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Biochemistry, Genetics and Molecular Biology » "An Integrated View of the Molecular Recognition and Toxinology - From Analytical Procedures to Biomedical Applications", book edited by Gandhi Rádis Baptista, ISBN 978-953-51-1151-1, Published: July 1, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 2

Toxins from Venomous Animals: Gene Cloning, Protein Expression and Biotechnological Applications

By Matheus F. Fernandes-Pedrosa, Juliana Félix-Silva and Yamara A. S. Menezes
DOI: 10.5772/52380

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Toxins from Venomous Animals: Gene Cloning, Protein Expression and Biotechnological Applications

Matheus F. Fernandes-Pedrosa1, Juliana Félix-Silva1 and Yamara A. S. Menezes1

1. Introduction

Venoms are the secretion of venomous animals, which are synthesized and stored in specific areas of their body i.e., venom glands. The animals use venoms for defense and/or to immobilize their prey. Most of the venoms are complex mixture of biologically active compounds of different chemical nature such as multidomain proteins, peptides, enzymes, nucleotides, lipids, biogenic amines and other unknown substances. Venomous animals as snakes, spiders, scorpions, caterpillars, bees, insects, wasps, centipedes, ants, toads and frogs have largely shown biotechnological or pharmacological applications. During long-term evolution, venom composition underwent continuous improvement and adjustment for efficient functioning in the killing or paralyzing of prey and/or as a defense against aggressors or predators. Different venom components act synergistically, thus providing efficiency of action of the components. Venom composition is highly species-specific and depends on many factors including age, sex, nutrition and different geographic regions. Toxins, occurring in venoms and poisons of venomous animals, are chemically pure toxic molecules with more or less specific actions on biological systems [1-3]. A large number of toxins have been isolated and characterized from snake venoms and snake venoms repertoire typically contain from 30 to over 100 protein toxins. Some of these molecules present enzymatic activities, whereas several others are non-enzymatic proteins and polypeptides. The most frequent enzymes in snake venoms are phospholipases A2, serine proteinases, metalloproteinases, acetylcholinesterases, L-amino acid oxidases, nucleotidases and hyaluronidases. Higher catalytic efficiency, heat stability and resistance to proteolysis as well as abundance of snake venom enzymes provide them attractive models for biotechnologists, pharmacologists and biochemists [3-4]. Scorpion toxins are classified according to their structure, mode of action, and binding site on different channels or channel subtypes. The venom is constituted by mucopolysaccharides, hyaluronidases, phospholipases, serotonins, histamines, enzyme inhibitors, antimicrobials and proteins namely neurotoxic peptides. Scorpion peptides presents specificity and high affinity and have been used as pharmacological tools to characterize various receptor proteins involved in normal ion channel functionating, as abnormal channel functionating in cases of diseases. The venoms can be characterized by identification of peptide toxins analysis of the structure of the toxins and also have proven to be among the most and selective antagonists available for voltage-gated channels permeable to K+, Na+, and Ca2+. The neurotoxic peptides and small proteins lead to dysfunction and provoke pathophysiological actions, such as membrane destabilization, blocking of the central, and peripheral nervous systems or alteration of smooth or skeletal muscle activity [5-8]. Spider venoms are complex mixtures of biologically active compounds of different chemical nature, from salts to peptides and proteins. Specificity of action of some spider toxins is unique along with high toxicity for insects, they can be absolutely harmless for members of other taxons, and this could be essential for investigation of insecticides. Several spider toxins have been identified and characterized biochemically. These include mainly ribonucleotide phosphohydrolase, hyaluronidases, serine proteases, metalloproteases, insecticidal peptides and phospholipases D [9-10]. Venoms from toads and frogs have been extensively isolated and characterized showing molecules endowed with antimicrobial and/or cytotoxic activities [11]. Studies involving the molecular repertoire of the venom of bees and wasps have revealed the partial isolation, characterization and biological activity assays of histamines, dopamines, kinins, phospholipases and hyaluronidases. The venom of caterpillars has been partially characterized and contains mainly ester hydrolases, phospholipases and proteases [12]. The purpose of this chapter is to present the main toxins isolated and characterized from the venom of venomous animals, focusing on their biotechnological and pharmacological applications.

2. Biotechnological and pharmacological applications of snake venom toxins

While the initial interest in snake venom research was to understand how to combat effects of snakebites in humans and to elucidate toxins mechanisms, snake venoms have become a fertile area for the discovery of novel products with biotechnological and/or pharmacological applications [13-14]. Since then, many different products have been developed based on purified toxins from snake venoms, as well recent studies have been showing new potential molecules for a variety of applications [15].

2.1. Toxins acting on cardiovascular system

Increase in blood pressure is often a transient physiological response to stressful stimuli, which allows the body to react to dangers or to promptly increase activity. However, when the blood pressure is maintained at high levels for an extended period, its long term effects are highly undesirable. Persistently high blood pressure could cause or accelerate multiple pathological conditions such as organ (heart and kidney) failure and thrombosis events (heart attack and stroke) [14]. So, it is important to lower the blood pressure of high-rick patients through use of specific anti-hypertensive agents, and in this scenario, snake venom toxins has been shown to be promising sources [14-15]. This is because it has long been noted that some snake venoms drastically lower the blood pressure in human victims and experimental animals [15]. The first successful example of developing a drug from an isolated toxin was the anti-hypertensive agent Capoten® (captopril), an angiotensin-converting enzyme (ACE) inhibitor modeled from a venom peptide isolated from Bothrops jararaca venom [16]. These bradykinin-potentiating peptides (BPPs) are venom components which inhibits the breakdown of the endogenous vasodilator bradykinin while also inhibiting the synthesis of the endogenous vasoconstrictor angiotensin II, leading to a reduction in blood pressure [15]. BPPs have also been identified in Crotalus durissus terrificus venom [17]. Snake venom represents one of the major sources of exogenous natriuretic peptides (NPs) [18]. The first venom NP was identified from Dendroaspis angusticeps snake venom and was named Dendroaspis natriuretic peptide (DNP) [19]. Other venom NPs were also reported in various snake species, such as Micrurus corallinus [20], B. jararaca [4], Trimeresurus flavoviridis, Trimeresurus gramineus, Agkistrodon halys blomhoffii [21], Pseudocerastes persicus [22], Crotalus durissus cascavella [23], Bungarus flaviceps [24], among others. L-type Ca2+-channels blockers identified in snake venoms include calciseptine [25] and FS2 toxins [26] from Dendroaspis polylepis polylepis, C10S2C2 from D. angusticeps [27], S4C8 from Dendroaspis jamesoni kaimosae [28] and stejnihagin, a metalloproteinase from Trimeresurus stejnegeri [29].

2.2. Toxins acting on hemostasis

Desintegrins are a family of cysteine-rich low molecular weight proteins that inhibits various integrins and that usually contain the integrin-binding RGD motif, that binds the GPIIa/IIIb receptor in platelets, thus prevents the binding of fibrinogen to the receptor and consequently platelet aggregation [13]. Two drugs, tirofiban (Aggrastat®) and eptifibatide (Integrillin®) were designed based on snake venom disintegrins and are avaliable in the market as antiplatelet agents, approved for preventing and treating thrombotic complications in patients undergoing percutaneous coronay intervention and in patients with acute cornonary sydrome [30-31]. Tirofiban has a non-peptide structure mimicking the RDG motif of the disintegrin echistatin from Echis carinatus [30]. Eptifibatide is a cyclic peptide based on the KGD motif of barbourin from Sisturus miliaris barbouri snake [31]. Recently, leucurogin, a new recombinant disintegrin was cloned from Bothrops leucurus, being a potent agent upon platelet aggregation [32]. Thrombin-like enzymes (TLEs) are proteases reported from many different crotalid, viperid and colubrid snakes that share some functional similarity with thrombin [13]. TLEs are not inactivated by heparin-antithrombin III complex (the physiological inhibitor of thrombin), and, differently to thrombin, they are not able to activate FXIII (the enzyme that covalently cross-links fibrin monomer to form insoluble clots). These are interesting properties, because although being procoagulants in vitro, TLEs have the clinical results of being anti-coagulants, by the depletion of plasma level of fibrinogen, and the clots formed are easily soluble and removed from the body. At same time, thrombolysis is enhanced by stimulation of endogenous plasminogen activators binding to the noncrosslinked fibrin [13]. Batroxobin (Defibrase®) was isolated and purified from Bothrops atrox venom [33] and ancrod (Viprinex®) from Agkistrodon rhodostoma [34]. Haemocoagulase® is a mixture of two proteinases isolated from B. atrox venom, acting on blood coagulation by two mechanisms: the first having a thrombin-like activity and the second having a thromboplastin-like activity, activating FX which in turn converts prothrombin into thrombin. It is indicated for the prevention and treatment of hemorrhages of a variety of origins [13]. Other toxins acting on hemostasis with potential biotechnological/pharmacological applications has been purified and characterized from several snake venoms, such as bhalternin from Bothrops alternatus [35], bleucMP from B. leucurus [36], VLH2 from Vipera lebetina [37], trimarin from Trimeresurus malabaricus [38], BE-I-PLA2 from Bothrops erythromelas [39], among others.

2.3. Toxins with antibiotic activity

Antibiotics are a heterogeneous group of molecules produced by several organisms, including bacteria and fungi, presenting an antimicrobial profile, inducing the death of the agent or inhibiting microbial growth [40]. L-amino acid oxidases (LAAOs) are enantioselective flavoenzymes catalyzing the stereospecific oxidative deamination of a wide range of L-amino acids to form α-keto acids, ammonia and hydrogen peroxide (H2O2). Antimicrobial activities are reported to various LAAOs, such as TJ-LAO from Trimeresurus jerdonii [41], Balt-LAAO-I from Bothrops alternatus [42], TM-LAO Trimeresurus mucrosquamatus [43], BpirLAAO-I from Bothrops pirajai [44], casca LAO from Crotalus durissus cascavella [45], a LAAO from Naja naja oxiana [46], BmarLAAO from Bothrops marajoensis [47], among others. Recently, studies revealed that B. jararaca venom induced programmed cell death in epimastigotes of Trypanossoma cruzi, being this anti-T. cruzi activity associated with fractions of venoms with LAAO activity [48]. Secreted phospholipases A2 (sPLA2s) constitute a diverse group of enzymes that are widespread in nature, being particularly abundant in snake venoms. In addition to their catalytic activity, hydrolyzing the sn-2 ester bond of glycerophospholipids, sPLA2s display a range of biological actions, which may be either dependent or independent of catalytic action [49]. Eight sPLA2 myotoxins purified from crotalid snake venoms, including both Lys49 and Asp49-type isoforms, were all found to express bactericidal activity [50]. EcTx-I from Echis carinatus [51], PnPLA2 from Porthidium nasutum [52] and BFPA [53] from Bungarus fasciatus also presented antimicrobial activity. Vgf-1, a small peptide from Naja atra venom had in vitro activity against clinically isolated multidrug-resistant strains of Mycobacterium tuberculosis [54]. Neuwiedase, a metalloproteinase from Bothrops neuwiedi snake venom, showed considerable effects of Toxoplasma gondii infection inhibition in vitro [55]. Recently, a study revealed that whole venom, crotoxin and sPLA2s (PLA2-CB and PLA2-IC) isolated from Crotalus durissus terrificus venom showed antiviral activity against dengue and yellow fever viruses, which are two of the most important arboviruses in public health [56].

2.4. Toxins acting on inflammatory and nociceptive responses

Various snake venoms are rich in secretory phospholipases A2 (sPLA2), which are potent pro-inflammatory enzymes producing different families of inflammatory lipid mediators such as arachidonic acid derived eicosanoids, various lysophospholipids and platelet activating factors through cyclooxygenase and lipoxygenase pathways [57]. In a recent study, was described the first complete nucleotide sequence of a βPLI from venom glands of Lachesis muta by a transcriptomic analysis [58]. Recently, was purified from the venom of Crotalus durissus terrificus a hyaluronidase (named Hyal) that was able to provide a highly antiedematogenic acitivity [59]. Crotapotin, a subunit of crotoxin, from C. d. terrificus, has been reported to possess immunossupressive activity, associated to an increase in the production of prostaglandin E2 by macrophages, consequently reducing the proliferative response of lymphocytes [60]. Various elapid and viperid venoms have been reported to induce antinociception through their neurotoxins and myotoxins [61]. C. d. terrificus venom induces neurological symptoms in their victims, but, contrary to most venoms from other species, it does not induce pain or severe tissue destruction at the site of inoculation, being usual the sensation of paresthesia in the affected area [62]. Based on this, several studies have been carried out with this venom, being reported in the literature several molecules with antinociceptive activity from C. d. terrificus venom, such as crotamine [63] and crotoxin [64]. Has been demonstrated that the anti-nociceptive effect of crotamine involve both central and peripheral mechanisms, being 30-fold higher than the produced by morphine [63]. Studies suggest that crotoxin has antinociceptive effect mediated by an action on the central nervous system, without involvement of muscarinic and opioid receptors [64]. Other antinociceptive peptides isolated from snake venoms are cobrotoxin, a neurotoxin isolated from Naja atra [65] and hannalgesin, a neurotoxin isolated from Ophiophagus hannah [66].

2.5. Toxins acting on immunological system

Venom-derived peptides are being evaluated as immunosuppressants for the treatment of autoimmune diseases and the prevention of graft rejection [67]. Studies have shown that anti-crotalic serum possesses an antibody content usually inferior to the antibody content of other anti-venom serum suggesting that the crotalic venom is a poor immunogen or that it has components with immunosuppressor activity [68]. Indeed, the immunosuppressive effect of venom and crotoxin (a toxin isolated from Crotalus durissus terrificus) was reported [68]. Crotapotin, an acidic and non-toxic subunit of crotoxin, administrated by intraperitoneal route, significantly reduces the severity of experimental autoimmune neuritis, an experimental model for Guillain-Barré syndrome, which indicate a novel path for neuronal protection in this autoimmune disease and other inflammatory demyelinating neuropathies [69]. Inappropriate activation of complement system occurs in a large number of inflammatory, ischaemic and other diseases. Cobra venom factor (CVF) is an unusual venom component which exists in the venoms of different snake species, such as Naja sp., Ophiophagus sp. and Hemachatus sp. that activate complement system [70]. Due its similarity with C3 complement system component, after binding to mammalian fB in plasma and cleavage of fB by fD, produces a C3 convertase, that is more stable than the other C3 convertases, and resistant to the fluid phase regulators. The CVF-Bb convertase consumes all plasma C3 obliterating the functionality of complement system [70]. Recently, a CVF named OVF was purified from the crude venom of Ophiophagus hannah and cloned by cDNA transcriptomic analysis of the snake venom glands [71].

2.6. Toxins with anticancer and cytotoxic activities

Anticancer therapy is an important area for the application of proteins and peptides from venomous animals. Integrins play multiple important roles in cancer pathology including tumor cell proliferation, angiogenesis, invasion and metastasis [72]. Inhibition of angiogenesis is one of the heavily explored treatment options for cancer, and in this scenario snake venom disintegrins represent a library of molecules with different structure, potency and specificity [1]. RGD-containing disintegrins was identified in several snake venoms, inhibiting tumor angiogenesis and metastasis, such as accutin (from Agkistrodon acutus) [73], salmosin (from Agkistrodon halys brevicaudus) [74], contortrostatin (from Agkistrodon contortrix) [75], jerdonin (from Trimeresurus jerdonii) [76], crotatroxin (from Crotalus atrox) [77], rhodostomin (from Calloselasma rhodostoma) [78] and a novel desintegrin from Naja naja [79]. The cytostatic effect of L-amino acid oxidases (LAAOs) have been demonstrated using various models of human and animal tumors. Studies show that LAAOs induces apoptosis in vascular endothelial cells and inhibits angiogenesis [80]. Examples of LAAOs isolated from snake venoms with anticancer potential are a LAAO isolated from Ophiophagus hannah [81], ACTX-6 from A. acutus [82], OHAP-1 from Trimeresurus flavoviridis [83] and Bl-LAAO from Bothrops leucurus [84]. Secretory phospholipases A2 (sPLA2) also figures the snake toxins with anticancer potential [1]. sPLA2 with cytotoxic activity to tumor cells was described in Bothrops neuwiedii [85], Bothrops brazili [86], Naja naja naja [87], among others. Crotoxin, the main polypeptide isolated from C. d. terrificus has shown potent antitumor activity as well the whole venom, highlighting thereby the potential of venom as a source of pharmaceutical templates for cancer therapy [88]. BJcuL, a lectin purified from Bothrops jararacussu venom [89] and a metalloproteinase [90] and a lectin from B. leucurus [91] are other examples of toxins from snake venoms with anticancer potential.

3. Biotechnological and pharmacological applications of scorpion venom toxins

Scorpions are venomous arthropods, members of Arachnida class and order Scorpiones. These animals are found in all continents except Antarctica, and are known to cause problems in tropical and subtropical regions. Actually these animals are represented by 16 families and approximately 1500 different species and subspecies which conserved their morphology almost unaltered [92-93]. The scorpion species that present medically importance belonging to the family Buthidae are represented by the genera Androctonus, Buthus, Mesobuthus, Buthotus, Parabuthus, and Leirus located in North Africa, Asia, the Middle East, and India. Centruroides spp. are located in Southwest of United States, Mexico, and Central America, while Tityus spp. are found in Central and South America and Caribbean. In these different regions of the world the scorpionism is considered a public health problem, with frequent statements that scorpion stings are dangerous [8]. It is generally known that scorpion venom is a complex mixture composed of a wide array of substances. It contains mucopolysaccharides, hyaluronidase, phopholipase, low relative molecular mass molecules like serotonin and histamine, protease inhibitors, histamine releasers and polypeptidyl compounds. Scorpion venoms are a particularly rich source of small, mainly neurotoxic proteins or peptides interacting specifically with various ionic channels in excitable membranes [94].

