Venoms Research Papers - Academia.edu (original) (raw)

Polyvalent antivenin was prepared against the Egyptian snake venons N~a Julje, N.tt;grlcollis, Cerastes eerastu and C. vipers, and tested by neutralization and immunodiffusion tests. The antivenin was of high potency against the Egyptian snake venons, especially C. ceraatea and C. vlpera, followed by F .chls carirruut, E. coloratur, N. /ulje, N. rt{gricollis and Walterinneaia aegyptia. The titre against the African and hidiaa cobra venons, N. nivea, N. hgje (Ethiopian) and N. rtgja was lower, while poor or no effect was shown against Bittyarietaru, B. galinnlea and 7ümeruurw flavovirldtr venons. The polyvalent serum prepared in horses not previously immunized, was comparable to sera obtained by using horses, which were previously immunized against a single venom. However, the latter sera, still maintained their higher titre against the original sensitizing venom. Comparison of polyvalent and monovaknt N. nigricollir aativwtina, revealed that while the polyvalent serum was of belles effectiveness against the Egyptian viper venons especially txtastes vanoma, more protection was provided by the nonovaknt serum against the raja venons .

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- Snakes, Rats, Lethal Dose, Venoms

Venoms of several animals have been used to study various physiopathologic processes, and also to offer opportunity to design and develop new therapeutic drugs. We briefly review certain wasp venom components and their biological effects,... more

Venoms of several animals have been used to study various physiopathologic processes, and also to offer
opportunity to design and develop new therapeutic drugs. We briefly review certain wasp venom components and their
biological effects, which may be potential sources of novel pharmacologically active compounds

- by Marta Monteiro
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- Animal venoms and toxins, Wasps, Wasps-Vespoidea, Social Wasps
- by Janine Deakin
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- Molecular Evolution, Biological Sciences, Reptiles, Peptides

Stoncfisb venom bas been fractionated on carboxymetbyl cellulose and Scphadex columns; of the fractions ol)tained only one was toxic to rats. The active fraction contained a relatively high proportion of aromatic amino acids. Whole venom was examined for enzyme activity and enzyme inhibition; the only significant aetivity found was tbat of hyaluronidase. The venom also eaused a marked increase in eapillary permeability. Ultracentrifuge measurements suggest that tbe toxie material has a molecular weigbt of tbe order of 150,000.

- by lloyd austin
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- Pharmacology, Immunology, Toxicology, Chromatography

Toxinology in Brazil developed specially during the 19th and 20th centuries. A very brief description of the main contributions made by pioneer toxinologists is presented here in an attempt to give an idea of the evolution of toxinology in our country, from its first steps until the XVI World Congress of the International Society on Toxinology, held in Recife, Brazil

- by Célia Carlini
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- Toxicology, Brazil, Biodiversity, Scientific Societies

Voltage-gated sodium, calcium, and potassium channels generate electrical signals required for action potential generation and conduction and are the molecular targets for a broad range of potent neurotoxins. These channels are built on a common structural motif containing six transmembrane segments and a pore loop. Their pores are formed by the S5/S6 segments and the pore loop between them and are gated by bending of the S6 segments at a hinge glycine or proline residue. The voltage sensor domain consists of the S1 to S4 segments, with positively charged residues in the S4 segment serving as gating charges. The diversity of toxin action on these channels is illustrated by sodium channels, which are the molecular targets for toxins that act at five or more distinct receptor sites on the channel protein. Both hydrophilic low molecular weight toxins and larger polypeptide toxins physically block the pore and prevent sodium conductance. Hydrophobic alkaloid toxins and related lipid-soluble toxins act at intramembrane sites and alter voltage-dependent gating of sodium channels via an allosteric mechanism. In contrast, polypeptide toxins alter channel gating by voltage-sensor trapping through binding to extracellular receptor sites, and this toxin interaction has now been modeled at the atomic level for a -scorpion toxin. The voltage sensor trapping mechanism may be a common mode of action for polypeptide gating modifier β toxins acting on all of the voltage gated ion channels.

