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Type II diabetes mellitus (T2DM) is a chronic non‐communicable disease due to abnormal insulin actions causing uncontrolled hyperglycaemia. The treatment for T2DM, for instance, metformin and incretin mimetic, mainly focuses on the restoration of insulin sensitivity and secretion. Exendin‐4 is a short incretin‐mimetic peptide consisting of 39 amino acids. It is discovered in the venom of Heloderma suspectum as a full agonist for the glucagon‐like peptide 1 (GLP‐1) receptor and produces insulinotropic effects. It is more resistant to enzymatic degradation by dipeptidyl‐peptidase‐4 and has a longer half‐life than the endogenous GLP‐1; thus, it is further developed as an incretin hormone analogue used to treat T2DM. The helical region of the peptide first interacts with the extracellular N‐terminal domain (NTD) of GLP‐1 receptor while the C‐terminal extension containing the tryptophan cage further enhances its binding affinity. After binding to the NTD of the receptor, it may cause the receptor to switch from its auto‐inhibited state of the receptor to its auto‐activated state. Exendin‐4 enhances the physiological functions of β‐cells and the up‐regulation of GLP‐1 receptors, thus reducing the plasma glucose levels. Moreover, exendin‐4 has also been found to ameliorate neuropathy, nephropathy and ventricular remodelling. The therapeutic effects of exendin‐4 have also been extrapolated into several clinical trials. Although exendin‐4 has a reasonable subcutaneous bioavailability, its half‐life is rather short. Therefore, several modifications have been undertaken to improve its pharmacokinetics and insulinotropic potency. This review focuses on the pharmacology of exendin‐4 and the structure‐function relationships of exendin‐4 with GLP‐1 receptor. The review also highlights some challenges and future directions in the improvement of exendin‐4 as an anti‐diabetic drug. [ABSTRACT FROM AUTHOR]

Venoms are produced by a wide variety of species including spiders, scorpions, reptiles, cnidarians, and fish for the purpose of harming or incapacitating predators or prey. While some venoms are of relatively simple composition, many contain hundreds to thousands of individual components with distinct pharmacological activity. Pain-inducing or "algesic" venom compounds have proven invaluable to our understanding of how physiological nociceptive neural networks operate. In this review, we present an overview of some of the diverse nociceptive pathways that can be modulated by specific venom components to evoke pain. [ABSTRACT FROM AUTHOR]

Rattlesnake venoms may be classified according to the presence/absence and relative abundance of the neurotoxic phospholipases A2s (PLA2s), such as Mojave toxin, and snake venom metalloproteinases (SVMPs). In Mexico, studies to determine venom variation in Mojave Rattlesnakes (Crotalus scutulatus scutulatus) are limited and little is known about the biological and proteolytic activities in this species. Tissue (34) and venom (29) samples were obtained from C. s. scutulatus from different locations within their distribution in Mexico. Mojave toxin detection was carried out at the genomic (by PCR) and protein (by ELISA) levels for all tissue and venom samples. Biological activity was tested on representative venoms by measuring LD50 and hemorrhagic activity. To determine the approximate amount of SVMPs, 15 venoms were separated by RP-HPLC and variation in protein profile and proteolytic activity was evaluated by SDS-PAGE (n = 28) and Hide Powder Azure proteolytic analysis (n = 27). Three types of venom were identified in Mexico which is comparable to the intraspecific venom diversity observed in the Sonoran Desert of Arizona, USA: Venom Type A (~Type II), with Mojave toxin, highly toxic, lacking hemorrhagic activity, and with scarce proteolytic activity; Type B (~Type I), without Mojave toxin, less toxic than Type A, highly hemorrhagic and proteolytic; and Type A + B, containing Mojave toxin, as toxic as venom Type A, variable in hemorrhagic activity and with intermediate proteolytic activity. We also detected a positive correlation between SVMP abundance and hemorrhagic and proteolytic activities. Although more sampling is necessary, our results suggest that venoms containing Mojave toxin and venom lacking this toxin are distributed in the northwest and southeast portions of the distribution in Mexico, respectively, while an intergradation in the middle of both zones is present. [ABSTRACT FROM AUTHOR]

The Nose-horned Viper (Vipera ammodytes) is one of the most widespread and venomous snakes in Europe, which causes high frequent snakebite accidents. The first comprehensive venom characterization of the regional endemic Transcaucasian Nose-horned Viper (Vipera ammodytes transcaucasiana) and the Transdanubian Sand Viper (Vipera ammodytes montandoni) is reported employing a combination of intact mass profiling and bottom-up proteomics. The bottom-up analysis of both subspecies identified the major snake protein families of viper venoms. Furthermore, intact mass profiling revealed the presence of two tripeptidic metalloprotease inhibitors and their precursors. While previous reports applied multivariate analysis techniques to clarify the taxonomic status of the subspecies, an accurate classification of Vipera ammodytes transcaucasiana is still part of the ongoing research. The comparative analysis of the viper venoms on the proteome level reveals a close relationship between the Vipera ammodytes subspecies, which could be considered to clarify the classification of the Transcaucasian Nose-horned Viper. However, the slightly different ratio of some venom components could be indicating interspecific variations of the two studied subspecies or intraspecies alternations based on small sample size. Additionally, we performed a bioactivity screening with the crude venoms against several human cancerous and non-cancerous cell lines, which showed interesting results against a human breast adenocarcinoma epithelial cell line. Several fractions of Vipera a. transcaucasiana demonstrated a strong cytotoxic effect on triple negative MDA MB 231 breast cancer cells. [ABSTRACT FROM AUTHOR]

Assessing the neutralization capability of nonlethal but medically relevant toxins in venom has been a challenging task. Nowadays, neutralization efficacy is evaluated based simply on the survival rates of animals injected with antivenom together with a predefined dose of venom, which can determine potency against neurotoxicity but not validate the capability to neutralize cytotoxin-induced complications. In this study, a high correlation with in-vivo and in-vitro neutralization assays was established using the immunoreactive peptides identified from short-chain neurotoxin and cytotoxin A3. These peptides contain conserved residues associated with toxin activities and a competition assay indicated that these peptides could specifically block the antibody binding to toxin and affect the neutralization potency of antivenom. Moreover, the titers of peptide-specific antibody in antivenoms or mouse antisera were determined by enzyme-linked immunosorbent assay (ELISA) simultaneously, and the results indicated that Taiwanese bivalent antivenom (BAV) and Vietnamese snake antivenom-Naja (SAV-Naja) exhibited superior neutralization potency against the lethal effect of short-chain neurotoxin (sNTX) and cytotoxicity of cardiotoxin/cytotoxin (CTX), respectively. Thus, the reported peptide ELISA shows not only its potential for antivenom prequalification use, but also its capability of justifying the cross-neutralization potency of antivenoms against Naja atra venom toxicity. [ABSTRACT FROM AUTHOR]

Different types of neuronal nicotinic acetylcholine receptors (nAChRs) are expected to occur in vivo, most structure-activity relationship studies have been carried out for just a few neuronal subtypes. The present review enlightens current aspects of venom modulators of nAChRs. Important electronic databases such as PubMed or Google scholar were explored for the collection of latest studies in the field. Clinical and basic research has shown that cholinergic receptors play a role in several disorders of the nervous system such as chronic pain, Alzheimer's disease and addiction to nicotine, alcohol and drugs. Unfortunately, the lack of selective modulators for each subtype of nAChR makes their pharmacological characterization difficult, which has slowed the development of therapeutic nAChR modulators with high selectivity and absence of off-target side-effects. Animal venoms have proven to be an excellent natural source of bioactive molecules with activity against ion channels. The present review concludes that the presence of small-molecule nAChR modulators in spider venoms support the use of venoms as a potential source of novel modulators. [ABSTRACT FROM AUTHOR]