3.1. Toxins acting on cardiovascular system

The first peptide from scorpion endowed effects of bradykinin and on arterial blood pressure was isolated from the Brazilian scorpion Tityus serrulatus [95]. These peptides named Tityus serrulatus Hypotensins have molecular masses ranging approximately from 1190 to 2700 Da [96]. Other scorpion bradykinin-potentiating peptides (BPPs) were reported to be found in the venom of the scorpions Buthus martensii Karsch [97] and Leiurus quinquestriatus [98]. These molecules can display potential as new drugs and could be of interest for biotechnological purposes.

3.2. Toxins with antibiotic activity

In order to defend themselves against the hostile environment, scorpions have developed potent defensive mechanisms that are part of innate and adaptive immunity [99]. Cysteine-free antimicrobial peptides have been identified and characterized from the venom of six scorpion species [100]. Antimicrobial peptides isolated from scorpion venom are important in the discovery of novel antibiotic molecules [101]. The first antimicrobial peptide isolated from scorpions were of the defensin type from Leiurus quinquestriatus hebraeus [102]. Later cytolitic and/or antibacterial peptides were isolated from scorpions belonging to the Buthidae, Scorpionidae, Ischnuridae, and Iuridae superfamilies hemo-lymph and venom [103-108]. The discovery of these peptides in venoms from Eurasian scorpions, Africa and the Americas, confirmed their widespread occurrence and significant biological function. Scorpine, a peptide from Pandinus imperator with 75 amino acids, three disulfide bridges, and molecular mass of 8350 Da has anti-bacterial and anti-malaria effects [104]. A cationic amphipatic peptide consisting of 45 amino acids has been purified from the venom of the southern African scorpion, Parabuthus schlechteri. At higher concentrations it forms non-selective pores into membranes causing depolarization of the cells [109]. Opistoporin1 and 2 (OP 1 and 2) was isolated from the venom of Opistophthalmus carinatus. These are amphipathic, cationic peptides which differ only in one amino acid residue. OP1 and PP were active against Gram-negative bacteria and both had hemolytic activity and antifungal activity. These effects are related to membrane permeabilization [106]. A new antimicrobial peptide, hadrurin, was isolated from Hadrurus aztecus. It is a basic peptide composed of 41 amino-acid residues with a molecular mass of 4436 Da, and contains no cysteines. It is a unique peptide among all known antimicrobial peptides described, only partially similar to the N-terminal segment of gaegurin 4 and brevinin 2e, isolated from frog skin. It would certainly be a model molecule for studying new antibiotic activities and peptide-lipid interactions [110]. Pandinin 1 and 2 are antimicrobial peptides have been identified and characterized from venom of the African scorpion Pandinus imperator [101]. Recently six novel peptides, named bactridines, were isolated from Tityus discrepans scorpion venom by mass spectrometry. The antimicrobial effects on membrane Na+ permeability induced by bactridines were observed on Yersinia enterocolitica [111]. The profile of gene in the venom glands of Tityus stigmurus scorpions was studied by transcriptome. Data revealed that 41 % of ESTs belong to recognized toxin-coding sequences, with transcripts encoding antimicrobial toxins (AMP-like) being the most abundant, followed by alfa KTx-like, beta KTx-like, beta NaTx-like and alfa NaTx-like. Parallel, 34% of the transcripts encode “other possible venom molecules”, which correspond to anionic peptides, hypothetical secreted peptides, metalloproteinases, cystein-rich peptides and lectins [7].

3.3. Toxins acting on acting on inflammatory and nociceptive response

The use of toxins as novel molecular probes to study the structure-function relationship of ion-channels and receptors as well as potential therapeutics in the treatment of wide variety of diseases is well documented. The high specificity and selectivity of these toxins have attracted a great deal of interest as candidates for drug development [8]. At least five peptides have been identified from Buthus martensii (Chinese scorpion) venom that have anti-inflammatory and antinociceptive properties [61]. One peptide, J123, blocks potassium channels that activate memory T-cells [112]. The venom also contains a 61-amino acid peptide that has demonstrated antiseizure properties in an animal model [113] as well as other constituents that act as analgesics in mice, rats, and rabbits [114]. The polypeptide BmK IT2 from scorpion Buthus martensi Karsh stops rats from reacting to experimentally-induced pain [115]. A protein from the Indian black scorpion, Heterometrus bengalensis, bengalin caused human leukemic cells to undergo apoptosis in vitro [116]. The peptide chlorotoxin, found in the venom of the scorpion Leiurus quinquestriatus, retarded the activity of human glioma cells in vitro [117]. An investigation about the role of kinins, prostaglandins and nitric oxide in mechanical hypernociception, spontaneous nociception and paw oedema after intraplantar have been done with Tityus serrulatus venom in male wistar rats, proving the potential of use of the venom to alleviate pain and oedema formation [118].

3.4. Toxins acting on acting on immunological system

OSK1 (alpha-KTx3.7) is a 38-residue toxin cross-linked by three disulphide bridges initially purified from the venom of the central Asian scorpion Orthochirus scrobiculosus [119]. OSK1 and several structural analogues were produced by solid-phase chemical synthesis, and were tested for lethality in mice and for their efficacy in blocking a series of 14 voltage-gated and Ca2+ activated K+ channels in vitro. The literature report that OSK1 could serve as leads for the design and production of new immunosuppressive drugs [119]. Margatoxin, a peptidyl inhibitor of K+ channels has been purified to homogeneity from venom of the new world scorpion Centruroides margaritatus showed that could be used as immunosuppressive agent [120]. Kaliotoxin, a peptidyl inhibitor of the high conductance Ca2+-activated K+ channels (KCa) has been purified to homogeneity from the venom of the scorpion Androctonus mauretanicus mauretanicus. This peptide appears to be a useful tool for elucidating the molecular pharmacology of the high conductance Ca2+-activated K+ channel [121]. Agitoxin 1, 2, and 3, from the venom of the scorpion Leiurus quinquestriatus var. hebraeus have been identified on the basis of their ability to block the shaker K+ channel [122]. Hongotoxin, a peptide inhibitor of shaker-type (K(v)1) K+ channels have been purified to homogeneity from venom of the scorpion Centruroides limbatus [123]. Noxiustoxin, component II-11 from the venom of scorpion Centruroides noxius Hoffmann, was obtained in pure form after fractionation by Sephadex G-50 chromatography followed by ion exchange separation on carboxy-methylcellulose columns. This peptide is the first short toxin directed against mammals and the first K+ channel blocking polypeptide-toxin found in scorpion venoms [124]. Pi1 is a peptide purified and characterized from the venom of the scorpion Pandinus imperato, showing ability to block the shaker K+ channel [125]. All of these peptides obtained from scorpions venoms are potential toxins acting on immunological system as immunosuppressant for autoimmune diseases.

3.5. Toxins with anticancer and cytotoxic activities

One of the most notable active principles found in scorpion venom is chlorotoxin (Cltx), a peptide isolated from the species Leiurus quinquestriatus. Cltx has 36 amino acids with four disulfide bonds, and inhibits chloride influx in the membrane of glioma cells [126]. This peptide binds only to glioma cells, displaying little or no activity at all in normal cells. The toxin appears to bind matrix metalloproteinase II [117]. A synthetic version of this peptide (TM601) is being produced by the pharmaceutical industry coupled to iodine 131 (131I-TM601), to carry radiation to tumor cells [127]. A recent study shows that TM601 inhibited angiogenesis stimulated by pro-angiogenic factors in cancer cells, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose [128]. A chlorotoxin-like peptide has also been isolated, cloned and sequenced from the venom of another scorpion species, Buthus martensii Karsch [129]. In reference [130] was expressed the recombinant chlorotoxin like peptide from Leiurus quinquestriatus and named rBmK CTa. Two novel peptides named neopladine 1 and neopladine 2 were purified from Tityus discrepans scorpion venom and found to be active on human breast carcinoma SKBR3 cells. Inmunohistochemistry assays revealed that neopladines bind to SKBR3 cell surface inducing FasL and BcL-2 expression [131]. Results indicate the venom from this scorpion represents a great candidate for the development of new clinical treatments against tumors.

3.6. Toxins with insecticides applications

Evidence for the potential application of scorpions toxins as insecticides has emerged in recent years. The precise action mechanism of several of these molecules remains unknown; many have their effects via interactions with specific ion channels and receptors of neuromuscular systems of insects and mammals. These highly potent and specific interactions make venom constituents attractive candidates for the development of novel therapeutics, pesticides and as molecular probes of target molecules [132].

Toxin Lqhα IT from the scorpion Leiurus quinquestriatus hebraeus venom is the best representative of anti-insect alpha toxins [133-134]. A similar effect was observed after applying the insect-selective toxin Bot IT1 from Buthus occitanus tunetanus venom [135]. Selective inhibition of the inactivation process of the insect para/tipNav expressed in Xenopus oocyteswas was observed in the presence of Bjα IT [136] and OD1 [137], which are toxins from Buthotus judaicus and Odonthobuthus doriae scorpion venom, respectively. A second group of scorpion toxins slowing insect sodium channel inactivation was called alpha-like toxins. The first precisely described toxins from this group were the Lqh III/Lqh3 (from L. q. hebraeus), Bom III/ Bom 3 and Bom IV/ Bom 4 (from B. o. mardochei). They were all tested on cockroach axonal preparation [138-139]. BmKM1 toxin from B. martensi Karsch was the first alpha-like toxin available in recombinant form that was tested also on cockroach axonal preparation [140]. Toxins Lqh6 and Lqh7 from L. q. hebraeus scorpion venom show high structural similarity with Lqh3 toxin. Their toxicity to cockroach is in the range found for other alpha-like toxins [141]. Alpha-like toxins from scorpion venoms show lower efficiency when applied to insects, as compared to α anti-insect toxins. Therefore they seem to be less interesting from the point of view of future insecticide development [132]. Scorpion contractive and depressant toxins are highly selective for insect sodium channels. Several of these toxins were tested on cockroach axonal preparations; toxin AaH IT1 from the A. australis scorpion venom was the first one [142-143]. All other contractive toxins tested on cockroach axon produced very similar effects, as for example Lqq IT1 from L. q. quinquestriatus [133]; Bj IT1 from B. judaicus [143], Bm 32-1 and Bm 33-1 from B. martensi [144].

4. Biotechnological and pharmacological applications of spider venom toxins

Spider venoms contain a complex mixture of proteins, polypeptides, neurotoxins, nucleic acids, free amino acids, inorganic salts and monoamines that cause diverse effects in vertebrates and invertebrates [145]. Regarding the pharmacology and biochemistry of spider venoms, they present a variety of ion channel toxins, novel non-neurotoxins, enzymes and low molecular weight compounds [146].

4.1. Toxins acting on cardiovascular system

Venom from the South American tarantula Grammostola spatulata presents GsMtx-4, a small peptide belonging to the "cysteine-knot" family that blocks cardiac stretch-activated ion channels and suppresses atrial fibrillation in rabbits [147]. Studies are being conducted to develop therapeutics for atrial fibrillation based on GsMtx-4.

4.2. Toxins acting on hemostasis

ARACHnase (Hemostasis Diagnostics International Co., Denver, CO) is a normal plasma that contains a venom extract from the brown recluse spider, Loxosceles reclusa, which mimics the presence of a lupus anticoagulant (LA). ARACHnase is a biotechnological product usefulness like a positive control for lupus anticoagulant testing [148]. Native dermonecrotic toxins (phospholipase-D) from Loxosceles sp. are agents that stimulate platelet aggregation [149].

4.3. Toxins with antibiotic activity

Two peptide toxins with antimicrobial activity, lycotoxins I and II, were identified from venom of the wolf spider Lycosa carolinensis (Araneae: Lycosidae). The lycotoxins may play a dual role in spider-prey interaction, functioning both in the prey capture strategy as well as to protect the spider from potentially infectious organisms arising from prey ingestion. Spider venoms may represent a potentially new source of novel antimicrobial agents with important medical implications [150].

4.4. Toxins acting on inflammatory and nociceptive response

Psalmotoxin 1, a peptide extracted from the South American tarantula Psalmopoeus cambridgei, has very potent analgesic properties against thermal, mechanical, chemical, inflammatory and neuropathic pain in rodents. It exerts its action by blocking acid-sensing ion channel 1a, and this blockade results in an activation of the endogenous enkephalin pathway [151]. Phospholipases from both Loxosceles laeta and Loxosceles reclusa cleaved LPC (lysophosphatidylcholine) to LPA (lysophosphatidic acid) and choline. LPA receptors are potential targets for Loxosceles sp. envenomation treatment [152]. The possibilities for biotechnological applications in this area are enormous. Recombinant dermonecrotic toxins could be used as reagents to establish a new model to study the inflammatory response, as positive inducers of the inflammatory response and edema [9, 153-154]. The phospholipase-D from Loxosceles venom could be used in phospholipid studies, specially studies on cell membrane constituents with emphasis upon sphingophospholipids, lysophospholipids, lysophosphatidic acid and ceramide-1-phosphate, as models for elucidating lipid product receptors, signaling pathways and biological activities; this new wide field of Loxosceles research could also reveal new targets for the treatment of envenomation [10].

4.5. Toxins acting on immunological system

The antiserum most commonly used for treatment of loxoscelism in Brazil is anti-arachnidic serum. This serum is produced by the Instituto Butantan (São Paulo, Brazil) by hyperimmunization of horses with venoms of the spiders Loxosceles gaucho and Phoneutria nigriventer and the scorpion Tityus serrulatus. Several studies have indicated that sphingomyelinase D (SMase D) in venom of Loxosceles sp. spiders is the main component responsible for local and systemic effects observed in loxoscelism [153, 155]. Neutralization tests showed that anti-SMase D serum has a higher activity against toxic effects of L. intermedia and L. laeta venoms and similar or slightly weaker activity against toxic biological effects of L. gaucho than that of Arachnidic serum. These results demonstrate that recombinant SMase D can replace venom for anti-venom production and therapy [155].

4.6. Toxins with anticancer and cytotoxic activities

Psalmotoxin 1 was evaluated on inhibited Na+ currents in high-grade human astrocytoma cells (glioblastoma multiforme, or GBM). These observations suggest this toxin may prove useful in determining whether GBM cells express a specific ASIC-containing ion channel type that can serve as a target for both diagnostic and therapeutic treatments of aggressive malignant gliomas [156]. The antitumor activity of a potent antimicrobial peptide isolated from hemocytes of the spider Acanthoscurria gomesiana, named gomesin, was tested in vitro and in vivo. Gomesin showed cytotoxic and antitumor activities in cell lines, such as melanoma, breast cancer and colon carcinoma [157].

4.7. Toxins with insecticides applications

Several spider toxins have been studied as potential insecticidal bioactive with great biotechnological possible applications [10]. A component of the venom of the Australian funnel web spider Hadronyche versuta that is a calcium channel antagonist retains its biological activity when expressed in a heterologous system. Transgenic expression of this toxin in tobacco effectively protected the plants from Helicoverpa armigera and Spodoptera littoralis larvae, with 100% mortality within 48h [158]. LiTxx1, LiTxx2 and LiTxx3 from Loxosceles intermedia venom were identified containing peptides that were active against Spodoptera frugiperda. These venom-derived products open a source of insecticide toxins that could be used as substitutes for chemical defensives and lead to a decrease in environmental problems [159]. An insecticidal peptide referred to as Tx4(6-1) was purified from the venom of the spider Phoneutria nigriventer by a combination of gel filtration, reverse-phase fast liquid chromatography on Pep-RPC, reverse-phase high performance liquid chromatography (HPLC) on Vydac C18 and ion-exchange HPLC. The protein contains 48 amino acids including 10 Cys and 6 Lys. The results showed that Tx4(6-1) has no toxicity for mice, and suggest that it is a specific anti-insect toxin [160]. SMase D and homologs in the SicTox gene family are the most abundantly expressed toxic protein in venoms of Loxosceles and Sicarius spiders (Sicariidae). A recombinant SMase D from Loxosceles arizonica was obtained and compared its enzymatic and insecticidal activity to that of crude venom. SMase D and crude venom have comparable and high potency in immobilization assays on crickets. These data indicate that SMase D is a potent insecticidal toxin, the role for which it presumably evolved [161]. δ-PaluIT1 and δ-paluIT2 are toxins purified from the venom of the spider Paracoelotes luctuosus. Similar in sequence to μ-agatoxins from Agelenopsis aperta, their pharmacological target is the voltage-gated insect sodium channel, of which they alter the inactivation properties in a way similar to α-scorpion toxins. Electrophysiological experiments on the cloned insect voltage-gated sodium channel heterologously co-expressed with the tipE subunit in Xenopus laevis oocytes, that δ-paluIT1 and δ-paluIT2 procure an increase of Na+ current [162]. Recently, several toxins have been isolated from spiders with potential biotechnological application as insecticide.

5. Biotechnological and pharmacological applications of toad and frog toxins

Amphibians (toads, frogs, salamanders etc.) during their evolution have developed skin glands covering most parts of their body surface. From these glands small amounts of a mucous slime are secreted permanently, containing substances with different pharmacologic activities such as cardiotoxins, neurotoxins, hypotensive as well as hypertensive agents, hemolysins, and many others. Chemically they belong to a wide variety of substance classes such as steroids, alkaloids, indolalkylamines, catecholamines and low molecular peptides [11, 163]. Several studies have been showing new potential molecules for a variety of pharmacological applications from toads and frogs venoms.

5.1. Toxins acting on cardiovascular system

Neurotensin-like peptides has been identified from frog skin, such as margaratensin, isolated from Rana margaratae [164], a potential antihypertensive drug. Similar to the cardiac glycosides, bufadienolides from Bufo bufo gargarizans toad skin are able of inhibiting Na+/K+-ATPase, having an important role on treatment of congestive heart failure and arterial hypertension [165]. Examples of these bufadienolides are arenobufagin [166], cinobufagin, bufalin, resibufogenin, among others [165]. In the skin of Rana temporaria and Rana igromaculata frogs, bradykinin, a hypotensive and smooth muscle exciting substance, has been found [11]. Atelopidtoxin, a water-soluble toxin from skin of Atelopus zeteki frog, when injected into mammals, produces hypotension and ventricular fibrillation [167]. Semi-purified skin extracts from Pseudophryne coriacea frog displayed effects on systemic blood pressure, reducing it by a probably cholinergic mechanism [168].