- by Keiichi Konoki
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- Ion Channels, Toxicity, Bacteria, Potassium

Bufalin is the major component of Chan-Su (a traditional Chinese medicine, TCM) extracts from the venom of Bufo bufo gargarizan. In the present study, we investigated the pharmacological mechanisms of cell cycle arrest and autophagic cell death induced by bufalin in SK-HEP-1 human hepatocellular carcinoma cells in vitro. Bufalin inhibited cell survival by MTT assay and increased cell death by trypan blue exclusion assay in a concentration-dependent manner. In addition, bufalin induced G2/M phase arrest by reducing CDK1 activity. Bufalin triggered DNA fragmentation and apoptotic cell death in SK-HEP-1 cells by DNA gel electrophoresis, TUNEL and caspase-3 activity assay, while bufalin induced autophagic cell death by double-membrane vacuoles (transmission electron microscopy, TEM), acidic vesicular organelles (acridine orange staining) and cleavage of microtubule-associated protein 1 light chain 3 (LC3). Protein expression levels of cyclin A and B, CDK1, phospho-CDK1 (Thr161), Cdc25c,...

- by Shih-Chang Tsai
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- Oncology, Molecular Medicine, Cancer, Cell Cycle

Acid-sensing ion channels (ASICs) are voltage-independent proton-gated cation channels that are largely expressed in the nervous system as well as in some non-neuronal tissues. In rodents, six different isoforms (ASIC1a, 1b, 2a, 2b, 3 and 4) can associate into homo-or hetero-trimers to form a functional channel. Specific polypeptide toxins targeting ASIC channels have been isolated from the venoms of spider (PcTx1), sea anemone (APETx2) and snakes (MitTx and mambalgins). They exhibit different and sometimes partially overlapping pharmacological profiles and are usually blockers of ASIC channels, except for MitTx, which is a potent activator. This review focuses on the use of these toxins to explore the structure-function relationships, the physiological and the pathophysiological roles of ASIC channels, illustrating at the same time the therapeutic potential of some of these natural compounds.

- by Emmanuel Deval and +2
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- Rodentia, Spiders, Snakes, Peptides

Nach Behandlung des Sartoriusmuskels von Rana temporaria mit Bu TX wurden die Endplattenpotentiale durch Tubocurarin und Atropin mit unveränderter Wirksamkeit blockiert. Bungarotoxin stabilisiert das Umkehrpotential der Endplatte, welches nachher durch eine Verminderung der äusseren Konzentration von K+ oder durch Atropin nicht mehr verändert werden kann.

- by Rana Bus
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- Physiology, Temperature, Anura, Snakes

Animal venoms and toxins are now recognized as major sources of bioactive molecules that may be tomorrow's new drug leads. Their complexity and their potential as drug sources have been demonstrated by application of modern analytical technologies, which have revealed venoms to be vast peptide combinatorial libraries. Structural as well as pharmacological diversity is immense, and mass spectrometry is now one of the major investigative tools for the structural investigation of venom components. Recent advances in its use in the study of venom and toxins are reviewed. The application of mass spectrometry techniques to peptide toxin sequence determination by de novo sequencing is discussed in detail, in the light of the search for novel analgesic drugs. We also present the combined application of LC-MALDI separation with mass fingerprinting and ISD fragmentation for the determination of structural and pharmacological classes of peptides in complex spider venoms. This approach now serves as the basis for the full investigation of complex spider venom proteomes, in combination with cDNA analysis.

- by L. Quinton
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- Pain, Mass Spectrometry, Proteomics, Structural Analysis

Serum therapy remains the only specific treatment against envenoming, but anti-venoms are still prepared by fragmentation of polyclonal antibodies isolated from hyper-immunized horse serum. Most of these anti-venoms are considered to be efficient, but their production is tedious, and their use may be associated with adverse effects. Recombinant antibodies and smaller functional units are now emerging as credible alternatives and constitute a source of still unexploited biomolecules capable of neutralizing venoms. This review will be a walk through the technologies that have recently been applied leading to novel antibody formats with better properties in terms of homogeneity, specific activity and possible safety. OPEN ACCESS Toxins 2014, 6 2542

- by Philippe Billiald
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- Monoclonal Antibodies, Toxins, Bites and Stings, Venoms
- by Valery Lipkin
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- Snakes, Amino Acids, Parasympatholytics, Amino Acid Sequence
- by Nicolas Vidal and +1
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- Herpetology, Phylogenetics, Molecular Evolution, Australia

Background: The spider family Sicariidae includes two genera, Sicarius and Loxosceles. Bites by Sicarius are uncommon in humans and, in Brazil, a single report is known of a 17-year old man bitten by a Sicarius species that developed a necrotic lesion similar to that caused by Loxosceles. Envenomation by Loxosceles spiders can result in dermonecrosis and severe ulceration. Sicarius and Loxosceles spider venoms share a common characteristic, i.e., the presence of Sphingomyelinases D (SMase D). We have previously shown that Loxosceles SMase D is the enzyme responsible for the main pathological effects of the venom. Recently, it was demonstrated that Sicarius species from Africa, like Loxosceles spiders from the Americas, present high venom SMase D activity. However, despite the presence of SMase D like proteins in venoms of several New World Sicarius species, they had reduced or no detectable SMase D activity. In order to contribute to a better understanding about the toxicity of New World Sicarius venoms, the aim of this study was to characterize the toxic properties of male and female venoms from the Brazilian Sicarius ornatus spider and compare these with venoms from Loxosceles species of medical importance in Brazil.