Background: Venom immunotherapy (VIT) is considered to be the gold standard treatment for patients with hymenoptera venom allergy. This treatment induces systemic reactions (SR) in a significant number of patients. Objective: To evaluate the outcome of VIT in patients with known risk factors for VIT-induced SR and to compare rush VIT (RVIT) and conventional VIT (CVIT). Methods: All of the patients who received VIT and had at least one of the following risk factors were included: current cardiovascular disease, uncontrolled asthma, high basal serum tryptase, current treatment with β-blockers or angiotensin-converting enzyme inhibitors, and age >70 or <5 years. Results: Sixty-four patients were included, and most of them (52; 81.5%) were allergic exclusively to bee venom. Thirty-five (54.7%) patients underwent RVIT and 29 CVIT. The incidence of patients who developed SR during the build-up phase was similar for RVIT and CVIT (25.7 and 27.5%, respectively; p = 1). However, the incidence of SR per injection was significantly higher in CVIT than in RVIT (5.6 and 2.75%, respectively; p = 0.01). Most reactions (79.1%) were mild, limited to the skin. Most of the patients (92.1%) reached the full maintenance dose of 100 μg. This dose was reached by a significantly larger number of patients receiving RVIT compared to CVIT (100 and 82.7%, respectively; p = 0.01). None of the patients experienced exacerbation of their concurrent chronic disease during VIT. Conclusion: VIT can be performed safely and efficiently in patients with risk factors for immunotherapy. In these patients RVIT appears to be safer and more efficient than CVIT. [ABSTRACT FROM AUTHOR]

The genus Conus comprises approximately 700 species of venomous marine cone snails that are highly efficient predators of worms, snails, and fish. In evolutionary terms, cone snails are relatively young with the earliest fossil records occurring in the Lower Eocene, 55 Ma. The rapid radiation of cone snail species has been accompanied by remarkably high rates of toxin diversification. To shed light on the molecular mechanisms that accompany speciation,we investigated the toxin repertoire of two sister species, Conus andremenezi and Conus praecellens, that were until recently considered a single variable species. A total of 196 and 250 toxin sequences were identified in the venom gland transcriptomes of C. andremenezi and C. praecellens belonging to 25 and 29 putative toxin gene superfamilies, respectively. Comparative analysis with closely (Conus tribblei and Conus lenavati) and more distantly related species (Conus geographus) suggests that speciation is associated with significant diversification of individual toxin genes (exogenes)whereas the expression pattern of toxin gene superfamilies within lineages remains largely conserved. Thus, changes within individual toxin sequences can serve as a sensitive indicator for recent speciation whereas changes in the expression pattern of gene superfamilies are likely to reflect more dramatic differences in a species' interaction with its prey, predators, and competitors. [ABSTRACT FROM AUTHOR]

Polybia paulista (Hymenoptera: Vespidae) is responsible for a high number of sting accidents and anaphylaxis events in Southeast Brazil, Argentina and Paraguay. The specific detection of allergy to the venom of this wasp is often hampered by the lack of recombinant allergens currently available for molecular diagnosis. Antigen 5 (~23 kDa) from P. paulista venom (Poly p 5) is a highly abundant and glycosylated allergenic protein that could be used for development of component-resolved diagnosis (CRD). Here, we describe the cloning and heterologous expression of the antigen 5 (rPoly p 5) from P. paulista venom using the eukaryotic system Pichia pastoris. The expression as a secreted protein yielded high levels of soluble rPoly p 5. The recombinant allergen was further purified to homogeneity (99%) using a two-step chromatographic procedure. Simultaneously, the native form of the allergen (nPoly p 5) was purified from the wasp venom by Ion exchange chromatography. The rPoly p 5 and nPoly p 5 were then submitted to a comparative analysis of IgE-mediated immunodetection using sera from patients previously diagnosed with sensitization to wasp venoms. Both rPoly p 5 and nPoly p 5 were recognized by specific IgE (sIgE) in the sera of the allergic individuals. The high levels of identity found between nPoly p 5 and rPoly p 5 by the alignment of its primary sequences as well as by 3-D models support the results obtained in the immunoblot. Overall, we showed that P. pastoris is a suitable system for production of soluble rPoly p 5 and that the recombinant allergen represents a potential candidate for molecular diagnosis of P.paulista venom allergy. [ABSTRACT FROM AUTHOR]

In regions at risk of scorpion envenomation, children remain the principal victims; they exhibit severe symptoms and represent a higher mortality rate compared to adults. The pathophysiology of envenomation is related to an excessive inflammatory response; however, no studies have identified the differences in immune responses to scorpion stings and mainly the mechanisms of inflammation between children and adults, which may be a determinant key of the susceptibility of children to scorpion envenomation. In this study, we compared the systemic (blood and lung) and the central (brain) inflammatory responses after injection of Androctonus australis hector ( Aah) venom to 7 and 21 postnatal days (pnds) and adult mice by subcutaneous route. Results revealed that 7 and 21 pnd mice were more sensitive to Aah venom than adults and presented also severe systemic and central inflammatory responses characterized by a high activation of immune cells, NO liberation, and lipid peroxidation. Lymphocyte levels were much lower in young animals than in adults; however, neutrophil levels seemed to be higher in immature mice. The antioxidant GSH and catalase levels were more reduced in 7 and 21 pnd mice compared to adults leading to more pronounced tissular alterations and edema formation in lung and brain. These findings show a relationship between the severity of the pathophysiological effects of Aah venom and the age. The vulnerability of immature animals to Aah venom might result from uncontrolled inflammatory response and central nervous system alterations. Data from the present study emphasize the need for the development of age-specific therapeutic modalities. [ABSTRACT FROM AUTHOR]

Secretion of granular glands from the skin of amphibians is a fascinating resource of active substances, particularly for cancer therapy in clinical practice of Traditional Chinese Medicine. A variety of anti‑tumor peptides have been isolated from different toads and frogs; however, no anti‑tumor peptides are reported in toad venom of Bufo gargarizans. Firstly, soluble fraction from fresh toad venom (FTV) was compared with that from dried toad venom (DTV), using HPLC analysis. It was revealed that FTV has a different HPLC chromatography compared with DTV. Soluble fraction of FTV is more toxic to SH‑SY5Y cells than that of DTV, as evaluated by MTT assay. Secondly, it was identified that protein components from soluble fractions of FTV and DTV possess different patterns by SDS‑PAGE analysis, and proteins from FTV are also more toxic than that from DTV. Thirdly, an immobilized basic fibroblast growth factor (bFGF) affinity column was used to isolate bFGF‑binding components from soluble fraction of FTV, and it was identified that bFGF‑binding components prohibited bFGF‑dependent neurite growth of SH‑SY5Y cells. Finally, it was identified that bFGF‑binding components activated apoptosis via upregulation of caspase‑3 and caspase‑8 expression in SH‑SY5Y cells. These data suggest that FTV contains active components that interact with bFGF and activate apoptosis in SH‑SY5Y cells. [ABSTRACT FROM AUTHOR]