5.2. Toxins acting on hemostasis

Annexins are a well-known multigene family of Ca2+-regulated membrane-binding and phospholipid-binding proteins. A novel annexin A2 (Bm-ANXA2) was isolated and purified from Bombina maxima skin homogenate, being the first annexin A2 protein reported to possess platelet aggregation-inhibiting activity [169].

5.3. Toxins with antibiotic activity

Toxins with antibiotic activity are the most well studied toxins in toads and frogs. Two antimicrobial bufadienolides, telocinobufagin and marinobufagin, were isolated from skin secretions of the Brazilian toad Bufo rubescens [170]. Antimicrobial peptides, named syphaxins (SPXs), were isolated from skin secretions of Leptodactylus syphax frog [171]. The alkaloids apinaceamine, 6-methyl-spinaceamine isolated from the skin gland secretions of Leptodactylus pentadactylus showed in screening tests bactericidal activity [172]. The cinobufacini and its active components bufalin and cinobufagin, from Bufo bufo gargarizans Cantor skin, presented anti-hepatitis B virus (HBV) activity [173]. Telocinobufagin from Rhinella jimi toad were demonstrated to be active against Leishmania chagasi promastigotes and Trypanosoma cruzi trypomastigotes, while hellebrigenin, from same source, was active against only T. cruzi trypomastigotes [174].

5.4. Toxins acting on inflammatory and nociceptive responses

Epibatidine, an azabicycloheptane alkaloid isolated from the skin of frog Epipedobates tricolor, was found to be a potent antinociceptive compound. Although its toxicity, this toxin could be a lead compound in the development of therapeutic agents for pain relief as well for treatment of disorders whose pathogenesis involves nicotinic receptors [175]. A variety of toxins acting on opioid receptors have been isolated from amphibians. Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) and related heptapeptide [Hyp6]-dermorphin isolated from the frog skin of Phyllomedusa sp., show higher affinity for µ-opioid receptors. Several peptides belonging to the dermorphin family have been isolated from frog skin [61]. Deltorphins (also referred as dermenkephalin) and related peptides isolated from the frog skin have been found to exhibit high selectivity for δ-opiate receptors [176].

5.5. Toxins with anticancer and cytotoxic activities

Venenum Bufonis is a traditional Chinese medicine obtained from the dried white secretion of auricular and skin glands of Chinese toads (Bufo melanostictus Schneider or Bufo bufo gargarzinas Cantor). Cinobufagin (CBG), isolated from Venenum Bufonis, had potential immune system regulatory effects and is suggested that this compound could be developed as a novel immunotherapeutic agent to treat immune-mediated diseases such as cancer [177]. Bufadienolides from toxic glands of toads are used as anticancer agents, mainly on leukemia cells. Bufalin and cinobufagin from Bufo bufo gargarizans Cantor were tested and studies shown that these toxins suppress cell proliferation and cause apoptosis in prostate cancer cells via a sequence of apoptotic modulators [178]. Bufotalin, one of the bufadienolides isolated from Formosan Ch’an Su, which is made of the skin and parotid glands of toads, induce apoptosis in human hepatocellular carcinoma, probably involving caspases and apopotosis-inducing factor [179]. Cutaneous venom of Bombina variegata pachypus toad presented a cytolitic effect on the growth of the human HL 60 cell line [180]. Brevinin-2R, a non-hemolytic defensin has been isolated from the skin of the frog Rana ridibunda, showing pronounced cytotoxicity towards malignant cells [181].

5.6. Toxins with insulin releasing activity

Diabetes mellitus is a disease in which the body is unable to sufficiently produce or properly use insulin. Newer therapeutic modalities for this disease are extremely needed. Peptides with insulin-releasing activity have been isolated from the skin secretions of the frog Agalychnis litodryas and may serve as templates for a novel class of insulin secretagogues [182].

6. Biotechnological and pharmacological applications of bee and wasp toxins

Stinging accidents caused by wasps and bees generally produce severe pain, local damage and even death in various vertebrates including man, caused by action of their venoms. Bee venom contains a variety of compounds peptides including melittin, apamin, adolapin, and mast cell degranulating (MCD) peptide, in addition of hyaluronidase and phospholipase A enzymes, that plays a variety of biological activities. The chemical constituents of venoms from wasps species include acetylcholine, serotonin, norepinephrine, hyaluronidase, histidine decarboxylase, phospholipase A2 and several polycationic peptides and proteins [12].

6.1. Toxins acting on cardiovascular system

Honey bee venom and its main constituents have a marked effect on the cardiovascular system, most notably a fall in arterial blood pressure [183]. From the hemodynamic point of view, the venom, in higher doses, is extremely toxic to the circulatory system and in smaller doses, however, produce a stimulatory effect upon the heart [184]. Melittin, a strongly basic 26 amino-acid polypeptide which constitutes 40–60% of the whole dry honeybee venom, induces contractures and depolarization in skeletal muscle [12]. Melittin is cardiotoxic in vitro, causing arrest of the rat heart, but only induces a slight hypertension in vivo [183]. Apamin, without direct effect on contraction or relaxation, could attenuate the relaxation evoked by melittin at lower concentrations, and thus contribute to the conversion of melittin’s relaxing activity into the contractile activity of the venom. Another peptide found in bee venom that outlines effects on the cardiovascular system is the Cardiopep. Cardiopep is a relatively nonlethal component, compared to phospholipase A, melittin, or whole bee venom itself. It is a potent nontoxic beta-adrenergio-like stimulant that possesses definite anti-arrhythmic properties [185]. Studies on the cardiovascular effects of mastoparan B, isolated from the venom of the hornet Vespa basalis, has shown that the peptide caused a dose-dependent inhibition of blood pressure and cardiac function in the rat. Research has shown that the cardiovascular effects of mastoparan B are mainly due to the actions of serotonin, and by a lesser extent to other autacoids, released from mast cells as well from other biocompartments [186].

6.2. Toxins acting on hemostasis

The mechanism by which bee venom affects the hemostatic system remains poorly understood [187]. Among the serine proteases isolated from bees, which acts as a fibrin(ogen)olytic enzyme, activator prothrombin and directly degrades fibrinogen into fibrin degradation products, are the Bi-VSP (Bombus ignitus) [188], Bt-VSP (Bombus terrestris) [189] and Bs-VSP (Bombus hypocrita sapporoensis) [190]. According reference [188], the activation of prothrombin and fibrin(ogen)olytic activity may cooperate to effectively remove fibrinogen, and thus reduce the viscosity of blood. The injection fibrin(ogen)olytic enzyme can be used to facilitate the propagation of components of bee venom throughout the bloodstream of mammals. Bumblebee venom also affects the hemostatic system through by Bi-KTI (B. ignitus), a Kunitz-type inhibitor, that strongly inhibited plasmin during fibrinolysis, indicating that Bi-KTI specifically targets plasmin [187]. A toxin protein named magnvesin was purified of Vespa magnifica. This protein contains serine protease-like activity inhibits blood coagulation, and was found to act on factors TF, VII, VIII, IX and X [191]. Other anticoagulant protein (protease I) with proteolytic activity was purified from Vespa orientalis venom, involving mainly coagulation factors VIII and IX [192]. Magnifin, a phospholipase A1 (PLA1) purified from wasp venoms of V. magnifica, is very similar to other (PLA1), especially to other wasp allergen PLA1. Magnifin can activate platelet aggregation and induce thrombosis in vivo. It was the first report of PLA1 from wasp venoms that can induce platelet aggregation [193].

6.3. Toxins with antibiotic activity

Antimicrobial peptides have attracted much attention as a novel class of antibiotics, especially for antibiotic-resistant pathogens. They provide more opportunities for designing novel and effective antimicrobial agents [194]. Melittin has various biological, pharmacological and toxicological actions including antibacterial and antifungal activities [195]. Bombolitin (structural and biological properties similar to those of melittin), isolated from the venom of B. ignitus worker bees, possesses antimicrobial activity and show inhibitory effects on bacterial growth for Gram-positive, Gram-negative bacteria and fungi, suggesting that bombolitin is a potential antimicrobial agent [196]. Osmin, isolated of solitary bee Osmia rufa, shows some similarities with the mast cell degranulation (MCD) peptide family. Free acid and C-terminally amidated osmins were chemically synthesized and tested for antimicrobial and haemolytic activities. Antimicrobial and antifungal tests indicated that both peptides were able to inhibit bacterial and fungal growth [197]. Two families of bioactive peptides which belongs to mastoparans (12a and 12b) and chemotactic peptides (5e, 5g and 5f) were purified and characterized from the venom of Vespa magnifica. MP-VBs (vespa mastoparan) and VESP-VBs (vespa chemotactic peptide) were purified from the venom of the wasp Vespa bicolor Fabricius and demonstrated antimicrobial action [198]. The amphipathic α-helical structure and net positive charge (which permits electrostatic interaction with the negatively charged microbial cell membrane) of mastoparan appear to be critical for MCD activity and because of these structural properties, mastoparans are often highly active against the cell membranes of bacteria, fungi, and erythrocytes, as well as mast cells [199].

6.4. Toxins acting on inflammatory and nociceptive responses

Bee venom has been used in Oriental medicine and evidence from the literature indicates that bee venom plays an anti-inflammatory or anti-nociceptive role against inflammatory reactions associated with arthritis and other inflammatory diseases [200]. Bee venom demonstrated neuroprotective effect against motor neuron cell death and suppresses neuroinflammation-induced disease progression in symptomatic amyotrophic lateral sclerosis (ALS) mice model [200]. Melittin has effects on the secretion of phospholipase A2 and inhibits its enzymatic activity, which is important because phospholipases may release arachidonic acid which is converted into prostaglandins [201]. Have also been reported that melittin decreased the high rate of lethality, attenuated hepatic inflammatory responses, alleviated hepatic pathological injury and inhibited hepatocyte apoptosis. Protective effects were probably carried out through the suppression of NF-jB activation, which inhibited TNF-α liberation. Therefore, melittin may be useful as a potential therapeutic agent for attenuating acute liver injury [202]. In addition of melittin, others agents has shown anti-inflammatory activity. Among them are adolapin and MCDP. Adolapin showed marked anti-inflammatory and anti-nociceptive properties due to inhibition of prostaglandin synthase system [203]. MCDP, isolated of Apis mellifera venom, is a strong mediator of mast cell degranulation and releases histamine at low concentrations [204].

6.5. Toxins acting on immunological system

Characterization of the primary structure of allergens is a prerequisite for the design of new diagnostic and therapeutic tools for allergic diseases. Major allergens in bee venom (recognized by IgE in more than 50% of patients) include phospholipase A2 (PLA2), acid phosphatase, hyaluronidase and allergen C, as well as several proteins of high molecular weights (MWs) [205]. Besides these, Api m 6, was frequently (42%) recognized by IgE from bee venom hypersensitive patients [206]; from wasp venom were purified Vesp c 1 (phospholipase A1) and Vesp c 5 (antigen-5) from Polistes gallicus, and Vesp ma 2 and Vesp ma 5 from Vespa magnifica, [207-208]. Formulations of poly(lactic-co-glycolic acid) (PLGA) microspheres represent a strategy for replacing immunotherapy in multiple injections of venom. The results obtained with bee venom proteins encapsulated showed that the allergens may still be effective in the induction of an immune response and so may be a new formulation for VIT [209]. Recombinant proteins with immunosuppressive properties have been reported in the literature, such as rVPr1 and rVRr3, identified, cloned and expressed from isolated VPR1 and VPr2 from Pimpla hypochondriaca [210]. Chemotactic peptide protonectin 1-6 (ILGTIL-NH2) was detected in the venom of the social wasp Agelaia pallipes pallipes [211]. Polybia-MPI and Polybia-CP were isolated from the venom of the social wasp Polybia paulista and characterized as chemotactic peptides for PMNL cells [212]. Under the diagnosis, the microarray was reported. Protein chips can be spotted with thousands of proteins or peptides, permitting to analyses the IgE responses against a tremendous variety of allergens. First attempts to microarray with Hymenoptera venom allergens included Api m 1, Api m 2, Ves v 5, Ves g 5 and Pol a 5 in a set-up with 96 recombinant or natural allergen molecules representative of most important allergen sources. The venom allergens from different bee, wasp and ant species can be offered on a single chip, allowing to differentiate the species that has stung based on species-specific markers. The allergen microarray allows the determination and monitoring of allergic patients’ IgE reactivity profiles to large numbers of disease-causing allergens by using single measurements and minute amounts of serum [213].

6.6. Toxins with anticancer and cytotoxic activities

Bee venom is the most studied among the arthropods covered in this chapter regarding its anti-cancer activities, due mainly to two substances that have been isolated and characterized: melittin and phospholipase A2 (PLA2). Melittin and PLA2 are the two major components in the venom of the species Apis mellifera [214]. Melittin is inhibitor of calmodulin activity and is an inhibitor of cell growth and clonogenicity of human and murine leukemic cells [215]. Study indicated that key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through down-regulation of the ERK and Akt signal pathway [216]. Furthermore recent reports indicate that BV is also able to inhibit tumor growth and exhibit anti-tumor activity in vitro and in vivo and can be used as a chemotherapeutic agent against malignancy [217]. The adjuvant treatment with PLA2 and phosphatidylinositol-(3,4)-bisphosphate was more effective in the blocking of tumor cell growth [218]. New peptides have been isolated from bee venom and tested in tumor cells, exhibiting promising activities in the treatment of cancer. Lasioglossins isolated from the venom of the bee Lasioglossum laticeps exhibited potency to kill various cancer cells in vitro [219]. Briefly the bee venom acts inhibiting cell proliferation and promoting cell death by different means: increasing Ca2+ influx; inducing cytochrome C release; binding calmodulin; decreasing or increasing the expression of proteins that control cell cycle or activating PLA2, causing damage to cell membranes interfering in the apoptotic pathway [220]. Among potential anticancer compounds, one of the most studied is mastoparan, peptide isolated from wasp venom that has been reported to induce a potent facilitation of the mitochondrial permeability transition. It should be noted that this recognized action of mastoparan is marked at concentrations <1 μM [221]. Two novel mastoparan peptides, Polybia-MP-II e Polybia-MP-III isolated from venom of the social wasp Polybia paulista, exhibited hemolytic activity on erythrocytes [222]. Polybia-MPI, also was purified from the venom of the social wasp P. paulista, synthesized and studied its antitumor efficacy and cell selectivity. Results revealed that polybia-MPI exerts cytotoxic and antiproliferative efficacy by pore formation and have relatively lower cytotoxicity to normal cells [223].

6.7. Toxins with insulin releasing activity

Bee venom inhibits insulitis and development of diabetes in non-obese diabetic (NOD) mice. The cumulative incidence of diabetes at 25 weeks of age in control was 58% and NOD mice bee venom treated was 21% [224]. Mastoparan, component of wasp venom, is known to affect phosphoinositide breakdown, calcium influx, exocytosis of hormones and neurotransmitters and stimulate the GTPase activity of guanine nucleotide-binding regulatory proteins [225]. Thus, it is reported in the literature that mastoparan stimulates insulin secretion in human, as well as in rodent. Furthermore, glucose and alpha-ketoisocaproate (alfa-KIC) increase the mastoparan-stimulated insulin secretion [226].

7. Biotechnological and pharmacological applications of ant, centipede and caterpillar venom toxins

Ant, centipede and caterpillar venoms have not been studied so extensively as the venoms of snakes, scorpions and spiders. Ant venoms are rich in the phospholipase A2 and B, hyaluronidase, and acid and alkaline phosphatase as well as in histamine itself [227]. Centipede venoms have been poorly characterized in the literature. Studies have reported in centipede venoms the presence of esterases, proteinases, alkaline and acid phosphatases, cardiotoxins, histamine, and neurotransmitter releasing compounds in Scolopendra genus venoms [228]. Among the most studied caterpillar venoms are Lonomia obliqua and Lonomia achelous venoms, which cause similar clinical effects [229]. Based on cDNA libraries, was possible to identify several proteins from L. obliqua, such as cysteine proteases, group III phospholipase A2, C-type lectins, lipocalins, in addition to protease inhibitors including serpins, Kazal-type inhibitors, cystatins and trypsin inhibitor-like molecules [230].

7.1. Toxins acting on cardiovascular system

A study showed that the Lonomia obliqua caterpillar bristles extract (LOCBE) directly releases kinin from low-molecular weight kininogen, being suggested that kallikrein-kinin system plays a role in the edematogenic and hypotensive effects during L. obliqua envenomation [231].

7.2. Toxins acting on hemostasis

There are numerous studies in literature reporting the effects on the hemostatic system of toxins from caterpillars. The effect of a crude extract of spicules from Lonomia obliqua caterpillar on hemostasis was found to activate both prothrombin and factor X [232]. Lopap is a prothrombin activator isolated from the bristles of L. obliqua caterpillar. Lopap demonstrated ability to induce activation, expression of adhesion molecules and to exert an anti-apoptotic effect on human umbilical vein endothelial cells [233]. Lonofibrase, an α-fibrinogenase from L. obliqua was isolated from venomous secretion [234]. Losac, a protein with procoagulant activity, which acts as a growth stimulator and an inhibitor of cellular death for endothelial cells, was purified of the bristle extract of L. obliqua. Losac may have biotechnological applications, including the reduction of cell death and consequently increased productivity of animal cell cultures [235]. Lonomin V, serine protease isolated from Lonomia achelous caterpillar, inhibited platelet aggregation, probably caused by the degradation of collagen. It is emphasized that Lonomin V shows to be a potentially useful tool for investigating cell-matrix and cell-cell interactions and for the development of antithrombotic agents in terms of their anti-adhesive activities [236]. The venom from the tropical ant, Pseudomyrmex triplarinus, inhibited arachidonic acid and induced platelet aggregation, suggesting that venom prevented the action of prostaglandins. The venom was fractionated and factor F (adenosine) with antiplatelet activity were detected [237].