Currently, 382 million people have been reported to have diabetes in the world, and 90% of them has type 2 diabetes mellitus (T2DM). Increase in obesity rates has been correlated with an increase in the prevalence of diabetes. Diabetes is now considered to be the world's biggest pandemic disease with a prevalence of 8%. Five million people have died in 2013 because of the secondary complications of diabetes including coronary heart disease and peripheral vascular diseases. Furthermore, diabetes has been reported to be the most important cause of blindness and renal failure in developed countries. Although diabetes is primarily managed by lifestyle changes and dietary modifications, administration of a pharmacological agent is required especially when treatment goals are not achieved. İntroduction 3 These conventional treatment agents include but not limited to biguanides, sulfonylureas, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors and insulin along with a recently developed amylin analogue pramlintide. Current guidelines recommend biguanide metformin as a first-line treatment, with subsequent addition of other agents when this monotherapy is no longer effective. Despite intensive therapy, glycaemic control can still be lost, leading to an increase in HbA1c levels of diabetic patients. Moreover, current therapies are often associated with weight gain and hypoglycaemia. Other adverse events include but not limited to gastrointestinal discomfort with the use of biguanides, and possible oedema, cardiac failure or fractures due to the use of thiazolidinediones.

- by Salih Sanlioglu
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- Medicine, Insulin, Peptides, Clinical Sciences

We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.

- by William Riboulet and +4
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- Treatment Outcome, Adolescent, Rodentia, Biological Sciences
- by Jaime Davidson
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- Obesity, Treatment Outcome, Hypoglycemia, Peptides
- by Richard Bergenstal
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- Diabetes, Treatment Outcome, Risk assessment, Peptides

Human envenomations by Heloderma species are a rare but clinically important medical problem. We report a case of an adult male bitten on the left hand by a 50-cm male, captive specimen of Heloderma suspectum (Gila monster). Immediate signs and symptoms included pain at the bite site radiating into the arm and axilla and swelling of the hand and forearm. Systemic complaints of nausea, diaphoresis, and dizziness (without a decrease in blood pressure) lasted approximately 1 hour, and laboratory studies were normal. The patient's course was uneventful except for persistent hyperesthesia, which eventually abated. Two types of helodermatid bites produce distinct clinical pictures. The chewing bite potentially causes more envenomation than the slashing bite. The venom contains a number of protein and nonprotein components including serotonin, a bradykinin-releasing substance, protease, hyaluronidase, helodermin, and gilatoxin. The clinical presentation of a helodermatid bite can inclu...

- by David Bahner
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- Lizards, Differential Diagnosis, Hand, Bites and Stings

Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy. Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are effective weight loss surgeries that also improve glucose metabolism. Rapid, early rises of circulating insulin and glucagon-like peptide-1 (GLP-1) concentrations following food ingestion are characteristic of these procedures. The purpose of the current study was to test the hypothesis that postprandial hormone release is due to increased nutrient emptying from the stomach. Radioscintigraphy and chemical and radiolabeled tracers were used to examine gastric emptying in rat models of VSG and RYGB surgery. Intraduodenal nutrient infusions were used to assess intestinal GLP-1 secretion and nutrient sensitivity in VSG rats compared with shams. Five minutes after a nutrient gavage, the stomachs of RYGB and VSG rats were completely emptied, whereas only 6.1% of the nutrient mixture had emptied from sham animals. Gastric pressure was increased in VSG animals, and rats with this procedure did not inhibit gastric emptying normally in response to increasing caloric loads of dextrose or corn oil, and they did not respond to neural or endocrine effectors of gastric motility. Finally, direct infusion of liquid nutrients into the duodenum caused significantly greater GLP-1 release in VSG compared with shams, indicating that increases in GLP-1 secretion after VSG are the result of both greater gastric emptying rates and altered responses at the level of the intestine. These findings demonstrate greatly accelerated gastric emptying in rat models of RYGB and VSG. In VSG this is likely due to increased gastric pressure and reduced responses to inhibitory feedback from the intestine. glucagon-like peptide-1

- by Todd Greer
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- Biological Sciences, Peptides, Rats, Oral Hypoglycemic Agents

and sharing with colleagues.