Rattlesnakes use prey chemical cues for ambush site selection and for relocating envenomated (E) prey following a predatory strike. The ability to discriminate between E and non-envenomated (NE) prey cues has been widely studied in rattlesnake species that produce type I venoms, which show high levels of snake venom metalloproteinase (SVMP) activity and low lethal toxicity [lethal dose which kills 50% of test animals (LD) >1.0 µg/g]. However, E vs. NE prey discrimination studies have not been conducted on rattlesnake species that produce a type II venom that consists of low SVMP activity and high lethal toxicity (LD <1.0 µg/g). In the current study, long-term captive Crotalus oreganus concolor, which produce a type II venom, were tested for their ability to discriminate between chemical cues of natural ( Sceloporus undulatus and Peromyscus maniculatus) and non-natural ( Hemidactylus frenatus and Mus musculus) prey cues, as well as for their ability to discriminate between E and NE mouse carcasses, when prey envenomation occurred by a conspecific. Snakes showed significant levels of tongue flicking towards the chemical extracts of P. maniculatus and M. musculus, suggesting that C. oreganus concolor exhibit both innate and experience-based plasticity in response to prey chemical cues. In addition, C. oreganus concolor were able to discriminate between E and NE prey sources, when envenomation occurred by a conspecific, indicating that a type II venomous species can also discriminate between E and NE chemical cues. [ABSTRACT FROM AUTHOR]

Compounds activating γ-aminobutyric acid type A receptor were isolated from the toad Bufo bufo venom as a result of chromatographic separation. Analysis of the structure of these compounds by mass spectrometry and nuclear magnetic resonance showed that they are arginine derivatives of dicarboxylic acids and represent suberylarginine, pimeloylarginine, and adipoylarginine. [ABSTRACT FROM AUTHOR]

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

Hemoscorpius lepturus is the most medically important scorpion in Iran. The clinical signs of H. lepturus envenomation are remarkably similar to those reported for brown spiders, including dermonecrosis, hematuria, renal failure and even death. The lethality and toxicity of brown spiders' venom have been attributed to its phospholipase D activity. This study aims to identify a phospholipase D with possible lethality and dermonecrotic activity in H. lepturus venom. In this study, a cDNA library of the venom glands was generated by Illumina RNA sequencing. Phospholipase D (PLD) from H. lepturus was characterized according to its significant similarity with PLDs from brown spiders. The main chain designated as Hl-RecPLD1 (the first recombinant isoform of H. lepturus PLD) was cloned, expressed and purified. Sphingomyelinase, dermonecrotic and lethal activities were examined. Hl-PLD1 showed remarkable sequence similarity and structural homology with PLDs of brown spiders. The conformation of Hl-PLD1 was predicted as a "TIM beta/alpha-barrel". The lethal dose 50 (LD50) and dermonecrotic activities of Hl-RecPLD1 were determined as 3.1 μg/mouse and 0.7 cm2 at 1 μg respectively. It is the first report indicating that a similar molecular evolutionary mechanism has occurred in both American brown spiders and this Iranian scorpion. In conclusion, Hl-RecPLD1 is a highly active phospholipase D, which would be considered as the lethal dermonecrotic toxin in H. lepturus venom. [ABSTRACT FROM AUTHOR]

Context: Although rare, coral snake envenomation is a serious health threat in Brazil, because of the highly neurotoxic venom and the scarcely available antivenom. The major bottleneck for antivenom production is the low availability of venom. Furthermore, the available serum is not effective against all coral snake species found in Brazil. An alternative to circumvent the lack of venom for serum production and the restricted protection of the actually available antivenom would be of great value. We compared the Brazilian coral snake and mono and polyvalent Australian antivenoms in terms of reactivity and protection. Methods: The immunoreactivity of venoms from 9 coral snakes species were assayed by ELISA and western blot using the Brazilian Micrurus and the Australian pentavalent as well as monovalent anti-Notechis, Oxyuranus and Pseudechis antivenoms. Neutralization assays were performed in mice, using 3 LD50 of the venoms, incubated for 30 minutes with 100 μL of antivenom/animal. Discussion: All the venoms reacted against the autologous and heterologous antivenoms. Nevertheless, the neutralization assays showed that the coral snake antivenom was only effective against M. corallinus, M. frontalis, M. fulvius, M. nigrocinctus and M. pyrrhocryptus venoms. On the other hand, the Australian pentavalent antivenom neutralized all venoms except the one from M. spixii. A combination of anti-Oxyuranus and Pseudechis monovalent sera, extended the protection to M. altirostris and, partially, to M. ibiboboca. By adding Notechis antivenom to this mixture, we obtained full protection against M. ibiboboca and partial neutralization against M. lemniscatus venoms. Conclusions: Our findings confirm the limited effectiveness of the Brazilian coral snake antivenom and indicate that antivenoms made from Australian snakes venoms are an effective alternative for coral snake bites in South America and also in the United States were coral snake antivenom production has been discontinued. [ABSTRACT FROM AUTHOR]

PURPOSE: We aimed to describe ultrasonography (US)-guided percutaneous aspiration thrombectomy in pregnant women with iliofemoral deep vein thrombosis. METHODS: This study included nine pregnant women with acute and subacute iliofemoral deep vein thrombosis, who were severe symptomatic cases with massive swelling and pain of the leg. Patients were excluded from the study if they had only femoropopliteal deep vein thrombosis or mild symptoms of deep vein thrombosis. US-guided percutaneous aspiration thrombectomy was applied to achieve thrombus removal and uninterrupted venous flow. The treatment was considered successful if there was adequate venous patency and symptomatic relief. RESULTS: Complete or significant thrombus removal and uninterrupted venous flow from the puncture site up to the iliac veins were achieved in all patients at first intervention. Complete relief of leg pain was achieved immediately in seven patients (77.8%). Two patients (22.2%) had a recurrence of thrombosis in the first week postintervention. One of them underwent a second intervention, where percutaneous aspiration thrombectomy was performed again with successful removal of thrombus and establishment of in line flow. Two patients were lost to follow-up after birth. None of the remaining seven patients had rethrombosis throughout the postpartum period. Symptomatic relief was detected clinically in these patients. CONCLUSION: Endovascular treatment with US-guided percutaneous aspiration thrombectomy can be considered as a safe and effective way to remove thrombus from the deep veins in pregnant women with acute and subacute iliofemoral deep vein thrombosis. [ABSTRACT FROM AUTHOR]

Background: Snakebite is a major public health problem in agricultural communities in the tropics leading to acute local and systemic impairments with resultant disabilities. Snakebite related long-term musculoskeletal disabilities have been a neglected area of research. We conducted a population-based, cross-sectional study in an agricultural community to describe the chronic musculoskeletal disabilities of snake envenoming. Methodology/Principal Findings: A sample representative of residents of a single district in a region of high incidence of snake envenoming was recruited to identify ever snakebite victims. They were evaluated for chronic musculoskeletal disabilities that had developed immediately or within four weeks after the snakebite and persisted over three months. In-depth interviews, validated musculoskeletal functional assessment criteria and specialists’ examinations were utilised. Among the 816 victims, 26 (3.2%, 95% confidence interval: 2.2–4.6%) had musculoskeletal disabilities, persisting on average for 13.4 years (SD = 14.4). The disabilities were mostly in lower limbs (61.5%) and ranged from swelling (34.6%), muscle wasting (46.1%), reduced motion (61.5%), reduced muscle power (50%), impaired balance (26.9%), chronic non-healing ulcers (3.85%), abnormal gait (3.85%), fixed deformities (19.2%) to amputations (15.4%). Based on disability patterns, six snakebite-related musculoskeletal syndromes were recognised. The offending snakes causing disabilities were cobra (30.8%), Russell’s viper (26.9%) and hump-nosed viper (7.7%). Cobra bites manifested muscle wasting (87.5%), reduced muscle power (87.5%), joint stiffness (62.5%) and deformities (37.5%) while viper bites manifested impaired balance (42.8%), pain (71.4%) and swelling (71.4%). Conclusions/Significance: Snakebite envenoming is associated with considerable long-term musculoskeletal disabilities. Facilities for specialized care and rehabilitation need to be established in high risk areas. [ABSTRACT FROM AUTHOR]