7.3. Toxins with antibiotic activity

Venom alkaloids from Solenopsis invicta, fire ant, inhibit the growth of Gram-positive and Gram-negative bacteria and presumably act as a brood antibiotic. Peptides named ponericins were identified from the venom of ant Pachycondyla goeldii. Fifteen peptides were classified into three different families according to their primary structure similarities: ponericins G, W, and L. Ponericin G1, G3, G4 and G6 demonstrated antimicrobial activity. Ponericins G share about 60% sequence similarity with cecropins and these have a broad spectrum of activity against bacteria. Peptides family W shares about 70% sequence similarity with Gaegurin 5 (Rana rugosa) and melittin (discussed in previous topics). Gaegurin 5 exhibits a broad spectrum of antimicrobial action against bacteria, fungi, and protozoa and has very little hemolytic action. The ponericin L2 from the third family has only an antibacterial action, and shares important sequence similarities with dermaseptin 5, which has strong antimicrobial action against bacteria, yeast, fungi, and protozoa [238]. A cytotoxic peptide from the venom of the ant Myrmecia pilosula, Pilosulin 1, was identified as a potential novel antimicrobial peptide sequence. It outlined a potent and broad spectrum antimicrobial activity including standard and multi-drug resistant gram-positive and gram-negative bacteria and Candida albicans [239]. Two antimicrobial peptides from centipede venoms, scolopin 1 and 2 were identified from venoms of Scolopendra subspinipes mutilan [240].

7.4. Toxins acting on inflammatory and nociceptive responses

Venom from the tropical ant Pseudomyrex triplarinus relieves pain and inflammation in rheumatoid arthritis [241]. Venom from the P. triplarinus contains peptides called myrmexins that relieve pain and inflammation in patients with rheumatoid arthritis and inhibit inflammatory carragenin-induced edema in mice [242].

7.5. Toxins acting on immunological system

The most frequent cause of insect venom allergy in the Southeastern USA is the imported fire ant and the allergens are among the most potent known. Fire ant venom is a potent allergy-inducing agent containing four major allergens, Sol i I, Sol i II, Sol i III and Sol i IV [243-244].

7.6. Toxins with anticancer and cytotoxic activities

Solenopsin A, a primary alkaloid from the fire ant Solenopsis invicta, exhibits antiangiogenic activity. Among the results obtained in this study, one of the most interesting was the selective inhibition of Akt by solenopsin in vitro, that is of great interest since few Akt inhibitors have been developed, and Akt is a key molecular target in the pharmacological treatment of cancer [245]. Glycosphingolipid 7, identified in the millipede Parafontaria laminata armigera, suppressed cell proliferation and this effect was associated with suppression of the activation of FAK (focal adhesion kinase), Erk (extracellular signal-regulated kinase), and Akt in melanoma B16F10 cells. Cells treated with glycosphingolipid 7 reduced the expression of the proteins responsible for the progression of cell cycle, cyclin D1 and CDK4 [246].

7.7. Toxins with insecticides applications

Peptides named ponericins from ant Pachycondyla goeldii have a marked action as insecticides. Among the peptides showed insecticidal activity are the ponericins G1, G2 and ponericins belonging to the family W [238].

In Table 1, is presented a summary of the main biotechnological/pharmacological applications of toxins from venomous animals covered in this chapter.

Toxins acting on cardiovascular system
SnakesAgkistrodon halys blomhoffiiNPAnti-hypertensive agent [21]
Bothrops jararacaBPPAnti-hypertensive agent (development of captopril and derivatives) [16]
NPAnti-hypertensive agent [4]
Bungarus flavicepsNPAnti-hypertensive agent [24]
Crotalus durissus cascavellaNPAnti-hypertensive agent [23]
Crotalus durissus terrificusBPPAnti-hypertensive agent [17]
Dendroaspis angusticepsDNPAnti-hypertensive agent: natriuretic peptide [19]
C10S2C2Anti-hypertensive drug: L-type Ca2+channels blocker [27]
Dendroaspis jamesoni kaimosaeS4C8Anti-hypertensive agent: L-type Ca2+channels blocker[27]
Dendroaspis polylepis polylepisCalciseptineAnti-hypertensive agent: L-type Ca2+channels blocker[25]
FS2 toxinsAnti-hypertensive agent: L-type Ca2+channels blocker[26]
Micrurus corallinusNPAnti-hypertensive agent[20]
Pseudocerastes persicusNPAnti-hypertensive agent[22]
Trimeresurus flavoviridisNPAnti-hypertensive agent[21]
Trimeresurus stejnegeriStejnihaginAnti-hypertensive agent: L-type Ca2+channels blocker[29]
ScorpionsButhus martensiiBPPAnti-hypertensive agent[97]
Leiurus quinquestriatusBPPAnti-hypertensive agent[98]
Tityus serrulatusBPPAnti-hypertensive agent[96]
SpidersGrammostola spatulataGsMtx-4Blocks cardiac stretch-activated ion channels and suppresses atrial fibrillation in rabbits[147]
Toads and FrogsAtelopus zetekiAtelopidtoxinHypotensive agent and ventricular fibrillation inductor[167]
Bufo bufo gargarizansBufalinNaK+-ATPase inhibitor[165]
Pseudophryne coriaceaSemi-purified skin extractsHypotensive agent [168]
Rana igromaculataBradykininHypotensive agent and smooth muscle exciting substance[11]
Rana margarataeMargaratensinNeurotensin-like peptide[164]
CinobufaginNaK+ATPase inhibitor[165]
Rana temporariaBradykininHypotensive agent and smooth muscle exciting substance[11]
Bees and WaspsApis melliferaCardiopepBeta-adrenergio-like stimulant and anti-arrhythmic agent[185]
Vespa basalisMastoparan BAnti-hypertensive agent [186]
Toxins acting on hemostasis
SnakesAgkistrodon rhodostomaAncrodAnticoagulant and defibrinogenating agent (Viprinex®)[34]
Bothrops alternatusBhalterninTreatment and prevention of thrombotic disorders[35]
Bothrops atroxBatroxobinAnticoagulant and defibrinogenating agent (Defibrase®)[33]
Mixture of a TLE with a thromboplastin-like enzymeTreatment of hemorrhages (Haemocoagulase®)[13]
Bothrops erythromelasBE-I-PLA2 Antiplatelet agent[39]
Bothrops leucurusBleucMPTreatment and prevention of cardiovascular disorders and strokes[36]
LeucuroginAntiplatelet agent[32]
Echis carinatusEchistatinAntiplatelet agent[30]
Sisturus miliaris barbouriBarbourinAntiplatelet agent[31]
Trimeresurus malabaricusTrimarinTreatment and prevention of thrombotic disorders[38]
Vipera lebetinaVLH2Treatment and prevention of thrombotic disorders[37]
SpidersLoxosceles.Phospholipase-DPlatelet aggregation inductor[149]
Toads and FrogsBombina maximaBm-ANXA2Antiplatelet agent[169]
Bees and WaspsBombus hypocrita sapporoensisBs-VSPProthrombin activator, thrombin-like protease and a plasmin-like protease agent[190]
Bombus ignites
Prothrombin activator, thrombin-like protease and a plasmin-like protease agent[188]
Bi-KTI Plasmin inhibitor agent[187]
Bombus terrestrisBt-VSPProthrombin activator, thrombin-like protease and a plasmin-like protease agent[189]
Vespa orientalisProtease IAnticoagulant agent[192]
Vespa magnificaMagnifinInductor platelet aggregation agent[193]
MagnvesinAnticoagulant agent[191]
Ants, Centipedes and Caterpillars
Lonomia achelousLonomin VInhibitor platelet aggregation agent[236]
Lonomia obliqua
LopapProthrombin activator agent[233]
LonofibraseFibrinogenolytic and fibrinolytic agent Agent[234]
LosacProcoagulant agent[235]
Toxins with antibiotic activity
SnakesBothrops alternatusBalt-LAAO-IAnti-bacterial agent[42]
Bothrops asperMyotoxin IIAnti-bacterial agent[50]
Bothrops jararacaLAAOAntiparasitic agent[48]
Bothrops marajoensisBmarLAAOAnti-bacterial, antifungal and antiparasitic agent[47]
Bothrops neuwiediNeuwiedaseAntiparasitic agent[55]
Bothrops pirajaiBpirLAAO-IAnti-bacterial and antiparasitic agent[44]
Bungarus fasciatusBFPAAnti-bacterial agent[53]
Crotalus durissus cascavellaCasca LAOAnti-bacterial agent[45]
Crotalus durissus terrificusCrotoxinAntiviral agent[56]
PLA2-CBAntiviral agent[56]
PLA2-ICAntiviral agent[56]]
Echis carinatusEcTx-IAnti-bacterial agent[51]
Naja atraVgf-1Anti-bacterial agent[54]
Naja naja oxianaLAAOAnti-bacterial agent[46]
Porthidium nasutumPnPLA2 Anti-bacterial agent[52]
Trimeresurus jerdoniiTJ-LAOAnti-bacterial agent[41]
Trimeresurus mucrosquamatusTM-LAOAnti-bacterial agent[43]
ScorpionsHadrurus aztecusHadrurinAnti-bacterial agent[110]
Leiurus quinquestriatusDefensinAnti-bacterial agent[102]
Opistophthalmus carinatusOpistoporin I/IIAnti-bacterial and antifungal agent[106]
Pandinus imperatorPandinin I/IIAntimicrobial agent[101]
ScorpineAnti-bacterial and antiparasitic agent[104]
Parabuthus schlechteriCationic amphipatic peptideAntimicrobial agent[109]
Tityus discrepansBactridinesAnti-bacterial agent[111]
SpidersLycosa carolinensisLycotoxins I/IIAntimicrobial agent[150]
Toads and FrogsBufo bufo gargarizans6-methyl-spinaceamineAnti-bacterial agent[172]
BufalinAntiviral agent[173]
CinobufaginAntiviral agent[173]
Bufo rubescensTelocinobufaginAnti-bacterial agent[170]
MarinobufaginAnti-bacterial agent[170]
Leptodactylus pentadactylusApinaceamineAnti-bacterial agent[172]
Leptodactylus syphaxSPXsAnti-bacterial agent[171]
Rhinella jimiTelocinobufaginAntiparasitic agent[174]
HellebrigeninAntiparasitic agent[174]
Bees and Wasps
Apis melliferaMelittinAnti-bacterial agent[195]
Bombus ignitesBi-BombolitinAnti-bacterial and antifungal agent[196]
Osmia rufaOsminAnti-bacterial and antifungal agent[197]
Vespa bicolorMP-VB1Anti-bacterial and antifungal agent[198]
VESP-VB1Anti-bacterial and antifungal agent[198]
Ants, Centipedes and CaterpillarsMyrmecia pilosulaPilosulin 1Anti-bacterial and antifungal agent[239]
Scolopendra subspinipes mutilanScolopin 1Anti-bacterial and antifungal agent[240]
Scolopin 2Anti-bacterial and antifungal agent[240]
Toxins acting on inflammatory and nociceptive responses
SnakesCrotalus durissus terrificusCrotamineAntinociceptive agent[63]
CrotoxinAntinociceptive agent[64]
HyalAnti-edematogenic agent[59]
Lachesis mutaβPLIPhospholipase inhibitor[58]
Naja atraCobrotoxinAntinociceptive agent[65]
Ophiophagus hannahHannalgesinAntinociceptive agent[66]
ScorpionsButhus martensiiBmKIT2Antinociceptive agent[115]
J123 peptideK+ channel blocker [112]
SpidersLoxosceles laetaSMase DPro-inflammatory agent[152]
Loxosceles reclusaPhospholipase DPro-inflammatory agent[152]
Psalmopoeus cambridgeiPsalmotoxin 1Antinociceptive and anti-inflammatory agent[151]
Toads and FrogsEpipedobates tricolorEpibatidineAntinociceptive agent[175]
Phyllomedusa spDeltorphinsOpioid analgesic agents[176]
DermorphinsOpioid analgesic agents[61]
Bees and WaspsApis melliferaMelittinAnti-inflammatory agent[202]
MCDPAnti-inflammatory agent[204]
Ants, Centipedes and CaterpillarsPseudomyrex triplarinusMyrmexinsAnti-inflammatory agent[242]
Toxins acting on immunological system
SnakesCrotalus durissus terrificusCrotapotinImmunossupressive agent[69]
CrotoxinImmunossupressive agent[68]
Ophiophagus hannahOVFComplement system activator agent[71]
ScorpionsAndroctonus mauretanicusKaliotoxinCa2+ activated K+ channel[121]
Centruroides limbatusHongotoxinK+ channel blocker[123]
Centruroides margaritatusMargatoxinImmunosuppressive agent[120]
Centruroides noxiusNoxiustoxinK+ channel blocker[124]
Leiurus quinquestriatusAgitoxin I/II/IIIK+ channel blocker[122]
Orthochirus scrobiculosusOSK1 Immunosuppressive agent[119]
Pandinus imperatorPi1K+ channel blocker[125]
SpidersLoxosceles laetaSMase DAntiserum[155]
Loxosceles reclusaSMase DAntiserum[155]
Bees and WaspsAgelaia pallipes pallipesProtonectin 1-6Chemotactic agent [211]
Apis melliferaApi m 1Allergen [213]
Api m 2Allergen [213]
Api m 6Allergen [206]
Pimpla hypochondriacarVPr1 Immunosuppressive agent[210]
rVPr3Immunosuppressive agent[210]
Polistes annularisPol a 5Allergen[213]
Polistes gallicusVesp c 1 (phospholipase A1)Allergen[207-208]
Vesp c 5 (antigen-5)Allergen[207-208]
Polybia paulistaPolybia-MPI Chemotactic agent [212]
Polybia-CPChemotactic agent [212]
Vespa magnificaVesp ma 2Allergen agent[207-208]
Vesp ma 5Allergen [207-208]
Vespula germanicaVes g 5 Allergen [213]
Vespula vulgarisVes v 5Allergen[213]
Ants, Centipedes and CaterpillarsSolenopsis invictaSol i IAllergen[244]
Sol i IIAllergen[243]
Sol i IIIAllergen[243]
Sol i IVAllergen[243]
Toxins with anticancer and cytotoxic activity
SnakesAgkistrodon acutusAccutinAnticancer agent: disintegrin[73]
ACTX-6Anticancer agent: L-amino acid oxidase[82]
Agkistrodon contortrixContortrostatinAnticancer agent: disintegrin[75]
Agkistrodon halys brevicaudusSalmosinAnticancer agent: disintegrin[74]
Bothrops brazilisPLA2Anticancer agent[86]
Bothrops jararacussuBJcuLAnticancer agent[89]
Bothrops leucurusBl-LAAOAnticancer agent[84]
MetalloproteinaseAnticancer agent[90]
LectinAnticancer agent[91]
Bothrops neuwiediisPLA2Anticancer agent[85]
Calloselasma rhodostomaRhodostominAnticancer agent: disintegrin[78]
Crotalus atroxCrotatroxinAnticancer agent: disintegrin[77]
Naja najaDisintegrinAnticancer agent[79]
Naja naja najasPLA2 Anticancer agent[87]
Ophiophagus hannahLAAOAnticancer agent[81]
Trimeresurus flavoviridisOHAP-1Anticancer agent: L-amino acid oxidase[83]
Trimeresurus jerdoniiJerdoninAnticancer agent: disintegrin[76]
ScorpionsHeterometrus bengalensisBengalinAnticancer agent[116]
Leiurus quinquestriatusChlorotoxinAnticancer agent[126]
rBmK CTaAnticancer agent[130]
Tityus discrepansNeopladine 1 and 2Anticancer agent[131]
SpidersAcanthoscurria gomesianaGomesinCytotoxic and anticancer agent[157]
Psalmopoeus cambridgeiPsalmotoxin 1Anticancer agent[156]
Toads and FrogsBombina variegata pachypusCutaneous venomAnticancer agent[180]
Bufo bufo gargarizansBufalinAnticancer agent[178]
CinobufaginAnticancer agent[178]
Formosan Ch’an SuBufotalinAnticancer agent[179]
Rana ridibundaBrevinin-2RAnticancer agent[181]
Venenum BufonisCBGAnticancer and immunotherapeutic agent to treat immune-mediated diseases[177]
Bees and WaspsLasioglossum laticepsLasioglossinsAnticancer agent[219]
Polybia paulistaPolybia-MPICytotoxic and antiproliferative agent[223]
Polybia-MP-IICytotoxic agent (hemolytic activity on erythrocytes)[222]
Polybia-MP-IIICytotoxic agent (hemolytic activity on erythrocytes)[222]
Ants, Centipedes and CaterpillarsParafontaria laminata armigeraGlycosphingolipid 7Anticancer agent[246]
Solenopsis invictaSolenopsin AAnticancer agent[245]
Toxins with insulin releasing activity
Toads and FrogsAgalychnis litodryasPeptides from skin secretionInsulin-releasing activity[182]
Bees and WaspsWasp venomMastoparanStimulator of insulin secretion agent[226]
Toxins with insecticides applications
ScorpionsAndroctonus australisAaH IT1Anti-insect agent[142]
Buthotus judaicuBjα ITAnti-insect agent[137]
Buthus martensiiBmKM1Anti-insect agent[140]
Buthus martensiiBm 32/33Anti-insect agent[144]
Buthus occitanusBot IT1Anti-insect agent[135]
Buthus occitanus mardocheiBom III/IVAnti-insect agent[139]
Leiurus quinquestriatusLqhα ITAnti-insect agent[134]
Leiurus quinquestriatus hebraeusLqh III/ VI/ VIIAnti-insect agent[141]
Odonthobuthus doriaeOD1Anti-insect agent[137]
SpidersLoxosceles arizonicaSMase DAnti-insect agent[161]
Loxosceles intermediaLiTxx1/ LiTxx2/ LiTxx3Anti-insect agent[158]
Paracoelotes luctuosusδ-PaluIT1/ δ-PaluIT2Anti-insect agent[162]
Phoneutria nigriventerTx4(6-1)Anti-insect agent[160]
Ants, Centipedes and CaterpillarsPachycondyla goeldiiPonericins G1Insecticide Agent[238]
Ponericins G2Insecticide Agent[238]
Ponericins family WInsecticide Agent[238]

Table 1.

