than 10 million bioactive peptides, making them a valuable resource for drug discovery. Here we review the structure and pharmacology of spider-venom peptides that are being used as leads for the development of therapeutics against a wide range of pathophysiological conditions including cardiovascular disorders, chronic pain, inflammation, and erectile dysfunction. Full article

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

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Open AccessArticle Chemical Constituents of the Bark of Dipteryx alata Vogel, an Active Species against Bothrops jararacussu Venom

by Pilar Puebla, Yoko Oshima-Franco, Luiz M. Franco, Marcio G. Dos Santos, Renata V. da Silva, Leandro Rubem-Mauro and Arturo San Feliciano

Molecules 2010, 15(11), 8193-8204; doi:10.3390/molecules15118193

Received: 25 September 2010 / Revised: 4 November 2010 / Accepted: 10 November 2010 / Published: 12 November 2010

Cited by 24 | Viewed by 8961 | PDF Full-text (126 KB)

Abstract

The effect of four sub-extracts prepared from the lyophilized hydroalcoholic bark of Dipteryx alata (Leguminosae-Papilionoideae) dissolved in a methanol-water (80:20) mixture through a liquid-liquid partition procedure has been investigated against the neuromuscular blockade of the venom of the snake Bothrops jararacussu. The

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The effect of four sub-extracts prepared from the lyophilized hydroalcoholic bark of Dipteryx alata (Leguminosae-Papilionoideae) dissolved in a methanol-water (80:20) mixture through a liquid-liquid partition procedure has been investigated against the neuromuscular blockade of the venom of the snake Bothrops jararacussu. The active CH₂Cl₂ sub-extract has been extensively analyzed for its chemical constituents, resulting in the isolation of four lupane-type triterpenoids: lupeol (1), lupenone (2), 28-hydroxylup-20(29)-en-3-one (3), betulin (4), nine isoflavonoids: 8-O-methylretusin (5), 7-hydroxy-5,6,4’-trimethoxyisoflavone (6), afrormosin (8), 7-hydroxy-8,3’,4’-trimethoxyisoflavone (9), 7,3’-dihydroxy-8,4’-dimethoxyisoflavone (10), odoratin (11), 7,8,3’-trihydroxy-4’-methoxyisoflavone (13), 7,8,3’-trihydroxy-6,4’-dimethoxyisoflavone (15), dipteryxin (17), one chalcone: isoliquiritigenin (7), one aurone: sulfuretin (14) and three phenolic compounds: vanillic acid (12),vanillin (16), and protocatechuic acid (18). Their chemical structures were elucidated on the basis of spectroscopic analysis, including HRMS, 1D- and 2D-NMR techniques. Full article

(This article belongs to the Section Natural Products)

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Open AccessReview Snake Venom Disintegrins and Cell Migration

by Heloisa S. Selistre-de-Araujo, Carmen L. S. Pontes, Cyntia F. Montenegro and Ana Carolina B. M. Martin

Toxins 2010, 2(11), 2606-2621; doi:10.3390/toxins2112606

Received: 24 August 2010 / Revised: 15 October 2010 / Accepted: 18 October 2010 / Published: 29 October 2010

Cited by 23 | Viewed by 4680 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text

Abstract

Cell migration is a key process for the defense of pluricellular organisms against pathogens, and it involves a set of surface receptors acting in an ordered fashion to contribute directionality to the movement. Among these receptors are the integrins, which connect the cell

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Cell migration is a key process for the defense of pluricellular organisms against pathogens, and it involves a set of surface receptors acting in an ordered fashion to contribute directionality to the movement. Among these receptors are the integrins, which connect the cell cytoskeleton to the extracellular matrix components, thus playing a central role in cell migration. Integrin clustering at focal adhesions drives actin polymerization along the cell leading edge, resulting in polarity of cell movement. Therefore, small integrin-binding proteins such as the snake venom disintegrins that inhibit integrin-mediated cell adhesion are expected to inhibit cell migration. Here we review the current knowledge on disintegrin and disintegrin-like protein effects on cell migration and their potential use as pharmacological tools in anti-inflammatory therapy as well as in inhibition of metastatic invasion. Full article

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

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