Venom secretions from snakes, scorpions, spiders and bees, have been widely applied in traditional medicine and current biopharmaceutical research. Possession of anticancer potential is another novel discovery for animal venoms and toxins. An increasing number of studies have shown the anticancer effects of venoms and toxins of snakes, and scorpions in vitro and in vivo, which were achieved mainly through the inhibition of cancer growth, arrest of cell cycle, induction of apoptosis and suppression of cancer metastasis. However, more evidence is needed to support this concept and the mechanisms of anticancer actions are not clearly understood. The present review is focused on the recant updates on anticancer venom research. [ABSTRACT FROM AUTHOR]

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

Thousands suffer poisonous snake bite, often from defibrinogenating species annually. Three rattlesnake species in particular, the timber rattlesnake, Eastern diamondback rattlesnake, and Southern Pacific rattlesnake, cause clinically relevant hypofibrinogenemia via thrombin-like activity in their venom. It has been demonstrated that iron (Fe) and carbon monoxide (CO) change the ultrastructure of plasma thrombi and improve coagulation kinetics. Thus, the present investigation sought to determine if pretreatment of plasma with Fe and CO could attenuate venom-mediated catalysis of fibrinogen via thrombin-like activity. Human plasma was pretreated with ferric chloride (0–10 μM) and CO-releasing molecule-2 (0–100 μM) prior to exposure to 2.5–10 μg/ml of venom obtained from the aforementioned three species of rattlesnake. Coagulation kinetics were determined with thrombelastography. All three snake venoms degraded plasmatic coagulation kinetics to a significant extent, especially diminishing the speed of clot growth and strength. Pretreatment of plasma with Fe and CO completely abrogated the effects of all three venoms on coagulation kinetics. Further in vitro investigation of other pit viper venoms that possess thrombin-like activity is indicated to see if there is significant conservation of venom enzymatic target recognition of specific amino acid sequences such that Fe and CO can reliably attenuate venom-mediated catalysis of fibrinogen. These data also serve as a rationale for future preclinical investigation. [ABSTRACT FROM AUTHOR]

Objective: Intra-arterial injection of Mesobuthus tamulus (BT) venom produces reflex vasosensory responses modulating cardiorespiratory parameters in albino rats. The present study was conducted to understand the role of kinin receptors in modulating vasosensory reflexes evoked by BT venom. Materials and Methods: In urethane-anesthetized rats, tracheostomy was performed to keep the airway patent. The femoral artery was cannulated proximally, as well as distally, to record the blood pressure (BP) and to inject the chemicals, respectively. Electrocardiographic and respiratory excursions were recorded to compute the heart rate (HR) and respiratory rate (RR). A group of animals was pretreated with saline/kinin receptor antagonists intra-arterially (B1/B2 receptor antagonists) before the injection of venom. Results: After intra-arterial injection of BT venom (1 mg/kg), there was an immediate increase in RR, which reached to 40% within 30 s, followed by a decrease of 40%. Further, there was sustained increase in RR (50%) up to 60 min. The BP started to increase at 40 s, peaking at 5 min (50%), and remained above the initial level up to 60 min. The bradycardiac response started after 5 min which peaked (50% of initial) at 25 min and remained at that level up to 60 min. In B1 receptor antagonist (des-Arg) pretreated animals, venom-induced cardiovascular responses were attenuated (by 20-25% in mean arterial pressure and HR) significantly but not in B2 receptor antagonist (Hoe-140) pretreated animals. Either of the antagonists failed to alter the RR responses. Conclusions: BT venom-induced vasosensory reflex responses modulating cardiovascular parameters are mediated via B1-kinin receptors in anesthetized rats. [ABSTRACT FROM AUTHOR]

Background Venom immunotherapy is efficient to desensitize people suffering from insect sting allergies. However, the numerous injections required over several years and important risks of severe side reactions complicate the widespread use of immunotherapy. In the search for novel approaches to blunt the overwhelming pro-allergic Th2 response, we evaluated the therapeutic efficacy of a treatment based on a denatured form of the major allergen, phospholipase A2, associated with microbubbles ( PLA2denat- MB) in a mouse model of honeybee venom allergy. Methods Antibodies measured by ELISA, T-cell responses assessed by CFSE-based proliferation assays and ELISA, and basophil degranulation were examined after PLA2denat- MB-based therapeutic treatment of sensitized mice. Mice were challenged with a lethal dose of PLA2 to evaluate protection against anaphylaxis. Results Therapeutic subcutaneous administration of two different PLA2denat- MB formulations, in contrast to PLA2denat alone, reduced allergic symptoms and protected all mice from anaphylaxis-mediated death after allergen challenge. At the functional level, the use of PLA2denat decreased IgE-mediated basophil degranulation as compared to the native form of the allergen. In comparison with PLA2denat alone, both PLA2denat- MB formulations decreased allergen-specific Th2 CD4 T-cell reactivity. At the mechanistic level, PLA2denat- MB containing 20% palmitic acid and PEG induced PLA2-specific IgA and increased Foxp3+ Treg frequencies and TGF-β production, whereas the formulation bearing 80% palmitic acid triggered the production of IFN-γ, IgG2a, and IgG3. Conclusions In contrast to conventional PLA2 subcutaneous immunotherapy, the therapeutic administration of PLA2- MB treatment to mice that already had established allergy to PLA2 protects all subsequently challenged animals. [ABSTRACT FROM AUTHOR]

Formation of correct disulfide bonds in the endoplasmic reticulum is a crucial step for folding proteins destined for secretion. Protein disulfide isomerases (PDIs) play a central role in this process. We report a previously unidentified, hypervariable family of PDIs that represents the most diverse gene family of oxidoreductases described in a single genus to date. These enzymes are highly expressed specifically in the venom glands of predatory cone snails, animals that synthesize a remarkably diverse set of cysteine-rich peptide toxins (conotoxins). Enzymes in this PDI family, termed conotoxin-specific PDIs, significantly and differentially accelerate the kinetics of disulfide-bond formation of several conotoxins. Our results are consistent with a unique biological scenario associated with protein folding: The diversification of a family of foldases can be correlated with the rapid evolution of an unprecedented diversity of disulfide-rich structural domains expressed by venomous marine snails in the superfamily Conoidea. [ABSTRACT FROM AUTHOR]

Cyanea nozakii Kishinouy e ( C. nozakii), a giant cnidarian of the class Scyphomedusae, order Semaeostomeae and family Cyaneidae, is widely distributed in the East China Sea, the Yellow Sea and the Bohai Sea, and is abundant from late summer to early autumn. Venom produced by C. nozakii during mass agglomerations can contaminate seawater resulting in death of the halobios and seriously damage commercial fisheries. Swimmers and fishermen commonly suff er painful stings from this jellyfish, resulting in local edema, tingling, breathing difficulties, depressed blood pressure and even death. Such effects arise from the complex mixture of biologically active molecules that make up jellyfish venom. In the present study, the hemolytic activity of venom from tentacles of C. nozakii and factors aff ecting its activity were assayed. The HU ( defined as the amount of protein required to lyse 50 % of erythrocytes) of the venom against dove and chicken erythrocytes was 34 and 59 μg/mL, respectively. Carboxylmethyl chitosan and glycerol could increase hemolytic activity at concentrations greater than 0.06% and 0.2 mol/L, respectively. [ABSTRACT FROM AUTHOR]