Summary of the main biotechnological/pharmacological applications of toxins from venomous animals.

8. Conclusion

The biodiversity of venoms and toxins made it a unique source of leads and structural templates from which new therapeutic agents may be developed. Such richness can be useful to biotechnology and/or pharmacology in many ways, with the prospection of new toxins in this field. Venoms of several animal species such as snakes, scorpions, toads, frogs and their active components have shown potential biotechnological applications. Recently, using molecular biology techniques and advanced methods of fractionation, researchers have obtained different native and/or recombinant toxins and enough material to afford deeper insight into the molecular action of these toxins. The mechanistic elucidation of toxins as well as their use as drugs will depend on insight into toxin biochemical classification, structure/conformation determination and elucidation of toxin biological activities based on their molecular organization, in addition to their mechanism of action upon different cell models as well as their cellular receptors. Furthermore, expansions in the fields of chemistry and biology have guided new drug discovery strategies to maximize the identification of biotechnological relevant toxins. In fact, with so much diversity in the terrestrial fauna to be explored in the future, is extremely important providing a further stimulus to the preservation of the precious ecosystem in order to develop the researches focusing on identify and isolate new molecules with importance in biotechnology or pharmacology.


Our research on this field is supported by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Norte (FAPERN), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).


1 - A. Gomes, P. Bhattacharjee, R. Mishra, A. K. Biswas, S. C. Dasgupta, B. Giri, A. Debnath, S. D. Gupta, T. Das, 2010 Anticancer potential of animal venoms and toxins. Indian Journal of Experimental Biology 48 2 93 103
2 - S. Braud, C. Bon, A. Wisner, 2000 Snake venom proteins acting on hemostasis. Biochimie 82 9-10 851 9
3 - T. S. Kang, D. Georgieva, N. Genov, M. T. Murakami, M. Sinha, R. P. Kumar, P. Kaur, S. Kumar, S. Dey, S. Sharma, A. Vrielink, C. Betzel, S. Takeda, R. K. Arni, T. P. Singh, R. M. Kini, 2011 Enzymatic toxins from snake venom: Structural characterization and mechanism of catalysis. FEBS Journal 278 23 4544 4576
4 - N. Murayama, M. A. F. Hayashi, H. Ohi, L. A. F. Ferreira, V. V. Hermann, H. Saito, Y. Fujita, S. Higuchi, B. L. Fernandes, T. Yamane, A. C. M. Camargo, 1997 Cloning and sequence analysis of a Bothrops jararaca cDNA encoding a precursor of seven bradykinin-potentiating peptides and a C-type natriuretic peptide Proceedings of the National Academy of Sciences of the United States of America 94 4 1189 1193
5 - V. Quintero-Hernández, E. Ortiz, M. Rendón-Anaya, E. F. Schwartz, B. Becerril, G. Corzo, L. D. Possani, 2011 Scorpion and spider venom peptides: Gene cloning and peptide expression. Toxicon 58 8 644 663
6 - T. Verano-Braga, C. Rocha-Resende, D. M. Silva, D. Ianzer, M. F. Martin-Eauclaire, P. E. Bougis, ME De Lima, R. A. S. Santos, A. M. C. Pimenta, 2008 Tityus serrulatus Hypotensins: A new family of peptides from scorpion venom. Biochemical and Biophysical Research Communications 371 3 515 520
7 - D. D. Almeida, K. C. Scortecci, L. S. Kobashi, L. F. Agnez-Lima, S. R. B. Medeiros, A. A. Silva-Junior, I. L. M. Junqueira-de-Azevedo, M. F. Fernandes-Pedrosa, 2012 Profiling the resting venom gland of the scorpion Tityus stigmurus through a transcriptomic survey. BMC Genomics 13 362
8 - V. L. Petricevich, 2010 Scorpion venom and the inflammatory response. Mediators of Inflammation 903295
9 - D. V. Tambourgi, M. F. F. Pedrosa, Berg. C. W. Van Den, R. M. Gonçalves-de-Andrade, M. Ferracini, D. Paixão-Cavalcante, B. P. Morgan, N. K. Rushmere, 2004 Molecular cloning, expression, function and immunoreactivities of members of a gene family of sphingomyelinases from Loxosceles venom glands. Molecular Immunology 41 8 831 840
10 - A. Senff-Ribeiro, da. Henrique, P. Silva, O. M. Chaim, L. H. Gremski, K. S. Paludo, R. Bertoni da. Silveira, W. Gremski, O. C. Mangili, S. S. Veiga, 2008 Biotechnological applications of brown spider (Loxosceles genus) venom toxins. Biotechnology Advances 26 3 210 218
11 - GG. Habermehl, 1995 Antimicrobial activity of amphibian venoms Studies in Natural Products Chemistry, Part C 327 339
12 - E. Habermann, 1972 Bee and wasp venoms. Science 177 4046 314 322
13 - T. Sajevic, A. Leonardi, I. Križaj, 2011 Haemostatically active proteins in snake venoms Toxicon 57 5 627 645
14 - C. Y. Koh, R. M. Kini, 2012 From snake venom toxins to therapeutics- cardiovascular examples. Toxicon 59 4 497 506
15 - W. C. Hodgson, G. K. Isbister, 2009 The application of toxins and venoms to cardiovascular drug discovery. Current Opinion in Pharmacology 9 2 173 176
16 - S. H. Ferreira, 1965 A bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca. British Journal of Pharmacology and Chemotherapy 24 1 163 169
17 - S. A. Barreto, L. C. A. G. Chaguri, B. C. Prezoto, I. Lebrun, 2012 Characterization of two vasoactive peptides isolated from the plasma of the snake Crotalus durissus terrificusBiomedicine and Pharmacotherapy66 4 256 265
18 - S. Vink, A. H. Jin, K. J. Poth, G. A. Head, P. F. Alewood, 2012 Natriuretic peptide drug leads from snake venom. Toxicon 59 4 434 445
19 - H. Schweitz, P. Vigne, D. Moinier, C. Frelin, M. Lazdunski, 1992 A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). Journal of Biological Chemistry Jul 15;267 20 13928 13932
20 - P. L. Ho, M. B. Soares, T. Maack, I. Gimenez, G. Puorto, M. D. F. D. Furtado, I. Raw, 1997 Cloning of an unusual natriuretic peptide from the South American coral snake Micrurus corallinus European Journal of Biochemistry 250 1 144 149
21 - S. Higuchi, N. Murayama, K. Saguchi, H. Ohi, Y. Fujita, A. C. M. Camargo, T. Ogawa, M. Deshimaru, M. Ohno, 1999 Bradykinin-potentiating peptides and C-type natriuretic peptides from snake venom. Immunopharmacology 44 1-2 129 135
22 - M. Amininasab, M. M. Elmi, N. Endlich, K. Endlich, N. Parekh, H. Naderi-Manesh, J. Schaller, H. Mostafavi, M. Sattler, M. N. Sarbolouki, C. Muhle-Goll, 2004 Functional and structural characterization of a novel member of the natriuretic family of peptides from the venom of Pseudocerastes persicus. FEBS Letters 557 1-3 104 108
23 - J. S. A. M. Evangelista, A. M. C. Martins, N. R. F. Nascimento, C. M. Sousa, R. S. Alves, D. O. Toyama, M. H. Toyama, J. J. F. Evangelista, D. B. Menezes, M. C. Fonteles, M. E. A. Moraes, H. S. A. Monteiro, 2008 Renal and vascular effects of the natriuretic peptide isolated from Crotalus durissus cascavella venom. Toxicon 52 7 737 744
24 - AS Siang, R. Doley, F. J. Vonk, R. M. Kini, 2010 Transcriptomic analysis of the venom gland of the red-headed krait (Bungarus flaviceps) using expressed sequence tags BMC Molecular Biology 11
25 - J. R. De Weille, H. Schweitz, P. Maes, A. Tartar, M. Lazdunski, 1991 Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L-type calcium channel. Proceedings of the National Academy of Sciences of the United States of America 88 6 2437 2440
26 - O. Yasuda, S. Morimoto, B. Jiang, H. Kuroda, T. Kimura, S. Sakakibara, K. Fukuo, S. Chen, M. Tamatani, T. Ogihara, 1994 FS2. A mamba venom toxin, is a specific blocker of the L-type calcium channels. Artery DCOM- 19961204 21 5 287 302
27 - F. J. Joubert, N. Taljaard, 1980 The complete primary structures of two reduced and S-carboxymethylated Angusticeps-type toxins from Dendroaspis angusticeps (green mamba) venom. BBA- Protein Structure 623 2 449 456
28 - F. J. Joubert, N. Taljaard, 1980 The primary structure of a short neurotoxin homologue (S4C8) from Dendroaspis jamesoni kaimosae (Jameson’s mamba) venom International Journal of Biochemistry 12 4 567 574
29 - P. Zhang, J. Shi, B. Shen, X. Li, Y. Gao, Z. Zhu, Z. Zhu, Y. Ji, M. Teng, L. Niu, 2009 Stejnihagin, a novel snake metalloproteinase from Trimeresurus stejnegeri venom, inhibited L-type Ca2+ channels Toxicon 53 2 309 315
30 - S. Bilgrami, S. Tomar, S. Yadav, P. Kaur, J. Kumar, T. Jabeen, S. Sharma, T. P. Singh, 2004 Crystal structure of Schistatin, a disintegrin homodimer from Saw-scaled Viper (Echis carinatus) at 2.5 Å Resolution. Journal of Molecular Biology 341 3 829 837
31 - R. M. Scarborough, J. W. Rose, MA Hsu, D. R. Phillips, V. A. Fried, A. M. Campbell, L. Nannizzi, I. F. Charo, 1991 Barbourin: a GPIIb-IIIa-specific integrin antagonist from the venom of Sistrurus m. barbouri. Journal of Biological Chemistry 266 15 9359 9362
32 - D. A. Higuchi, M. C. Almeida, C. C. Barros, E. F. Sanchez, P. R. Pesquero, E. A. S. Lang, M. Samaan, R. C. Araujo, J. B. Pesquero, J. L. Pesquero, 2011 Leucurogin, a new recombinant disintegrin cloned from Bothrops leucurus (white-tailed-jararaca) with potent activity upon platelet aggregation and tumor growth Toxicon 58 1 123 129
33 - K. Stocker, G. H. Barlow, 1976 The coagulant enzyme from Bothrops atrox venom (batroxobin). Methods in Enzymology 45 214
34 - C. Nolan, L. S. Hall, G. H. Barlow, 1976 Ancrod, the coagulating enzyme from Malayan pit viper (Agkistrodon rhodostoma) venom. Methods in Enzymology 45 205
35 - J. O. Costa, K. C. Fonseca, C. C. N. Mamede, M. E. Beletti, N. A. Santos-Filho, A. M. Soares, E. C. Arantes, S. N. S. Hirayama, H. S. Selistre-de-Araújo, F. Fonseca, F. Henrique-Silva, N. Penha-Silva, F. Oliveira, 2010 Bhalternin: functional and structural characterization of a new thrombin-like enzyme from Bothrops alternatus snake venom. Toxicon 55 7 1365 1377
36 - M. S. R. Gomes, M. R. Queiroz, C. C. N. Mamede, MM Mendes, A. Hamaguchi, M. I. Homsi-Brandeburgo, M. V. Sousa, E. N. Aquino, MS Oliveira. F. Castro, V. M. Rodrigues, 2011 Purification and functional characterization of a new metalloproteinase (BleucMP) from Bothrops leucurus snake venom Comparative Biochemistry and Physiology, Part C: Toxicology and Pharmacology 153 3 290 300
37 - L. Hamza, C. Gargioli, S. Castelli, S. Rufini, F. Laraba-Djebari, 2010 Purification and characterization of a fibrinogenolytic and hemorrhagic metalloproteinase isolated from Vipera lebetina venom Biochimie 92 7 797 805
38 - R. V. Kumar, C. D. R. Gowda, H. V. Shivaprasad, J. M. Siddesha, B. K. Sharath, B. S. Vishwanath, 2010 Purification and characterization of ‘Trimarin’ a hemorrhagic metalloprotease with factor Xa-like activity, from Trimeresurus malabaricus snake venom. Thrombosis Research 126 5 e356 e364
39 - J. C. A. Modesto, P. J. Spencer, M. Fritzen, R. C. Valença, M. L. V. Oliva, M. B. Silva, A. M. Chudzinski-Tavassi, M. C. Guarnieri, 2006 BE-I-PLA2, a novel acidic phospholipase A2 from Bothrops erythromelas venom: isolation, cloning and characterization as potent anti-platelet and inductor of prostaglandin I2 release by endothelial cells. Biochemical Pharmacology 72 3 377 384
40 - I. Chopra, L. Hesse, A. J. O’Neill, 2002 Exploiting current understanding of antibiotic action for discovery of new drugs.Symposium Series Society for Applied Microbiology;31 4S 15S
41 - Q. M. Lu, Q. Wei, Y. Jin, J. F. Wei, W. Y. Wang, Y. L. Xiong, 2002 L-amino acid oxidase from Trimeresurus jerdonii snake venom: purification, characterization, platelet aggregation-inducing and antibacterial effects. Journal of Natural Toxins 11 4 345 352
42 - R. G. Stábeli, S. Marcussi, G. B. Carlos, R. C. L. R. Pietro, H. S. Selistre-de-Araújo, J. R. Giglio, E. B. Oliveira, A. M. Soares, 2004 Platelet aggregation and antibacterial effects of an L-amino acid oxidase purified from Bothrops alternatus snake venom. Bioorganic and Medicinal Chemistry 12 11 2881 2886
43 - J. F. Wei, Q. Wei, Q. M. Lu, H. Tai, Y. Jin, W. Y. Wang, Y. L. Xiong, 2003 Purification, characterization and biological activity of an L-amino acid oxidase from Trimeresurus mucrosquamatus venom. Acta Biochimica et Biophysica Sinica 35 3 219 224
44 - L. F. M. Izidoro, M. C. Ribeiro, G. R. L. Souza, C. D. Sant’Ana, A. Hamaguchi, M. I. Homsi-Brandeburgo, L. R. Goulart, R. O. Beleboni, A. Nomizo, S. V. Sampaio, A. M. Soares, V. M. Rodrigues, 2006 Biochemical and functional characterization of an L-amino acid oxidase isolated from Bothrops pirajai snake venom. Bioorganic and Medicinal Chemistry 14 20 7034 7043
45 - M. H. Toyama, D. D. O. Toyama, L. F. D. Passero, M. D. Laurenti, C. E. Corbett, T. Y. Tomokane, F. V. Fonseca, E. Antunes, P. P. Joazeiro, L. O. S. Beriam, M. A. C. Martins, H. S. A. Monteiro, M. C. Fonteles, 2006 Isolation of a new L-amino acid oxidase from Crotalus durissus cascavella venom. Toxicon 47 1 47 57
46 - M. Samel, K. Tõnismägi, G. Rönnholm, H. Vija, J. Siigur, N. Kalkkinen, E. Siigur, 2008 L-amino acid oxidase from Naja naja oxiana venom. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 149 4 572 580
47 - A. F. C. Torres, R. T. Dantas, M. H. Toyama, E. Diz-Filho, F. J. Zara, M. G. R. Queiroz, N. A. P. Nogueira, M. R. Oliveira, D. O. Toyama, H. S. A. Monteiro, A. M. C. Martins, 2010 Antibacterial and antiparasitic effects of Bothrops marajoensis venom and its fractions: phospholipase A2 and L-amino acid oxidase. Toxicon 55 4 795 804
48 - P. Deolindo, A. S. Teixeira-Ferreira, R. A. Da Matta, E. W. Alves, 2010 L-Amino acid oxidase activity present in fractions of Bothrops jararaca venom is responsible for the induction of programmed cell death in Trypanosoma cruzi. Toxicon 56 6 944 955
49 - R. K. Arni, R. J. Ward, 1996 Phospholipase A2- a structural review. Toxicon 34 8 827 841
50 - C. Santamaría, S. Larios, Y. Angulo, J. Pizarro-Cerda, J. Gorvel-P, E. Moreno, B. Lomonte, 2005 Antimicrobial activity of myotoxic phospholipases A2 from crotalid snake venoms and synthetic peptide variants derived from their C-terminal region Toxicon 45 7 807 815
51 - R. P. Samy, P. Gopalakrishnakone, H. Bow, P. N. Puspharaj, V. T. K. Chow, 2010 Identification and characterization of a phospholipase A2 from the venom of the Saw-scaled viper: novel bactericidal and membrane damaging activities. Biochimie 92 12 1854 1866
52 - L. J. Vargas, M. Londoño, J. C. Quintana, C. Rua, C. Segura, B. Lomonte, V. Núñez, 2012 An acidic phospholipase A2 with antibacterial activity from Porthidium nasutum snake venom. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 161 4 341 347
53 - C. Xu, D. Ma, H. Yu, Z. Li, J. Liang, G. Lin, Y. Zhang, R. Lai, 2007 A bactericidal homodimeric phospholipases A2 from Bungarus fasciatus venom. Peptides 28 5 969 973
54 - J. P. Xie, J. Yue, Y. L. Xiong, W. Y. Wang, S. Q. Yu, H. H. Wang, 2003 In vitro activities of small peptides from snake venom against clinical isolates of drug-resistant Mycobacterium tuberculosis. International Journal of Antimicrobial Agents 22 2 172 174