A transcriptomic analysis of the saliva of T. pallidipennis together with a short proteomic analysis were carried out to reveal novel primary structures of the lipocalin/triabin protein families in this reduviid. Although triabins share some structural characteristics to lipocalins and they are classified as in the calcyn/lipocalin superfamily, triabins differ from lipocalins in the direction of β-strands in the general conformation of the β-barrel. The triabin protein family encompasses a wide variety of proteins, which disrupt the hemostasis of warm-blooded animals. Likewise, the function of proteins classified as triabins includes proteins that are carriers of small molecules, protease inhibitors, binders of specific cell-surface receptors as well as proteins that form complexes with other macromolecules. For example, triabin and pallidipin from the saliva of T. pallidipennis are thrombin and platelet aggregation inhibitors, respectively; triplatin from T. infestans binds to thromboxane A2; and nitrophorin from Rhodnius prolixus carries nitric oxide. Therefore, based on 42 new transcriptome sequences of triabins from the salivary glands of T. pallidipennis reported at present, and on triabin sequences of other American hematophagous reduviids already reported in the literature, subfamilies of triabins were proposed following phylogenetic analyses and functional characterization of triabin members. Eight subfamilies of proteins were recognized with known functions, which were the nitrophorin and amine binding proteins, Rhodnius prolixus aggregation inhibitor, triafestin, triatin, dipetalodipin and pallidipin, triplatin and infestilin, dimiconin and triabin, and procalin subfamilies. Interestingly, 70% of the analyzed sequences came from these eight subfamilies because there was no biological function associated with them, implying the existence of a vast number of proteins with potential novel biological activities. [ABSTRACT FROM AUTHOR]

A novel conotoxin, named as PiVIIA, was isolated from the venom of Conus princeps, a marine predatory cone snail collected in the Pacific Southern Coast of Mexico. Chymotryptic digest of the S-alkylated peptide in combination with liquid chromatography coupled to tandem mass spectrometry, were used to define the sequencing of this peptide. Eleven N-terminal amino acids were verified by automated Edman degradation. PiVIIA is a 25-mer peptide (CDAOTHYCTNYW CCSGYC HSHCW) with six cysteine residues forming three disulphide bonds, a hydroxyproline (O) and two gamma carboxyglutamic acid (γ) residues. Based on the arrangement of six Cys residues (C-C-CC-C-C), this conotoxin might belong to the O2-superfamily. Moreover, PiVIIA has a conserved motif (- CCS-) that characterizes -conotoxins from molluscivorous Conus. Peptide PiVIIA has 45% sequence identity with -PnVIIA-the prototype of this family. Biological activity of PiVIIA was assessed by voltage-clamp recording in rat dorsal root ganglion neurons. Perfusion of PiVIIA in the μM range produces a significant increase in the Ca2+ currents, without significantly modifying the Na+, K+ or proton-gated acid sensing ionic currents. These results indicate that PiVIIA is a new conotoxin whose activity deserves further studies to define its potential use as a positive modulator of neuronal activity. [ABSTRACT FROM AUTHOR]

The primary functions of venoms from solitary and social wasps are different. Whereas most solitary wasps sting their prey to paralyze and preserve it, without killing, as the provisions for their progeny, social wasps usually sting to defend their colonies from vertebrate predators. Such distinctive venom properties of solitary and social wasps suggest that the main venom components are likely to be different depending on the wasps' sociality. The present paper reviews venom components and properties of the Aculeata hunting wasps, with a particular emphasis on the comparative aspects of venom compositions and properties between solitary and social wasps. Common components in both solitary and social wasp venoms include hyaluronidase, phospholipase A2, metalloendopeptidase, etc. Although it has been expected that more diverse bioactive components with the functions of prey inactivation and physiology manipulation are present in solitary wasps, available studies on venom compositions of solitary wasps are simply too scarce to generalize this notion. Nevertheless, some neurotoxic peptides (e.g., pompilidotoxin and dendrotoxin-like peptide) and proteins (e.g., insulin-like peptide binding protein) appear to be specific to solitary wasp venom. In contrast, several proteins, such as venom allergen 5 protein, venom acid phosphatase, and various phospholipases, appear to be relatively more specific to social wasp venom. Finally, putative functions of main venom components and their application are also discussed. [ABSTRACT FROM AUTHOR]

Drug delivery across the blood-brain barrier (BBB) is a formidable challenge for therapies targeting the central nervous system. Although BBB shuttle peptides enhance transport into the brain non-invasively, their application is partly limited by lability to proteases. The present study proposes the use of cyclic peptides derived from venoms as an affordable way to circumvent this drawback. Apamin, a neurotoxin from bee venom, was minimized by reducing its complexity, toxicity, and immunogenicity, while preserving brain targeting, active transport, and protease resistance. Among the analogues designed, the monocyclic lactambridged peptidomimetic MiniAp-4 was the most permeable. This molecule is capable of translocating proteins and nanoparticles in a human-cell-based BBB model. Furthermore, MiniAp-4 can efficiently deliver a cargo across the BBB into the brain parenchyma of mice. [ABSTRACT FROM AUTHOR]

OBJECTIVE:The aim of the study was to assess immune response to honeybee venom in relation to the degree of exposure, time after a sting and clinical symptoms. MATERIALS AND METHOD:Fifty-four volunteers were divided into 2 groups: beekeepers and a control group. The serum levels of total IgE (tIgE), bee venom-specific IgE (venom sIgE), phospholipase A2-specific IgE (phospholipase A2 sIgE), tryptase and venom-specific IgG4 (venom sIgG4) were determined. In beekeepers, diagnostic tests were performed within 3 hours following a sting and were repeated after a minimum of 6 weeks from the last sting. In individuals from the control group, the tests were performed only once, without a sting. RESULTS:The tests showed significant differences in venom sIgE (beekeepers' median = 0.34 kUA/l, control group median = 0.29 kUA/l), baseline serum tryptase (beekeepers' median = 4.25 µg/l, control group median = 2.74 µg/l) and sIgG4 (beekeepers' median = 21.2 mgA/l, control group median = 0.14 mgA/l), confirming higher levels of the tested substances in the beekeepers than in the control group. A significant positive correlation was observed between phospholipase A2 sIgE concentration and severity of clinical symptoms after a sting in the group of beekeepers. It was also demonstrated that the clinical symptoms after a sting became less severe with increasing age of the beekeepers. CONCLUSIONS:The differences in the immune response to a bee sting between the beekeepers and individuals not exposed to bees were probably due to the high exposure of the beekeepers to honeybee venom allergens. This may suggest a different approach to the bee venom allergy diagnostic tests in this occupational group. [ABSTRACT FROM AUTHOR]

The Chinese scorpion, Mesobuthus martensii (Karsch, 1879), is a medically important arthropod, with its venom representing a rich resource for bioactive molecules. Very little is known about the natural enemies of scorpion, albeit some populations are on the verge of extinction due to human over-exploitation. In this study, we found, for the first time, that a medically and forensically important flesh fly, Sarcophaga dux (Thompson, 1869), can parasitize M. martensii in China. We identified the flesh flies by both morphology and DNA-based methods employing the mitochondrial cytochrome C oxidase I gene. Our phylogenetic analyses indicated that S. dux was not monophyletic with respect to Sarcophaga aegyptica (Salem, 1935) and Sarcophaga harpax (Pandelle, 1896), and was comprised of two distinct mitochondrial lineages. The flesh flies infesting the Chinese scorpion formed one of the paraphyletic lineages of S. dux. These lineages together with S. aegyptica and S. harpax represented a species complex with genetic distances ranging from 1.0 to 1.5%. Our findings suggested that S. dux was capable of larviposition nocturnally. [ABSTRACT FROM AUTHOR]

Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components. [ABSTRACT FROM AUTHOR]

The present study evaluated the acute bio-physiological effects of Lethal dose 50 (LD 50) of crude venom of Black Pakistani Cobra, Naja naja karachiensis, collected from Southern Punjab, Pakistan. Adult mice (n=20) were injected intramuscularly with normal saline (n/s) or LD50 of crude venom (1.2mg/kg). Blood was collected by cardiac puncture after anesthesia at intervals 0 (n/s), and 1, 1.5, 2 (LD50 venom) hours. Complete blood count, glucose, serum Alanine aminotransferase (ALT), albumin, total proteins and urea were measured to assess the physiology. One way ANOVA was used to analyze the data (P<0.05). A significant increase in erythrocyte count, its indices and thrombocytosis was observed during the study. Leukocyotsis was observed after a transient leucopenia at 1 hour post envenomation. No significant difference was observed for lymphocytes and monocytes. Serum concentrations of urea, total proteins, albumin and ALT were also increased significantly with all time intervals. Hypoglycemia was observed initially followed by hyperglycemia at 1.5 and 2 hours. The changes indicate that venom has severe hemotoxic potential and disrupts physiological processes by affecting vital organs like kidneys and liver in mice. [ABSTRACT FROM AUTHOR]

Background: Russell’s viper envenoming is a major problem in South Asia and causes venom induced consumption coagulopathy. This study aimed to investigate the kinetics and dynamics of venom and clotting function in Russell’s viper envenoming. Methodology/Principal Findings: In a prospective cohort of 146 patients with Russell’s viper envenoming, we measured venom concentrations, international normalised ratio [INR], prothrombin time (PT), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, and von Willebrand factor antigen. The median age was 39y (16–82y) and 111 were male. The median peak INR was 6.8 (interquartile range[IQR]:3.7 to >13), associated with low fibrinogen [median,<0.01g/L;IQR:<0.01–0.9g/L), low factor V levels [median,<5%;IQR:<5–4%], low factor VIII levels [median,40%;IQR:12–79%] and low factor X levels [median,48%;IQR:29–67%]. There were smaller reductions in factors II, IX and VII over time. All factors recovered over 48h post-antivenom. The median INR remained >3 at 6h post-antivenom but had reduced to <2, by 24h. The aPTT had also returned to close to normal (<50sec) at 24h. Factor VII, VIII and IX levels were unusually high pre-antivenom, median peak concentrations of 393%, 307% and 468% respectively. Pre-antivenom venom concentrations and the INR (r = 0.20, p = 0.02) and aPTT (r = 0.19, p = 0.03) were correlated (non-parametric Spearman analysis). Conclusions: Russell’s viper coagulopathy results in prolonged aPTT, INR, low fibrinogen, factors V, VIII and X which recover over 48h. Severity of clotting abnormalities was associated with venom concentrations. [ABSTRACT FROM AUTHOR]

Hymenopteravenoms are known to cause life-threatening IgE-mediated anaphylactic reactions in allergic individuals. Venom immunotherapy is a recommended treatment of insect allergy with still the mechanism not being completely understood. We decided to assess the serum CCL5/RANTES level in patients who experienced severe anaphylactic reaction toHymenopteravenom and to find out changes in the course of immunotherapy. Twenty patients (9 men, 11 women, mean age: 31.91 ± 7.63 years) with history of anaphylactic reaction after insect sting were included into the study. Diagnosis was made according to sIgE and skin tests. All of them were enrolled into rush venom immunotherapy with bee or wasp venom extracts (Pharmalgen, ALK-Abello, Horsholm, Denmark). Serum levels of CCL5/RANTES were measured using a commercially available ELISA kit (R&D Systems, Minneapolis, MN). CCL5/RANTES serum concentration are higher in insect venom allergic patients than in healthy controls (887.5 ± 322.77 versus 387.27 ± 85.11 pg/ml). Serum concentration of CCL5/RANTES in insect venom allergic patient was significantly reduced in the course of allergen immunotherapy already after 6 days of vaccination (887.5 ± 322.77 versus 567.32 ± 92.16 pg/ml). CCL5/RANTES serum doesn’t correlate with specific IgE. Chemokine CCL5/RANTES participates in allergic inflammation induced byHymenopteravenom allergens. Specific immunotherapy reduces chemokine CCL5/RANTES serum level already after initial days of venom immunotherapy. [ABSTRACT FROM PUBLISHER]

Neurodegenerative diseases are relentlessly progressive, severely impacting affected patients, families and society as a whole. Increased life expectancy has made these diseases more common worldwide. Unfortunately, available drugs have insufficient therapeutic effects on many subtypes of these intractable diseases, and adverse effects hamper continued treatment. Wasp and bee venoms and their components are potential means of managing or reducing these effects and provide new alternatives for the control of neurodegenerative diseases. These venoms and their components are well-known and irrefutable sources of neuroprotectors or neuromodulators. In this respect, the present study reviews our current understanding of the mechanisms of action and future prospects regarding the use of new drugs derived from wasp and bee venom in the treatment of major neurodegenerative disorders, including Alzheimer's Disease, Parkinson's Disease, Epilepsy, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. [ABSTRACT FROM AUTHOR]

Parasitoid wasps inject insect hosts with a cocktail of venoms to manipulate the physiology, development, and immunity of the hosts and to promote development of the parasitoid offspring. The jewel wasp Nasonia vitripennis is a model parasitoid with at least 79 venom proteins. We conducted a high-throughput analysis of Nasonia venom effects on temporal changes of 249 metabolites in pupae of the flesh fly host ( Sarcophaga bullata), over a 5-day time course. Our results show that venom does not simply arrest the metabolism of the fly host. Rather, it targets specific metabolic processes while keeping hosts alive for at least 5 days post venom injection by the wasp. We found that venom: (a) activates the sorbitol biosynthetic pathway while maintaining stable glucose levels, (b) causes a shift in intermediary metabolism by switching to anaerobic metabolism and blocking the tricarboxylic acid cycle, (c) arrests chitin biosynthesis that likely reflects developmental arrest of adult fly structures, (d) elevates the majority of free amino acids, and (e) may be increasing phospholipid degradation. Despite sharing some metabolic effects with cold treatment, diapause, and hypoxia, the venom response is distinct from these conditions. Because Nasonia venom dramatically increases sorbitol levels without changing glucose levels, it could be a useful model for studying the regulation of the sorbitol pathway, which is relevant to diabetes research. Our findings generally support the view that parasitoid venoms are a rich source of bioactive molecules with potential biomedical applications. [ABSTRACT FROM AUTHOR]

This study reports on a cytotoxic toxin derived from the venom of the crown-of-thorns starfish Acanthaster planci (CAV). The protein toxin was isolated through both ion-exchange and gel-filtration chromatography, and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrum analyzes. The CAV was identified as plancitoxin I protein. The mechanistic role of the CAV toxin was explored in human malignant melanoma A375.S2 cell death. The results indicated that after incubation with CAV toxin, cells significantly decreased in A375.S2 cell viability and increased in the lactate dehydrogenase (LDH) level in a dose-dependent manner. The assays indicated that CAV toxin promoted reactive oxygen species (ROS) production, induced nitric oxide (NO) formation, lost mitochondrial membrane potential (ΔΨm) and induced inter-nucleosomal DNA fragmentation in A375.S2 cells. The molecular cytotoxicity of the CAV toxin was tested through evaluation of the apoptosis/necrosis ratio by double staining with annexin V-FITC and a propidium iodide (PI) assay. The results suggested that CAV toxin induced a cytotoxic effect in A375.S2 cells via the apoptotic procedure, and may be associated with the regulation of the p38 pathways. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: An alarming number of fatal accidents involving snakes are annually reported in Africa and most of the victims suffer from permanent local tissue damage and chronic disabilities. Envenomation by snakes belonging to the genus Bitis, Viperidae family, are common in Sub-Saharan Africa. The accidents are severe and the victims often have a poor prognosis due to the lack of effective specific therapies. In this study we have biochemically characterized venoms from three different species of Bitis, i.e., Bitis arietans, Bitis gabonica rhinoceros and Bitis nasicornis, involved in the majority of the human accidents in Africa, and analyzed the in vitro neutralizing ability of two experimental antivenoms. Methodology/Principal Findings: The data indicate that all venoms presented phospholipase, hyaluronidase and fibrinogenolytic activities and cleaved efficiently the FRET substrate Abz-RPPGFSPFRQ-EDDnp and angiotensin I, generating angiotensin 1–7. Gelatinolytic activity was only observed in the venoms of B. arietans and B. nasicornis. The treatment of the venoms with protease inhibitors indicated that Bitis venoms possess metallo and serinoproteases enzymes, which may be involved in the different biological activities here evaluated. Experimental antivenoms produced against B. arietans venom or Bitis g. rhinoceros plus B. nasicornis venoms cross-reacted with the venoms from the three species and blocked, in different degrees, all the enzymatic activities in which they were tested. Conclusion: These results suggest that the venoms of the three Bitis species, involved in accidents with humans in the Sub-Saharan Africa, contain a mixture of various enzymes that may act in the generation and development of some of the clinical manifestations of the envenomations. We also demonstrated that horse antivenoms produced against B. arietans or B. g. rhinoceros plus B. nasicornis venoms can blocked some of the toxic activities of these venoms. [ABSTRACT FROM AUTHOR]

Aim: To determine the indications for, duration of, complications, duration of hospitalisation and outcomes in patients treated with positive-pressure ventilation (PPV) in Australia. Materials and Methods: Medical records of 302 patients (262 dogs and 40 cats) treated with PPV were reviewed for the indication for ventilation, duration of PPV, complications, duration of hospitalisation and outcome. Patients were assigned into one of four groups based on the indication for ventilation. Results: The present study showed higher survival rates for patients treated with PPV than previously reported. Patients ventilated for hypoventilation and unsustainable respiratory effort had the highest survival rates. Snake envenomation and tick paralysis were the most common underlying diseases in patients treated with PPV and had good survival rates. Conclusion: The indication for ventilation is associated with outcome. PPV should be instigated early when unsustainable respiratory effort is evident to give patients the best chance of survival. [ABSTRACT FROM AUTHOR]

A retrospective study was conducted in cats and dogs with Mainland tiger snake (Notechis scutatus) and Eastern brown snake (Pseudonaja textillis) envenomation in Melbourne, Australia, to compare clinical signs and treatment and to determine if a coagulopathy is seen as frequently as in human envenomation cases. Neurotoxicity was common in both tiger and brown snake envenomation. Myotoxicity was seen in 83% of dogs and 96% of cats with tiger snake envenomation. Prolonged coagulation tests were common in animals with tiger snake envenomation, but not in those with brown snake envenomation. Clinical bleeding was less common than laboratory evidence of a coagulopathy. Dogs were treated with a median of 2 vials and cats with a median of 1 vial of tiger/brown polyvalent antivenom. The overall proportion of cases presenting for snake envenomation that were euthanased for financial reasons was 12% for dogs and 13% for cats. Of the remaining cases, 95% of dogs and 97% of cats survived. Due to the similarity of clinical signs in tiger and brown snake envenomation, it is not recommended that diagnosis and choice of antivenom be based on clinical signs alone. [ABSTRACT FROM AUTHOR]

Background. Crotaline snakebites are routinely assessed with serial external examinations. We sought to correlate external findings with changes observed on ultrasound imaging. Methods. This was a prospective, observational study of consecutive rattlesnake envenomation in patients treated at a single hospital in central California. Information recorded for each case included clinical data, gross external examination, and ultrasound images of tissue edema, localized fluid collections, and video footage of muscle fasciculations. Results. Thirteen patients were enrolled. Ultrasound imaging of the bitten extremity was consistent with external examination of the bitten limb. The most common sonographic finding was subcutaneous tissue edema. Edema and necrosis in 3 patients with rapidly progressive leg swelling spared the deeper muscle layers and fascial planes. In 2 patients with bites on the fingers, edema and tendon involvement were readily visualized using a water-bath technique (placement of the hand in a pool of water, allowing more detailed examination of the tissue planes). Conclusion. Ultrasound imaging may allow for a more complete understanding of the local effects of snakebite. We were also able to document normal deeper muscle integrity in cases with diffuse leg edema. More studies are needed to fully elaborate the strengths and limitations of bedside ultrasound as a diagnostic adjunct in envenomation assessment. [ABSTRACT FROM AUTHOR]

During the summer period 2011-2012, seven widow spider bites in Greece were reported to the Hellenic Center for Disease Control and Prevention. Widow spiders (in the genus Latrodectus) are found all over the world, including Europe, Asia, Africa, Australia, and the US. Alpha-latrotoxin (main mammalian toxin) causes the toxic effects observed in humans. Victims should receive timely medical care to avoid suffering. Latrodectus bites are very rarely fatal. All the patients reported having an insect bite 30 minutes to 2 hours before they arrived at the Emergency Department of the local hospital. Severe muscle cramps, weakness, tremor, abdominal pain, and increased levels of creatinine phosphokinase were present in all patients. The Emergency Operation Center of the Hellenic Center for Disease Control and Prevention was informed immediately in all cases. Antivenin was administered to four patients upon the request of their physicians. All patients recovered fully. It is essential that health care workers recognize early the symptoms and signs of Latrodectus bites to provide the necessary care. The management of mild to moderate Latrodectus envenomations is primarily supportive. Hospitalization and possibly antivenin should be reserved for patients exhibiting serious systemic symptoms or inadequate pain control. The most important thing for all of these patients is early pain relief. [ABSTRACT FROM AUTHOR]

Introduction and objective. Mast cells (MC) are effector cells during severe systemic reactions (SR) to Hymenoptera stings. Venom specific immunotherapy (VIT) is the treatment of choice for prevention of SR to stings. Tryptase and prostaglandin D2 metabolites (PGD2) are the markers of MC activation. The study design was to 1. compare baseline values of serum tryptase concentration (BST) and PGD2 metabolites in children with/without venom sensitization, 2. to evaluate an influence of rush VIT on MC markers in treated children. Materials and methods. Sensitized group: 25 children with SR to Hymenoptera sting. Control group: 19 healthy children. Active treatment: 5-day-rush-VIT. BST was evaluated by ImmunoCAP, PGD2 metabolites in blood and urine by GC-NICI-MS. Results. The baseline blood levels of MC markers were significantly higher, while urinary concentration of 9α,11β-PGF2 was significantly lower in the whole group of venom-sensitized children compared to controls. Severity of SR showed negative correlation with urinary PGD2 metabolites, while positive with plasma 9α,11β-PGF2 and BST concentration The highest sensitivity was obtained for plasma 9α,11β-PGF2 whereas the highest specificity for urinary PGD-M. Conclusions. In children with IgE-mediated SR to Hymenoptera stings, elevation of baseline values of PGD2 metabolites in blood is accompanied by decreased excretion of its urinary metabolites. Assessment of stable PGD2 metabolites might serve as an independent MC marker to identify allergic children. There is an association between urinary PGD2 metabolites and severity of the SR to Hymenoptera stings. [ABSTRACT FROM AUTHOR]