55 - L. M. Bastos, R. J. O. Júnior, D. A. O. Silva, J. R. Mineo, C. U. Vieira, D. N. S. Teixeira, M. I. Homsi-Brandeburgo, V. M. Rodrigues, A. Hamaguchi, 2008 Toxoplasma gondii: Effects of neuwiedase, a metalloproteinase from Bothrops neuwiedi snake venom, on the invasion and replication of human fibroblasts in vitro Experimental Parasitology 120 4 391 396
56 - V. D. M. Muller, R. R. Russo, Cintra. A. C. Oliveira, M. A. Sartim, R.d. M. Alves-Paiva, L. T. M. Figueiredo, S. V. Sampaio, V. H. Aquino, 2012 Crotoxin and phospholipases A2 from Crotalus durissus terrificus showed antiviral activity against dengue and yellow fever viruses. Toxicon 59 4 507 515
57 - R. M. Kini, 2003 Excitement ahead: structure, function and mechanism of snake venom phospholipase A2 enzymes. Toxicon 42 8 827 840
58 - R. M. Lima, M. I. Estevão-Costa, I. L. M. Junqueira-de-Azevedo, Ho. P. Lee, Diniz. M. R. Vasconcelos, C. L. Fortes-Dias, 2011 Phospholipase A2 inhibitors (βPLIs) are encoded in the venom glands of Lachesis muta (Crotalinae, Viperidae) snakes. Toxicon 57 1 172 175
59 - K. C. F. Bordon, M. G. Perino, J. R. Giglio, E. C. Arantes, 2012 198. Isolation, enzymatic characterization and action as spreading factor of a hyaluronidase from Crotalus durissus terrificus snake venom. Toxicon 60 2 197
60 - F. Garcia, M. H. Toyama, F. R. Castro, P. L. Proença, S. Marangoni, L. M. B. Santos, 2003 Crotapotin induced modification of T lymphocyte proliferative response through interference with PGE2 synthesis Toxicon 42 4 433 437
61 - W. Rajendra, A. Armugam, K. Jeyaseelan, 2004 Toxins in anti-nociception and anti-inflammation Toxicon 44 1 1 17
62 - R. Giorgi, MM Bernardi, Y. Cury, 1993 Analgesic effect evoked by low molecular weight substances extracted from Crotalus durissus terrificus venom. Toxicon 31 10 1257 1265
63 - A. C. Mancin, A. M. Soares, S. H. Andrião-Escarso, V. M. Faça, L. J. Greene, S. Zuccolotto, I. R. Pelá, J. R. Giglio, 1998 The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: A biochemical and pharmacological study. Toxicon 36 12 1927 1937
64 - H. L. Zhang, R. Han, Z. X. Chen, B. W. Chen, Z. L. Gu, P. F. Reid, L. N. Raymond, Z. H. Qin, 2006 Opiate and acetylcholine-independent analgesic actions of crotoxin isolated from Crotalus durissus terrificus venom. Toxicon 48 2 175 182
65 - R. Chen, S. E. Robinson, 1992 The effect of cobrotoxin on cholinergic neurons in the mouse. Life Sciences 51 13 1013 1019
66 - X. C. Pu, P. T. H. Wong, P. Gopalakrishnakone, 1995 A novel analgesic toxin (Hannalgesin) from the venom of king cobra (Ophiophagus hannah). Toxicon 33 11 1425 1431
67 - A. Mirshafiey, 2007 Venom therapy in multiple sclerosis Neuropharmacology 53 3 353 361
68 - A. Rangel-Santos, C. Lima, M. Lopes-Ferreira, D. F. Cardoso, 2004 Immunosuppresive role of principal toxin (crotoxin) of Crotalus durissus terrificus venom Toxicon 44 6 609 616
69 - F. R. Castro, AS Farias, P. L. F. Proença, C. De La Hoz, F. Langone, E. C. Oliveira, M. H. Toyama, S. Marangoni, L. M. B. Santos, 2007 The effect of treatment with crotapotin on the evolution of experimental autoimmune neuritis induced in Lewis rats. Toxicon 49 3 299 305
70 - C. W. Vogel, D. C. Fritzinger, 2010 Cobra venom factor: structure, function, and humanization for therapeutic complement depletion. Toxicon 56 7 1198 1222
71 - L. Zeng, Q. Y. Sun, Y. Jin, Y. Zhang, W. H. Lee, Y. Zhang, 2012 Molecular cloning and characterization of a complement-depleting factor from king cobra, Ophiophagus hannah Toxicon 60 3 290 301
72 - S. L. Goodman, M. Picard, 2012 Integrins as therapeutic targets Trends in Pharmacological Sciences 33 7 405 412
73 - C. H. Yeh, H. C. Peng, T. F. Huang, 1998 Accutin, a new disintegrin, inhibits angiogenesis in vitro and in vivo by acting as integrin α(v)β3 antagonist and inducing apoptosis. Blood 92 9 3268 3276
74 - I. C. Kang, DS Kim, Y. Jang, K. H. Chung, 2000 Suppressive mechanism of salmosin, a novel disintegrin in B16 melanoma cell metastasis Biochemical and Biophysical Research Communications 275 1 169 173
75 - R. Minea, S. Swenson, F. Costa, T. C. Chen, F. S. Markland, 2006 Development of a novel recombinant disintegrin, contortrostatin, as an effective anti-tumor and anti-angiogenic agent Pathophysiology of Haemostasis and Thrombosis 34 4-5 177 183
76 - X. D. Zhou, Y. Jin, R. Q. Chen, Q. M. Lu, J. B. Wu, W. Y. Wang, Y. L. Xiong, 2004 Purification, cloning and biological characterization of a novel disintegrin from Trime resurus jerdonii venom.Toxicon43 1 69 75
77 - J. A. Galán, E. E. Sánchez, A. Rodríguez-Acosta, J. G. Soto, S. Bashir, M. A. Mc Lane, C. Paquette-Straub, J. C. Pérez, 2008 Inhibition of lung tumor colonization and cell migration with the disintegrin crotatroxin 2 isolated from the venom of Crotalus atrox. Toxicon 51 7 1186 1196
78 - C. H. Yeh, H. C. Peng, R. S. Yang, T. F. Huang, 2001 Rhodostomin, a snake venom disintegrin, inhibits angiogenesis elicited by basic fibroblast growth factor and suppresses tumor growth by a selective αv/β3 blockade of endothelial cells. Molecular Pharmacology 59 5 133 1342
79 - R. Thangam, P. Gunasekaran, K. Kaveri, G. Sridevi, S. Sundarraj, M. Paulpandi, S. Kannan, 2012 A novel disintegrin protein from Naja naja venom induces cytotoxicity and apoptosis in human cancer cell lines in vitro Process Biochemistry 47 8 1243 1249
80 - C. Guo, S. Liu, Y. Yao, Q. Zhang, M. Z. Sun, 2012 Past decade study of snake venom L-amino acid oxidase Toxicon 60 3 302 311
81 - M. Y. Ahn, B. M. Lee, Y. S. Kim, 1997 Characterization and cytotoxicity of L-amino acid oxidase from the venom of king cobra (Ophiophagus hannah). International Journal of Biochemistry and Cell Biology 29 6 911 919
82 - L. Zhang, W. T. Wu, 2008 Isolation and characterization of ACTX-6: a cytotoxic L-amino acid oxidase from Agkistrodon acutus snake venom Natural Product Research 22 6 554 563
83 - L. K. Sun, Y. Yoshii, A. Hyodo, H. Tsurushima, A. Saito, T. Harakuni, Y. P. Li, K. Kariya, M. Nozaki, N. Morine, 2003 Apoptotic effect in the glioma cells induced by specific protein extracted from Okinawa Habu (Trimeresurus flavoviridis) venom in relation to oxidative stress Toxicology in Vitro 17 2 169 177
84 - G. B. Naumann, L. F. Silva, L. Silva, G. Faria, M. Richardson, K. Evangelista, M. Kohlhoff, C. M. F. Gontijo, A. Navdaev, F. F. Rezende, J. A. Eble, E. F. Sanchez, 2011 Cytotoxicity and inhibition of platelet aggregation caused by an L-amino acid oxidase from Bothrops leucurus venom. Biochimica et Biophysica Acta (BBA)- General Subjects 1810 7 683 694
85 - J. J. Daniele, I. D. Bianco, C. Delgado, D. B. Carrillo, G. D. Fidelio, 1997 A new phospholipase A2 isoform isolated from Bothrops neuwiedii (Yarara chica) venom with novel kinetic and chromatographic properties. Toxicon 35 8 1205 1215
86 - T. R. Costa, D. L. Menaldo, C. Z. Oliveira, N. A. Santos-Filho, S. S. Teixeira, A. Nomizo, A. L. Fuly, M. C. Monteiro, B. M. De Souza, M. S. Palma, R. G. Stábeli, S. V. Sampaio, A. M. Soares, 2008 Myotoxic phospholipases A2 isolated from Bothrops brazili snake venom and synthetic peptides derived from their C-terminal region: cytotoxic effect on microorganism and tumor cells. Peptides 29 10 1645 1656
87 - L. M. S. Rudrammaji, T. V. Gowda, 1998 Purification and characterization of three acidic, cytotoxic phospholipases A2 from Indian cobra (Naja naja naja) venom. Toxicon 36 6 921 932
88 - M. A. Soares, P. B. Pujatti, C. L. Fortes-Dias, L. Antonelli, R. G. Santos, 2010 Crotalus durissus terrificus venom as a source of antitumoral agents. Journal of Venomous Animals and Toxins Including Tropical Diseases 16 3 480 492
89 - S. Nolte, D. C. Damasio, A. C. Baréa, J. Gomes, A. Magalhães, L. F. C. M. Zischler, P. M. Stuelp-Campelo, S. L. Elífio-Esposito, M. C. Roque-Barreira, CA Reis-Amaral, A. N. Moreno, 2012 BJcuL, a lectin purified from Bothrops jararacussu venom, induces apoptosis in human gastric carcinoma cells accompanied by inhibition of cell adhesion and actin cytoskeleton disassembly Toxicon 59 1 81 85
90 - L. M. Gabriel, E. F. Sanchez, S. G. Silva, R. G. dos Santos, 2012 Tumor cytotoxicity of leucurolysin-B, a P-III snake venom metalloproteinase from Bothrops leucurus. Journal of Venomous Animals and Toxins Including Tropical Diseases 18 1 24 33
91 - E. S. Nunes, M. A. A. Souza, A. F. M. Vaz, T. G. Silva, J. S. Aguiar, A. M. Batista, M. M. P. Guerra, M. C. Guarnieri, L. C. B. B. Coelho, M. T. S. Correia, 2012 Cytotoxic effect and apoptosis induction by Bothrops leucurus venom lectin on tumor cell lines. Toxicon 59 7-8 667 671
92 - M. Dehesa-Dávila, BM Martin, M. Nobile, G. Prestipino, L. D. Possani, 1994 Isolation of a toxin from Centruroides infamatus infamatus Koch scorpion venom that modifies Na+ permeability on chick dorsal root ganglion cells. Toxicon 32 12 1487 1493
93 - G. Chowell, P. Díaz-Dueñas, R. Bustos-Saldaña, AA Mireles, V. Fet, 2006 Epidemiological and clinical characteristics of scorpionism in Colima, Mexico (2000-2001). Toxicon 47 7 753 758
94 - C. Goudet, C. W. Chi, J. Tytgat, 2002 An overview of toxins and genes from the venom of the Asian scorpion Buthus martensi Karsch Toxicon 40 9 1239 1258
95 - L. A. F. Ferreira, E. W. Alves, O. B. Henriques, 1993 Peptide T, a novel bradykinin potentiator isolated from Tityus serrulatus scorpion venom. Toxicon 31 8 941 947
96 - A. M. C. Pimenta, M. E. De Lima, 2005 Small peptides, big world: Biotechnological potential in neglected bioactive peptides from arthropod venoms. Journal of Peptide Science 11 11 670 676
97 - X. C. Zeng, W. X. Li, F. Peng, Z. H. Zhu, 2000 Cloning and characterization of a novel cDNA sequence encoding the precursor of a novel venom peptide (BmKbpp) related to a bradykinin- potentiating peptide from Chinese scorpion Buthus martensii Karsch. IUBMB Life 49 3 207 210
98 - M. A. M. El -Saadani, M. F. El -Sayed, 2003 A bradykinin potentiating peptide from Egyptian cobra venom strongly affects rat atrium contractile force and cellular calcium regulation. Comparative Biochemistry and Physiology Part C: Toxicology and Pharmacology 136 4 387 395
99 - P. Bulet, R. Stöcklin, L. Menin, 2004 Anti-microbial peptides: From invertebrates to vertebrates Immunological Reviews 198 169
100 - D. Elgar, J. Du Plessis, L. Du Plessis, 2006 Cysteine-free peptides in scorpion venom: Geographical distribution, structure-function relationship and mode of action. African Journal of Biotechnology 5 25 2495 2502
101 - G. Corzo, P. Escoubas, E. Villegas, K. J. Barnham, W. He, R. S. Norton, T. Nakajima, 2001 Characterization of unique amphipathic antimicrobial peptides from venom of the scorpion Pandinus imperator. Biochemical Journal 359 1 35 45
102 - S. Cociancich, M. Goyffon, F. Bontems, P. Bulet, F. Bouet, A. Menez, J. Hoffmann, 1993 Purification and Characterization of a Scorpion Defensin, a 4kDa Antibacterial peptide presenting structural similarities with insect defensins and scorpion toxins Biochemical and Biophysical Research Communications 194 1 17 22
103 - L. Ehret-Sabatier, D. Loew, M. Goyffon, P. Fehlbaum, J. A. Hoffmann, A. Van Dorsselaer, P. Bulet, 1996 Characterization of novel cysteine-rich antimicrobial peptides from scorpion blood. Journal of Biological Chemistry 271 47 29537 29544
104 - R. Conde, F. Z. Zamudio, M. H. Rodrı́guez, L. D. Possani, 2000 Scorpine, an anti-malaria and anti-bacterial agent purified from scorpion venom. FEBS Letters 471 2-3 165 168
105 - L. Dai, G. Corzo, H. Naoki, M. Andriantsiferana, T. Nakajima, 2002 Purification, structure-function analysis, and molecular characterization of novel linear peptides from scorpion Opisthacanthus madagascariensis. Biochemical and Biophysical Research Communications 293 5 1514 1522
106 - L. Moerman, S. Bosteels, W. Noppe, J. Willems, E. Clynen, L. Schoofs, K. Thevissen, J. Tytgat, J. Van Eldere, J. Van Der Walt, F. Verdonck, 2002 Antibacterial and antifungal properties of α-helical, cationic peptides in the venom of scorpions from southern Africa. European Journal of Biochemistry 269 19 4799 4810
107 - Vega. R. C. Rodríguez La, B. I. García, C. D’Ambrosio, E. Diego-García, A. Scaloni, L. D. Possani, 2004 Antimicrobial peptide induction in the haemolymph of the Mexican scorpion Centruroides limpidus limpidus in response to septic injury. Cellular and Molecular Life Sciences 61 12 1507 1519
108 - N. Uawonggul, S. Thammasirirak, A. Chaveerach, T. Arkaravichien, W. Bunyatratchata, W. Ruangjirachuporn, P. Jearranaiprepame, T. Nakamura, M. Matsuda, M. Kobayashi, S. Hattori, S. Daduang, 2007 Purification and characterization of Heteroscorpine-1 (HS-1) toxin from Heterometrus laoticus scorpion venom. Toxicon 49 1 19 29
109 - D. Elgar, F. Verdonck, A. Grobler, C. Fourie, Plessis. J. Du, 2006 Ion selectivity of scorpion toxin-induced pores in cardiac myocytes Peptides 27 1 55 61
110 - A. Torres-Larios, G. B. Gurrola, F. Z. Zamudio, L. D. Possani, 2000 Hadrurin, a new antimicrobial peptide from the venom of the scorpion Hadrurus aztecus European Journal of Biochemistry 267 16 5023 5031
111 - P. Díaz, G. D’Suze, V. Salazar, C. Sevcik, JD Sherman. N. E. Shannon, J. W. Fox, 2009 Antibacterial activity of six novel peptides from Tityus discrepans scorpion venom. A fluorescent probe study of microbial membrane Na+ permeability changes Toxicon 54 6 802 817
112 - Y. Shijin, Y. Hong, M. Yibao, C. Zongyun, S. Han, W. Yingliang, C. Zhijian, L. Wenxin, 2008 Characterization of a new Kv1.3 channel-specific blocker, J123, from the scorpion Buthus martensii Karsch Peptides 29 9 1514 1520
113 - Z. Wang, W. Wang, Z. Shao, B. Gao, J. Li, J. H. Che, W. Zhang, 2009 Eukaryotic expression and purification of anti-epilepsy peptide of Buthus martensii Karsch and its protein interactions Molecular and Cellular Biochemistry 330 1-2 97 104
114 - J. Shao, N. Kang, Y. Liu, S. Song, C. Wu, J. Zhang, 2007 Purification and characterization of an analgesic peptide from Buthus martensii Karsch. Biomedical Chromatography 21 12 1266 1271
115 - Z. T. Bai, T. Liu, X. Y. Pang, Z. F. Chai, Y. H. Ji, 2007 Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos expression induced by formalin Brain Research Bulletin 73 4-6 248 253
116 - S. D. Gupta, A. Gomes, A. Debnath, A. Saha, 2010 Apoptosis induction in human leukemic cells by a novel protein Bengalin, isolated from Indian black scorpion venom: Through mitochondrial pathway and inhibition of heat shock proteins Chemico-Biological Interactions 183 2 293 303
117 - J. Deshane, C. C. Garner, H. Sontheimer, 2003 Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2. Journal of Biological Chemistry 278 6 4135 4144
118 - A. C. Pessini, A. Kanashiro, Dd. C. Malvar, R. R. Machado, D. M. Soares, MJ Figueiredo, E. Kalapothakis, G. E. P. Souza, 2008 Inflammatory mediators involved in the nociceptive and oedematogenic responses induced by Tityus serrulatus scorpion venom injected into rat paws. Toxicon 52 7 729 736
119 - V. A. Jaravine, D. E. Nolde, M. J. Reibarkh, Y. V. Korolkova, S. A. Kozlov, K. A. Pluzhnikov, E. V. Grishin, A. S. Arseniev, 1997 Three-dimensional structure of toxin OSK1 from Orthochirus scrobiculosus scorpion venom. Biochemistry 36 6 1223 1232
120 - M. Garcia-Calvo, R. J. Leonard, J. Novick, S. P. Stevens, W. Schmalhofer, G. J. Kaczorowski, M. L. Garcia, 1993 Purification, characterization, and biosynthesis of margatoxin, a component of Centruroides margaritatus venom that selectively inhibits voltage-dependent potassium channels. Journal of Biological Chemistry 268 25 18866 18874
121 - M. Crest, G. Jacquet, M. Gola, H. Zerrouk, A. Benslimane, H. Rochat, P. Mansuelle, M. F. Martin-Eauclaire, 1992 Kaliotoxin, a novel peptidyl inhibitor of neuronal BK-type Ca2+-activated K+ channels characterized from Androctonus mauretanicus mauretanicus venom. Journal of Biological Chemistry 267 3 1640 1647
122 - ML. Garcia, 1994 Purification and characterization of three inhibitors of voltage-dependent K+ channels from Leiurus quinquestriatus var. Hebraeus venom. Biochemistry 33 22 6834 6839
123 - A. Koschak, R. M. Bugianesi, J. Mitterdorfer, G. J. Kaczorowski, M. L. Garcia, H. G. Knaus, 1998 Subunit composition of brain voltage-gated potassium channels determined by hongotoxin-1, a novel peptide derived from Centruroides limbatus venom. Journal of Biological Chemistry 273 5 2639 2644
124 - Possani. L. Domingos, BM Martin, I. B. Svendsen, 1982 The primary structure of noxiustoxin: A K+ channel blocking peptide, purified from the venom of the scorpion Centruroides noxius Hoffmann Carlsberg Research Communications 47 5 285 289
125 - T. Olamendi-Portugal, F. Gómez-Lagunas, G. B. Gurrola, L. D. Possani, 1996 A novel structural class of K+-channel blocking toxin from the scorpion Pandinus imperator. Biochemical Journal 315 3 977 981
126 - L. Soroceanu, T. J. Manning Jr, H. Sontheimer, 1999 Modulation of glioma cell migration and invasion using Cl- and K+ ion channel blockers. Journal of Neuroscience 19 14 5942 5954
127 - A. N. Mamelak, D. B. Jacoby, 2007 Targeted delivery of antitumoral therapy to glioma and other malignancies with synthetic chlorotoxin (TM-601). Expert Opinion on Drug Delivery 4 2 175 186
128 - D. B. Jacoby, E. Dyskin, M. Yalcin, K. Kesavan, W. Dahlberg, J. Ratliff, E. W. Johnson, S. A. Mousa, 2010 Potent pleiotropic anti-angiogenic effects of TM601, a synthetic chlorotoxin peptide. Anticancer Research 30 1 39 46
129 - J. J. Wu, L. Dai, Z. D. Lan, C. W. Chi, 2000 The gene cloning and sequencing of Bm-12, a Chlorotoxin-like peptide from the scorpion Buthus martensi Karsch. Toxicon 38 5 661 668
130 - Y. J. Fu, L. T. Yin, A. H. Liang, C. F. Zhang, W. Wang, B. F. Chai, J. Y. Yang, X. J. Fan, 2007 Therapeutic potential of chlorotoxin-like neurotoxin from the Chinese scorpion for human gliomas. Neuroscience Letters 412 1 62 67
131 - G. D’Suze, A. Rosales, V. Salazar, C. Sevcik, 2010 Apoptogenic peptides from Tityus discrepans scorpion venom acting against the SKBR3 breast cancer cell line Toxicon 56 8 1497 1505
132 - ME De Lima, S. G. Figueiredo, A. M. C. Pimenta, D. M. Santos, M. H. Borges, M. N. Cordeiro, M. Richardson, L. C. Oliveira, M. Stankiewicz, M. Pelhate, 2007 Peptides of arachnid venoms with insecticidal activity targeting sodium channels. Comparative Biochemistry and Physiology Part C: Toxicology and Pharmacology 146 1-2 264 279
133 - M. Eitan, E. Fowler, R. Herrmann, A. Duval, M. Pelhate, E. Zlotkin, 1990 A scorpion venom neurotoxin paralytic to insects that affects sodium current inactivation: purification, primary structure, and mode of action. Biochemistry 29 25 5941 5947
134 - I. Karbat, F. Frolow, O. Froy, N. Gilles, L. Cohen, M. Turkov, D. Gordon, M. Gurevitz, 2004 Molecular basis of the high insecticidal potency of scorpion alpha-toxins. The Journal of Biological Chemistry 279 30 31679 31686
135 - L. Borchani, M. Stankiewicz, C. Kopeyan, P. Mansuelle, R. Kharrat, S. Cestèle, H. Karoui, H. Rochat, M. Pelhate, M. El Ayeb, 1997 Purification, structure and activity of three insect toxins from Buthus occitanus tunetanus venom. Toxicon 35 3 365 382
136 - T. Arnon, T. Potikha, D. Sher, M. Elazar, W. Mao, T. Tal, F. Bosmans, J. Tytgat, N. Ben-Arie, E. Zlotkin, 2005 BjαIT: a novel scorpion α-toxin selective for insects- unique pharmacological tool. Insect Biochemistry and Molecular Biology 35 3 187 195
137 - A. Jalali, F. Bosmans, M. Amininasab, E. Clynen, E. Cuypers, A. Zaremirakabadi, M. N. Sarbolouki, L. Schoofs, H. Vatanpour, J. Tytgat, 2005 OD1, the first toxin isolated from the venom of the scorpion Odonthobuthus doriae active on voltage-gated Na+ channels. FEBS Letters 579 19 4181 4186
138 - I. Krimm, N. Gilles, P. Sautière, M. Stankiewicz, M. Pelhate, D. Gordon, J. Lancelin-M, 1999 NMR structures and activity of a novel α-like toxin from the scorpion Leiurus quinquestriatus hebraeus. Journal of Molecular Biology 285 4 1749 1763
139 - S. Cestèle, M. Stankiewicz, P. Mansuelle, M. De Waard, B. Dargent, N. Gilles, M. Pelhate, H. Rochat, M. Martin-Eauclaire-F, D. Gordon, 1999 Scorpion α-like toxins, toxic to both mammals and insects, differentially interact with receptor site 3 on voltage-gated sodium channels in mammals and insects. European Journal of Neuroscience 11 3 975 985
140 - C. G. Wang, M. H. Ling, C. W. Chi, D. C. Wang, M. Stankiewicz, M. Pelhate, 2003 Purification of two depressant insect neurotoxins and their gene cloning from the scorpion Buthus martensi KarschThe Journal of Peptide Research 61 1 7 16
141 - A. Hamon, N. Gilles, P. Sautière, A. Martinage, C. Kopeyan, C. Ulens, J. Tytgat, J. M. Lancelin, D. Gordon, 2002 Characterization of scorpion α-like toxin group using two new toxins from the scorpion Leiurus quinquestriatus hebraeus. European Journal of Biochemistry 269 16 3920 3933
142 - M. Pelhate, E. Zlotkin, 1982 Actions of insect toxin and other toxins derived from the venom of the scorpion Androctonus australis on isolated giant axons of the cockroach (Periplaneta americana). The Journal of Experimental Biology 97 67
143 - M. Pelhate, M. Stankiewicz, Khalifa. R. Ben, 1998 Anti-insect scorpion toxins: historical account, activities and prospects. Comptes Rendus des Séances de la Société de Biologie et de Ses Filiales 192 3 463 484
144 - P. Escoubas, M. Stankiewicz, T. Takaoka, M. Pelhate, R. Romi-Lebrun, F. Q. Wu, T. Nakajima, 2000 Sequence and electrophysiological characterization of two insect-selective excitatory toxins from the venom of the Chinese scorpion Buthus martensi. FEBS Letters 483 2-3 175 80
145 - M. Ori, H. Ikeda, 1998 Spider venoms and spider toxins Journal of Toxicology- Toxin Reviews 17 3 405 426
146 - L. D. Rash, W. C. Hodgson, 2001 Pharmacology and biochemistry of spider venoms. Toxicon 40 3 225 254
147 - F. Bode, F. Sachs, M. R. Franz, 2001 Tarantula peptide inhibits atrial fibrillation. Nature 409 6816 35 36
148 - D. L. Mc Glasson, J. L. Babcock, L. Berg, D. A. Triplett, 1993 ARACHnase: An evaluation of a positive control for platelet neutralization procedure testing with seven commercial activated partial thromboplastin time reagents. American Journal of Clinical Pathology 100 5 576 578
149 - J. M. Futrell, 1992 Loxoscelism. American Journal of the Medical Sciences 304 4 261 267
150 - L. Yan, M. E. Adams, 1998 Lycotoxins, antimicrobial peptides from venom of the wolf spider Lycosa carolinensis. Journal of Biological Chemistry 273 4 2059 2066
151 - M. Mazzuca, C. Heurteaux, A. Alloui, S. Diochot, A. Baron, N. Voilley, N. Blondeau, P. Escoubas, A. Gelot, A. Cupo, A. Zimmer, A. M. Zimmer, A. Eschalier, M. Lazdunski, 2007 A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nature Neuroscience 10 8 943 945
152 - L. A. Van Meeteren, F. Frederiks, B. N. G. Giepmans, Pedrosa. M. F. Fernandes, S. J. Billington, B. H. Jost, D. V. Tambourgi, W. H. Moolenaar, 2004 Spider and bacterial Sphingomyelinases D target cellular lysophosphatidic acid receptors by hydrolyzing lysophosphatidylcholine. Journal of Biological Chemistry 279 12 10833 10836
153 - Pedrosa. M. F. Fernandes, Azevedo. I. D. L. M. Junqueira de, R. M. Gonçalves-de-Andrade, Berg. C. W. Van Den, C. R. R. Ramos, Ho. P. Lee, D. V. Tambourgi, 2002 Molecular cloning and expression of a functional dermonecrotic and haemolytic factor from Loxosceles laeta venom Biochemical and Biophysical Research Communications 298 5 638 645
154 - M. T. Murakami, M. F. Fernandes-Pedrosa, D. V. Tambourgi, R. K. Arni, 2005 Structural basis for metal ion coordination and the catalytic mechanism of sphingomyelinases D. Journal of Biological Chemistry 280 14 13658 13664
155 - D. M. De Almeida, M. F. Fernandes-Pedrosa, Andrade. R. M. Gonçalves de, J. R. Marcelino, H. Gondo-Higashi, Azevedo. I. D. L. M. Junqueira de, P. L. Ho, Berg. C. Van Den, D. V. Tambourgi, 2008 A new anti-loxoscelic serum produced against recombinant sphingomyelinase D: Results of preclinical trials. American Journal of Tropical Medicine and Hygiene 79 3 463 470
156 - J. K. Bubien, H. L. Ji, G. Y. Gillespie, C. M. Fuller, J. M. Markert, T. B. Mapstone, D. J. Benos, 2004 Cation selectivity and inhibition of malignant glioma Na+ channels by Psalmotoxin 1. American Journal of Physiology- Cell Physiology 287 5 56-5) C1282 C1291
157 - E. G. Rodrigues, A. S. S. Dobroff, C. F. Cavarsan, T. Paschoalin, L. Nimrichter, R. A. Mortara, E. L. Santos, MA Fázio, A. Miranda, S. Daffre, L. R. Travassos, 2008 Effective topical treatment of subcutaneous murine B16F10-Nex2 melanoma by the antimicrobial peptide gomesin. Neoplasia 10 1 61 68
158 - S. A. Khan, Y. Zafar, R. W. Briddon, K. A. Malik, Z. Mukhtar, 2006 Spider venom toxin protects plants from insect attack Transgenic Research 15 3 349 357
159 - C. S. De Castro, F. G. Silvestre, S. C. Araújo, G. D. M. Yazbeck, O. C. Mangili, I. Cruz, C. Chávez-Olórtegui, E. Kalapothakis, 2004 Identification and molecular cloning of insecticidal toxins from the venom of the brown spider Loxosceles intermedia Toxicon 44 3 273 280
160 - S. G. Figueiredo, M. E. L. P. Garcia, A. D. C. Valentim, M. N. Cordeiro, C. R. Diniz, M. Richardson, 1995 Purification and amino acid sequence of the insecticidal neurotoxin Tx4(6-1) from the venom of the’armed’ spider Phoneutria nigriventer (Keys). Toxicon 33 1 83 93
161 - P. A. Zobel-Thropp, A. E. Kerins, G. J. Binford, 2012 Sphingomyelinase D in sicariid spider venom is a potent insecticidal toxin. Toxicon 60 3 265 271
162 - G. Ferrat, F. Bosmans, J. Tytgat, C. Pimentel, B. Chagot, N. Gilles, T. Nakajima, H. Darbon, G. Corzo, 2005 Solution structure of two insect-specific spider toxins and their pharmacological interaction with the insect voltage-gated Na+ channel. Proteins Structure, Function and Genetics 59 2 368 379
163 - R. C. Toledo, C. Jared, 1995 Cutaneous granular glands and amphibian venoms Comparative Biochemistry and Physiology Part A: Physiology 111 1 1 29
164 - Y. Q. Tang, Sh. Tian, Jc. Hua, Sx. Wu, G. Zou, Gf. Wu, Em. Zhao, 1990 Isolation, chemical and biological characterization of margaratensin, a neurotensin-related peptide from the skin of Rana margaratae. Science in China (Scientia Sinica) Series B 33 7 828 834
165 - D. L. Wang, F. H. Qi, W. Tang, F. S. Wang, 2011 Chemical constituents and bioactivities of the skin of Bufo bufo gargarizans cantor Chemistry and Biodiversity 8 4 559 567
166 - J. S. Cruz, H. Matsuda, 1993 Arenobufagin, a compound in toad venom, blocks Na+-K+ pump current in cardiac myocytes. European Journal of Pharmacology
167 - J. Shindelman, H. S. Mosher, F. A. Fuhrman, 1969 Atelopidtoxin from the Panamanian frog, Atelopus zeteki. Toxicon 7 4 315 319
168 - G. F. Erspamer, C. Severini, V. Erspamer, P. Melchiorri, 1989 Pumiliotoxin B-like alkaloid in extracts of the skin of the australian myobatrachid frog Pseudophryne coriacea: effects on the systemic blood pressure of experimental animals and the rat heart. Neuropharmacology 28 4 319 328
169 - Y. Zhang, G. Yu, Y. Wang, J. Zhang, S. Wei, W. Lee, Y. Zhang, 2010 A novel annexin A2 protein with platelet aggregation-inhibiting activity from amphibian Bombina maxima skin Toxicon 56 3 458 465
170 - Filho. G. A. Cunha, C. A. Schwartz, I. S. Resck, M. M. Murta, S. S. Lemos, M. S. Castro, C. Kyaw, O. R. Pires Jr, J. R. S. Leite, C. Bloch Jr, E. F. Schwartz, 2005 Antimicrobial activity of the bufadienolides marinobufagin and telocinobufagin isolated as major components from skin secretion of the toad Bufo rubescens. Toxicon 45 6 777 782
171 - F. S. Dourado, J. R. S. A. Leite, L. P. Silva, J. A. T. Melo, C. Bloch Jr, E. F. Schwartz, 2007 Antimicrobial peptide from the skin secretion of the frog Leptodactylus syphax. Toxicon 50 4 572 580
172 - H. J. Preusser, G. Habermehl, M. Sablofski, Haury. D. Schmall, 1975 Antimicrobial activity of alkaloids from amphibian venoms and effects on the ultrastructure of yeast cells. Toxicon 13 4 285 289
173 - X. Cui, Y. Inagaki, H. Xu, D. Wang, F. Qi, N. Kokudo, D. Fang, W. Tang, 2010 Anti-hepatitis B virus activities of cinobufacini and its active components bufalin and cinobufagin in HepG2.2.15 Cells Biological and Pharmaceutical Bulletin 33 10 1728 1732
174 - A. G. Tempone, D. C. Pimenta, I. Lebrun, P. Sartorelli, N. N. Taniwaki, H. F. de Andrade Jr, MM Antoniazzi, C. Jared, 2008 Antileishmanial and antitrypanosomal activity of bufadienolides isolated from the toad Rhinella jimi parotoid macrogland secretion. Toxicon 52 1 13 21
175 - P. Yogeeswari, D. Sriram, T. R. Bal, R. Thirumurugan, 2006 Epibatidine and its analogues as nicotinic acetylcholine receptor agonist: an update Natural Product Research 20 5 497 505
176 - V. Erspamer, P. Melchiorri, G. Falconieri-Erspamer, L. Negri, R. Corsi, C. Severini, D. Barra, M. Simmaco, G. Kreil, 1989 Deltrophins: a family of naturally occurring peptides with high affinity and selectivity for δ opioid binding sites. Proceedings of the National Academy of Sciences of the United States of America 86 13 5188 5192
177 - X. L. Wang, G. H. Zhao, J. Zhang, Q. Y. Shi, W. X. Guo, X. L. Tian, J. Z. Qiu, L. Z. Yin, X. M. Deng, Y. Song, 2011 Immunomodulatory effects of cinobufagin isolated from Chan Su on activation and cytokines secretion of immunocyte in vitro Journal of Asian Natural Products Research 13 5 383 392
178 - F. Qi, Y. Inagaki, B. Gao, X. Cui, H. Xu, N. Kokudo, A. Li, W. Tang, 2011 Bufalin and cinobufagin induce apoptosis of human hepatocellular carcinoma cells via Fas- and mitochondria-mediated pathways. Cancer Science 102 5 951 958
179 - C. L. Su, T. Y. Lin, C. N. Lin, S. J. Won, 2009 Involvement of caspases and apoptosis-inducing factor in bufotalin-induced apoptosis of hep 3B cells. Journal of Agricultural and Food Chemistry 57 1 55 61