Viper bites cause high morbidity and mortality worldwide and regarded as a neglected tropical disease affecting a large healthy population. Classical antivenom therapy has appreciably reduced the snakebite mortality rate; it apparently fails to tackle viper venom-induced local manifestations that persist even after the administration of antivenom. Recently, viper venom-induced oxidative stress and vital organ damage is deemed as yet another reason for concern; these are considered as postmedicated complications of viper bite. Thus, treating viper bite has become a challenge demanding new treatment strategies, auxiliary to antivenin therapy. In the last decade, several studies have reported the use of plant products and clinically approved drugs to neutralize venom-induced pharmacology. However, very few attempts were undertaken to study oxidative stress and vital organ damage. Based on this background, the present study evaluated the protective efficacy of melatonin in Echis carinatus ( EC) venom-induced tissue necrosis, oxidative stress, and organ toxicity. The results demonstrated that melatonin efficiently alleviated EC venom-induced hemorrhage and myonecrosis. It also mitigated the altered levels of inflammatory mediators and oxidative stress markers of blood components in liver and kidney homogenates, and documented renal and hepatoprotective action of melatonin. The histopathology of skin, muscle, liver, and kidney tissues further substantiated the overall protection offered by melatonin against viper bite toxicities. Besides the inability of antivenoms to block local effects and the fact that melatonin is already a widely used drug promulgating a multitude of therapeutic functionalities, its use in viper bite management is of high interest and should be seriously considered. [ABSTRACT FROM AUTHOR]

Background: We recently showed a desensitization of FcεRI-mediated basophil response after short-term VIT. Our aim was to evaluate the allergen specificity of this desensitization. Methods: In 11 Hymenoptera-venom double positive subjects, basophil threshold sensitivity (CD-sens) to anti-FcεRI, honeybee, and Vespula venom was assessed at the beginning and just before the first maintenance dose (MD) of single ultra-rush VIT. In some patients we also monitored CD-sens to rApi m 1 and/or rVes v 5 or other co-sensitizations (i.e., grass pollen). In additional 7 patients, basophils were stripped and sensitized with house dust mite (HDM) IgEs at the same time points. Results: We demonstrated a marked reduction of CD-sens to anti-FcεRI and VIT-specific venom before the first MD in all 18 subjects included. Furthermore, in 10 out of 11 double positive subjects, a significant and comparable decrease before the first MD was also evident for non-VIT venom; this nonspecific decrease was further supported by the opposite recombinant species-specific major allergen. In one subject with additional grass pollen allergy, a decrease of CD-sens to grass allergen was also demonstrated. Similarly, in 7 cases of patients with passively HDM-sensitized basophils, a significant reduction of CD-sens was also evident to de novo sensitized HDM allergen. Conclusions: Short-term VIT induced basophil desensitization to VIT-specific as well as to VIT-nonspecific venom. As opposed to long-term VIT, which induces venom-specific changes, the effect of short-term VIT seems to be venom-nonspecific. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect acetic acid (vinegar) has on discharged nematocysts in a simulated sting from Chironex fleckeri. Method: This research was performed in 2 parts: 1 C. fleckeri tentacles placed on amniotic membrane were electrically stimulated, and venom washings collected before and after application of vinegar. Lyophilised venom washings were run through a fast-performance protein liquid chromatography column to confirm the venom profile, with a quantitative measure of venom from each washing calculated using UNICORN™ software. 2 The toxicity of the washings was determined by application to human cardiomyocytes, with percentage of cell detachment providing a measure of cell mortality, and hence toxicity. Results: Part 1: There was a 69 +/- 32% (F = 77, P < 0.001) increase in venom discharge after vinegar was applied compared to post electrical stimulation. Part 2: Venom collected after the administration of vinegar demonstrated the same toxicity as venom from electrically stimulated C. fleckeri tentacles and milked venom, causing cell mortality of 59 +/- 13% at 10 µg ml-1 compared to 57 +/- 10% and 65 +/- 7% respectively. Conclusion: This in-vitro research suggests that vinegar promotes further discharge of venom from already discharged nematocysts. This raises concern that vinegar has the potential to do harm when used as first aid in C. fleckeri envenomation. [ABSTRACT FROM AUTHOR]

Background: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI. Methodology: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score). Principal Findings: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone. Conclusion: SP administered simultaneously with BV, in an approximate 10∶1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR. [ABSTRACT FROM AUTHOR]

Proteases from Russell's viper venom (RVV) induce a variety of toxic effects in victim. Therefore, four new RVV protease isoenzymes of molecular mass 32901.044 Da, 333631.179 Da, 333571.472 Da, and 34594.776 Da, were characterized in this study. The first 10 N-terminal residues of these serine protease isoenzymes showed significant sequence homology with N-terminal sequences of snake venom thrombin-like and factor V-activating serine proteases, which was reconfirmed by peptide mass fingerprinting analysis. These proteases were found to be different from previously reported factor V activators isolated from snake venoms. These proteases showed significantly different fibrinogenolytic, BAEE-esterase and plasma clotting activities but no fibrinolytic, TAME-esterase or amidolytic activity against the chromogenic substrate for trypsin, thrombin, plasmin and factor Xa. Their Km and Vmax values towards fibrinogen were determined in the range of 6.6 to 10.5 µM and 111.0 to 125.5 units/mg protein, respectively. On the basis of fibrinogen degradation pattern, they may be classified as A/B serine proteases isolated from snake venom. These proteases contain ∼42% to 44% of N-linked carbohydrates by mass whereas partially deglycosylated enzymes showed significantly less catalytic activity as compared to native enzymes. In vitro these protease isoenzymes induce blood coagulation through factor V activation, whereas in vivo they provoke dose-dependent defibrinogenation and anticoagulant activity in the mouse model. At a dose of 5 mg/kg, none of these protease isoenzymes were found to be lethal in mice or house geckos, suggesting therapeutic application of these anticoagulant peptides for the prevention of thrombosis. [ABSTRACT FROM AUTHOR]

The members of Scorpaenidae family, including stonefish (genus Synanceja) are among the most dangerous and venomous fishes in the word that inhibit in the tropical shallow waters. The toxinology of the venom of stonefish (genus Synanceja) showed that it is a mixture of proteins, containing several enzymes like hyaluronidase. The crude venom can produce cytolytic, hemolytic, neurotoxic and hypotensive effects in vivo. Immediate increasing intensive pain, local ischemia followed by cyanosis, edema and swelling are the local clinical presentations. Systemic manifestations are not uncommon. Hot water immersion of the injured limb, a local anesthetic agent without adrenaline, infiltrated into and around the wound, debridement of the necrotic tissue and the prescription of prophylactic antibiotic are the main therapeutic measures. The administration of antivenom may be considered. [ABSTRACT FROM AUTHOR]