180 - F. Balboni, P. A. Bernabei, C. Barberio, A. Sanna, Ferrini. P. Rossi, G. Delfino, 1992 Cutaneous venom of Bombina variegata pachypus (Amphibia, anura): effects on the growth of the human HL 60 cell line. Cell Biology International Reports 16 4 329 338
181 - S. Ghavami, A. Asoodeh, T. Klonisch, A. J. Halayko, K. Kadkhoda, T. J. Kroczak, S. B. Gibson, E. P. Booy, H. Naderi-Manesh, M. Los, 2008 Brevinin-2R1 semi-selectively kills cancer cells by a distinct mechanism, which involves the lysosomal-mitochondrial death pathway. Journal of Cellular and Molecular Medicine 12 3 1005 1022
182 - L. Marenah, C. Shaw, D. F. Orr, S. Mc Clean, P. R. Flatt, Y. H. A. Abdel-Wahab, 2004 Isolation and characterisation of an unexpected class of insulinotropic peptides in the skin of the frog Agalychnis litodryas Regulatory Peptides 120 1-3 33 38
183 - N. A. Marsh, B. C. Whaler, 1980 The effects of honey bee (Apis mellifera L.) venom and two of its constituents, melittin and phospholipase A2, on the cardiovascular system of the rat. Toxicon 18 4 427 435
184 - E. Kaplinsky, J. Ishay, D. Ben-Shachar, S. Gitter, 1977 Effects of bee (Apis mellifera) venom on the electrocardiogram and blood pressure. Toxicon 15 3 251 256
185 - J. A. Vick, W. H. Shipman, R. Jr Brooks, 1974 Beta adrenergic and anti-arrhythmic effects of cardiopep, a newly isolated substance from whole bee venom. Toxicon 12 2 139 144
186 - C. L. Ho, L. L. Hwang, Y. L. Lin, C. T. Chen, H. M. Yu, K. T. Wang, 1994 Cardiovascular effects of mastoparan B and its structural requirements. European Journal of Pharmacology 259 3 259 264
187 - Y. M. Choo, K. S. Lee, H. J. Yoon, Y. Qiu, H. Wan, M. R. Sohn, H. D. Sohn, B. R. Jin, 2012 Antifibrinolytic role of a bee venom serine protease inhibitor that acts as a plasmin Inhibitor PLoS ONE 7 2
188 - Y. M. Choo, K. S. Lee, H. J. Yoon, B. Y. Kim, M. R. Sohn, J. Y. Roh, Y. H. Je, N. J. Kim, I. Kim, S. D. Woo, H. D. Sohn, B. R. Jin, 2010 Dual function of a bee venom serine protease: prophenoloxidase-activating factor in arthropods and fibrin(ogen)olytic enzyme in mammals. PLoS ONE 5 5 1
189 - Y. Qiu, Y. M. Choo, H. J. Yoon, J. Jia, Z. Cui, D. Wang, D. H. Kim, H. D. Sohn, B. R. Jin, 2011 Fibrin(ogen)olytic activity of bumblebee venom serine protease. Toxicology and Applied Pharmacology 255 2 207 213
190 - Y. Qiu, Y. M. Choo, H. J. Yoon, B. R. Jin, 2012 Molecular cloning and fibrin(ogen)olytic activity of a bumblebee (Bombus hypocrita sapporoensis) venom serine protease. Journal of Asia-Pacific Entomology 15 1 79 82
191 - J. Han, D. You, X. Xu, W. Han, Y. Lu, R. Lai, Q. Meng, 2008 An anticoagulant serine protease from the wasp venom of Vespa magnifica. Toxicon 51 5 914 922
192 - B. Haim, A. Rimon, J. S. Ishay, S. Rimon, 1999 Purification, characterization and anticoagulant activity of a proteolytic enzyme from Vespa orientalis venom. Toxicon 37 5 825 829
193 - H. Yang, X. Xu, Ma D. Zhang, K. Lai, R. , 2008 A phospholipase A1 platelet activator from the wasp venom of Vespa magnifica (Smith) Toxicon 51 2 289 296
194 - X. Xu, J. Li, Q. Lu, H. Yang, Y. Zhang, R. Lai, 2006 Two families of antimicrobial peptides from wasp (Vespa magnifica) venom Toxicon 47 2 249 253
195 - V. N. Lazarev, T. M. Parfenova, S. K. Gularyan, O. Y. Misyurina, T. A. Akopian, V. M. Govorun, 2002 Induced expression of melittin, an antimicrobial peptide, inhibits infection by Chlamydia trachomatis and Mycoplasma hominis in a HeLa cell line. International journal of antimicrobial agents 19 2 133 7
196 - Y. M. Choo, K. S. Lee, H. J. Yoon, Y. H. Je, S. W. Lee, H. D. Sohn, B. R. Jin, 2010 Molecular cloning and antimicrobial activity of bombolitin, a component of bumblebee Bombus ignitus venom. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 156 3 168 173
197 - R. Stöcklin, P. Favreau, R. Thai, J. Pflugfelder, P. Bulet, D. Mebs, 2010 Structural identification by mass spectrometry of a novel antimicrobial peptide from the venom of the solitary bee Osmia rufa (Hymenoptera: Megachilidae) Toxicon 55 1 20 27
198 - W. Chen, X. Yang, X. Yang, L. Zhai, Z. Lu, J. Liu, H. Yu, 2008 Antimicrobial peptides from the venoms of Vespa bicolor Fabricius. Peptides 29 11 1887 1892
199 - J. H. Baek, S. H. Lee, 2010 Isolation and molecular cloning of venom peptides from Orancistrocerus drewseni (Hymenoptera: Eumenidae). Toxicon 55 4 711 718
200 - E. J. Yang, J. H. Jiang, S. M. Lee, S. C. Yang, H. S. Hwang, M. S. Lee, S. Choi-M, 2010 Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models. Journal of Neuroinflammation 7 1 69
201 - J. Lee, S. Kim, T. Kim, S. Lee, H. Yang, D. Lee, Y. Lee, 2004 Anti-inflammatory effect of bee venom on type II collagen-induced arthritis. The American journal of Chinese medicine 32 3 361 7
202 - J. H. Park, K. H. Kim, W. R. Lee, S. M. Han, K. K. Park, 2012 Protective effect of melittin on inflammation and apoptosis in acute liver failure. Apoptosis 17 1 61 69
203 - S. Shkenderov, K. Koburova, 1982 Adolapin- a newly isolated analgetic and anti-inflammatory polypeptide from bee venom. Toxicon 20 1 317 321
204 - P. Haux, 1969 Amino acid sequence of MCD-peptide, a specific mast cell-degranulating peptide from bee venom. Hoppe-Seyler’s Zeitschrift fur Physiologische Chemie 350 5 536 546
205 - A. Kettner, H. Henry, G. J. Hughes, G. Corradin, F. Spertini, 1999 IgE and T-cell responses to high-molecular weight allergens from bee venom. Clinical & Experimental Allergy 29 3 394 401
206 - A. Kettner, G. J. Hughes, S. Frutiger, M. Astori, M. Roggero, F. Spertini, G. Corradin, 2001 Api m 6: a new bee venom allergen Journal of Allergy and Clinical Immunology 107 5 914 920
207 - B. Pantera, D. R. Hoffman, L. Carresi, G. Cappugi, S. Turillazzi, G. Manao, M. Severino, I. Spadolini, G. Orsomando, G. Moneti, L. Pazzagli, 2003 Characterization of the major allergens purified from the venom of the paper wasp Polistes gallicus. Biochimica et Biophysica Acta (BBA)- General Subjects 1623 2-3 72 81
208 - S. An, L. Chen, J. F. Wei, X. Yang, D. Ma, X. Xu, S. He, J. Lu, R. Lai, 2012 Purification and characterization of two new allergens from the venom of Vespa magnifica. PLoS One 7 2 27
209 - R. A. Trindade, P. K. Kiyohara, P. S. de Araujo, M. H. Bueno da. Costa, 2012 PLGA microspheres containing bee venom proteins for preventive immunotherapy. International Journal of Pharmaceutics 423 1 124 133
210 - M. P. Dani, E. H. Richards, 2010 Identification, cloning and expression of a second gene (vpr1) from the venom of the endoparasitic wasp, Pimpla hypochondriaca that displays immunosuppressive activity. Journal of Insect Physiology 56 2 195 203
211 - N. B. Baptista-Saidemberg, D. M. Saidemberg, B. M. de Souza, L. M. Cesar-Tognoli, V. M. Ferreira, M. A. Mendes, M. P. Cabrera, Neto. J. Ruggiero, M. S. Palma, 2010 Protonectin (1-6): a novel chemotactic peptide from the venom of the social wasp Agelaia pallipes pallipes. Toxicon 56 6 880 889
212 - B. M. Souza, M. A. Mendes, L. D. Santos, M. R. Marques, L. M. Cesar, R. N. Almeida, F. C. Pagnocca, K. Konno, M. S. Palma, 2005 Structural and functional characterization of two novel peptide toxins isolated from the venom of the social wasp Polybia paulista. Peptides 26 11 2157 2164
213 - D. C. Graaf, M. Aerts, E. Danneels, B. Devreese, 2009 Bee, wasp and ant venomics pave the way for a component-resolved diagnosis of sting allergy. Journal of Proteomics 72 2 145 154
214 - C. L. Ownby, J. R. Powell, M. S. Jiang, J. E. Fletcher, 1997 Melittin and phospholipase A2 from bee (Apis mellifera) venom cause necrosis of murine skeletal muscle in vivo. Toxicon 35 1 67 80
215 - W. N. Hait, L. Grais, C. Benz, E. C. Cadman, 1985 Inhibition of growth of leukemic cells by inhibitors of calmodulin: phenothiazines and melittin. Cancer Chemotherapy and Pharmacology 14 3 202 205
216 - D. O. Moon, S. Y. Park, M. S. Heo, K. C. Kim, C. Park, W. S. Ko, Y. H. Choi, G. Y. Kim, 2006 Key regulators in bee venom-induced apoptosis are Bcl-2 and caspase-3 in human leukemic U937 cells through downregulation of ERK and Akt. International Immunopharmacology 6 12 1796 1807
217 - N. Orsolic, L. Sver, S. Verstovsek, S. Terzic, I. Basic, 2003 Inhibition of mammary carcinoma cell proliferation in vitro and tumor growth in vivo by bee venom. Toxicon 41 7 861 870
218 - T. Putz, R. Ramoner, H. Gander, A. Rahm, G. Bartsch, M. Thurnher, 2006 Antitumor action and immune activation through cooperation of bee venom secretory phospholipase A2 and phosphatidylinositol-(3,4)-bisphosphate Cancer Immunology Immunotherapy 55 11 1374 1383
219 - V. Cerovsky, M. Budesinsky, O. Hovorka, J. Cvacka, Z. Voburka, J. Slaninova, L. Borovickova, V. Fucik, L. Bednarova, I. Votruba, J. Straka, 2009 Lasioglossins: three novel antimicrobial peptides from the venom of the eusocial bee Lasioglossum laticeps (Hymenoptera: Halictidae). ChemBioChem 10 12 2089 2099
220 - T. E. Heinen, A. B. da Veiga, 2011 Arthropod venoms and cancer. Toxicon 57 4 497 511
221 - D. R. Pfeiffer, T. I. Gudz, S. A. Novgorodov, W. L. Erdahl, 1995 The peptide mastoparan is a potent facilitator of the mitochondrial permeability transition. The Journal of Biological Chemistry 270 9 4923 4932
222 - B. M. Souza, A. V. Silva, V. M. Resende, H. A. Arcuri, Cabrera. M. P. Santos, Neto. J. Ruggiero, M. S. Palma, 2009 Characterization of two novel polyfunctional mastoparan peptides from the venom of the social wasp Polybia paulista. Peptides 30 8 1387 1395
223 - K. R. Wang, B. Z. Zhang, W. Zhang, J. X. Yan, J. Li, R. Wang, 2008 Antitumor effects, cell selectivity and structure-activity relationship of a novel antimicrobial peptide polybia-MPI. Peptides 29 6 963 968
224 - J. Y. Kim, S. H. Cho, Y. W. Kim, E. C. Jang, S. Y. Park, E. J. Kim, S. K. Lee, 1999 Effects of BCG, lymphotoxin and bee venom on insulitis and development of IDDM in non-obese diabetic mice. J Korean Med Sci 14 6 648 652
225 - Y. Shin, R. W. Moni, J. E. Lueders, J. W. Daly, 1994 Effects of the amphiphilic peptides mastoparan and adenoregulin on receptor binding, G proteins, phosphoinositide breakdown, cyclic AMP generation, and calcium influx. Cell Mol Neurobiol 14 2 133 157
226 - S. G. Straub, R. F. James, M. J. Dunne, G. W. Sharp, 1998 Glucose augmentation of mastoparan-stimulated insulin secretion in rat and human pancreatic islets. Diabetes 47 7 1053 1057
227 - F. Mc Gain, K. D. Winkel, 2002 Ant sting mortality in Australia. Toxicon 40 8 1095 1100
228 - M. B. Malta, MS Lira, S. L. Soares, G. C. Rocha, I. Knysak, R. Martins, S. P. Guizze, M. L. Santoro, K. C. Barbaro, 2008 Toxic activities of Brazilian centipede venoms. Toxicon 52 2 255 263
229 - L. C. Carrijo-Carvalho, A. M. Chudzinski-Tavassi, 2007 The venom of the Lonomia caterpillar: an overview. Toxicon 49 6 741 757
230 - A. B. Veiga, J. M. Ribeiro, J. A. Guimaraes, I. M. Francischetti, 2005 A catalog for the transcripts from the venomous structures of the caterpillar Lonomia obliqua: identification of the proteins potentially involved in the coagulation disorder and hemorrhagic syndrome. Gene 355 11
231 - C. B. Bohrer, Junior. J. Reck, D. Fernandes, R. Sordi, J. A. Guimaraes, J. Assreuy, C. Termignoni, 2007 Kallikrein-kinin system activation by Lonomia obliqua caterpillar bristles: involvement in edema and hypotension responses to envenomation Toxicon 49 5 663 669
232 - J. L. Donato, R. A. Moreno, S. Hyslop, A. Duarte, E. Antunes, B. F. Le Bonniec, F. Rendu, G. de Nucci, 1998 Lonomia obliqua caterpillar spicules trigger human blood coagulation via activation of factor X and prothrombin. Thromb Haemost 79 3 539 542
233 - A. M. Chudzinski-Tavassi, M. Schattner, M. Fritzen, R. G. Pozner, C. V. Reis, D. Lourenco, MA Lazzari, 2001 Effects of lopap on human endothelial cells and platelets. Haemostasis 31 3-6 257 265
234 - A. F. Pinto, R. Dobrovolski, A. B. Veiga, J. A. Guimaraes, 2004 Lonofibrase, a novel alpha-fibrinogenase from Lonomia obliqua caterpillars. Thrombosis Research 113 2 147 154
235 - Flores. M. P. Alvarez, M. Fritzen, C. V. Reis, A. M. Chudzinski-Tavassi, 2006 Losac, a factor X activator from Lonomia obliqua bristle extract: its role in the pathophysiological mechanisms and cell survival. Biochemical and Biophysical Research Communications 343 4 1216 1223
236 - B. Guerrero, C. L. Arocha-Pinango, A. M. Salazar, A. Gil, EE Sanchez-Acosta, A. Rodriguez., S. Lucena, 2011 The effects of Lonomin V, a toxin from the caterpillar (Lonomia achelous), on hemostasis parameters as measured by platelet function Toxicon 58 4 293 303
237 - W. F. Hink, K. J. Romstedt, J. W. Burke, R. W. Doskotch, D. R. Feller, 1989 Inhibition of human platelet aggregation and secretion by ant venom and a compound isolated from venom. Inflammation 13 2 175 184
238 - J. Orivel, V. Redeker, J. P. Le Caer, F. Krier, A. M. Revol-Junelles, A. Longeon, A. Chaffotte, A. Dejean, J. Rossier, 2001 Ponericins, new antibacterial and insecticidal peptides from the venom of the ant Pachycondyla goeldii. The Journal of Biological Chemistry 276 21 17823 17829
239 - I. Zelezetsky, U. Pag, N. Antcheva, H. G. Sahl, A. Tossi, 2005 Identification and optimization of an antimicrobial peptide from the ant venom toxin pilosulin. Archives of Biochemistry and Biophysics 434 2 358 364
240 - K. Peng, Y. Kong, L. Zhai, X. Wu, P. Jia, J. Liu, H. Yu, 2010 Two novel antimicrobial peptides from centipede venoms. Toxicon 55 2-3 274 279
241 - R. D. Altman, D. R. Schultz, B. Collins-Yudiskas, J. Aldrich, P. I. Arnold, H. E. Brown, 1984 The effects of a partially purified fraction of an ant venom in rheumatoid arthritis. Arthritis & Rheumatism 27 3 277 284
242 - J. Pan, W. F. Hink, 2000 Isolation and characterization of myrmexins, six isoforms of venom proteins with anti-inflammatory activity from the tropical ant, Pseudomyrmex triplarinus. Toxicon 38 10 1403 1413
243 - D. R. Hoffman, 1993 Allergens in Hymenoptera venom XXIV: the amino acid sequences of imported fire ant venom allergens Sol i II, Sol i III, and Sol i IV. Journal of Allergy and Clinical Immunology 91 1 71 78
244 - D. R. Hoffman, R. H. Sakell, M. Schmidt, 2005 Sol i 1, the phospholipase allergen of imported fire ant venom. Journal of Allergy and Clinical Immunology 115 3 611 616
245 - J. L. Arbiser, T. Kau, M. Konar, K. Narra, R. Ramchandran, S. A. Summers, C. J. Vlahos, K. Ye, B. N. Perry, W. Matter, A. Fischl, J. Cook, P. A. Silver, J. Bain, P. Cohen, D. Whitmire, S. Furness, B. Govindarajan, J. P. Bowen, 2007 Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis Blood 109 2 560 565
246 - Y. Sonoda, N. Hada, T. Kaneda, T. Suzuki, T. Ohshio, T. Takeda, T. Kasahara, 2008 A synthetic glycosphingolipid-induced antiproliferative effect in melanoma cells is associated with suppression of FAK, Akt, and Erk activation Biological and Pharmaceutical Bulletin 31 6 1279 1283