Several kinases have been implicated in the metabolic response of human and rat myocytes to glucagon-like peptide-1 (GLP-1), exendin-4 (Ex-4) and exendin-9 (Ex-9). We have investigated, in isolated rat adipocytes, the changes caused by GLP-1, Ex-4 and Ex-9 compared with those provoked by insulin or glucagon, upon the activity of phosphatidylinositol-3-kinase (PI3K), protein kinase B (PKB), p42/44 MAP kinases (MAPKs) and p70s6 kinase (p70s6k), and the participation of these kinases and protein kinase C (PKC) in their action upon 2-deoxy-D-glucose uptake, lipolysis and lipogenesis. The study was conducted in normal rats, and extended to a streptozotocin-induced type-2 diabetic model (STZ-rats). The participation of distinct kinases was estimated by using potential kinase inhibitors, including wortmannin, PD98059, rapamycin, H-7 and RO31-8220. In normal rat adipocytes, GLP-1 and both exendins share with insulin an increasing action upon the activity of all kinases studied (except PKB), PI3K, p44 and p42 MAPKs and possibly PKC, all being required for their stimulating effect upon glucose uptake. Ex-4 and Ex-9, like GLP-1 and insulin, have lipogenic action, while only Ex-4 shares with GLP-1 its lipolytic effect which is antagonized by Ex-9. MAP kinases and PKC seem to have an essential role in the GLP-1 and Ex-4 lipolytic action, as does PI3K in that of Ex-4. An increase in PI3K and MAPKs activity for the lipogenic effect of Ex-4, Ex-9 and GLP-1 are required, and in the case of Ex-4 and Ex-9, a stimulation of p70s6k activity is also needed. In cells from STZ-rats the magnitude of the above parameters was, in general, comparable to that in normal animals, with some exceptions: basal PI3K activity and lipogenesis were higher, GLP-1, Ex-4 and Ex-9 failed to modify basal lipogenesis but increased PKB activity, insulin failed to affect the activity of MAPKs and the insulin-induced glucose uptake was impaired. The impaired insulin effects upon some of the variables in the STZ-rat, distinct from those of GLP-1 and exendins, adds knowledge to the mechanism of the beneficial action of GLP-1 and Ex-4 in diabetic states. V SANCHO and others · Effects of GLP-1 and exendins on adipocytes of normal and diabetic rats

- by Nieves Gonzalez
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- Molecular endocrinology, Molecular, Lipids, Protein Kinases

Strong overexpression of glucagonlike peptide-1 (GLP-1) receptors in human insulinoma provides an attractive target for imaging. The first clinical trials demonstrated that GLP-1 receptor SPECT/CT using [Lys 40 (Ahx [6-aminohexanoic acid]-DOTA-111 In)NH 2 ]-exendin-4 can localize hardly detectable insulinomas. However, In)NH 2 ]-exendin-4 imaging has drawbacks related to the use of 111 In in that it is costly and carries a relatively high radiation burden for the patient. The aim of this study was the preclinical evaluation of [Lys 40 (Ahx-DOTA-68 Ga)NH 2 ]-exendin-4 for PET/CT and [Lys 40 (Ahx-hydrazinonicotinamide [HYNIC]-99m Tc)NH 2 ]-exendin-4 for SPECT/CT. Methods: Internalization, biodistribution, dosimetry, and imaging studies were performed in the Rip1Tag2 mouse model of pancreatic b-cell carcinogenesis and compared with our gold standard [Lys 40 (Ahx-DOTA-111 In)NH 2 ]-exendin-4. Poly-glutamic acid and Gelofusine, a gelatin-based plasma expander, were used for renal uptake reduction studies. Results: The tumor uptake of [Lys 40 (Ahx-DOTA-68 Ga)NH 2 ]-exendin-4 was 205 6 59 percentage injected activity per gram of tissue at 4 h. Other GLP-1 receptor-positive organs showed more than 4.8 times lower radioactivity uptake. [Lys 40 (Ahx-HYNIC-99m Tc/ethylenediaminediacetic acid [EDDA])NH 2 ]-exendin-4, compared with its 111 In-and 68 Galabeled sister compounds, showed significantly less tumor and organ uptake. The significantly lower tumor and organ uptake of [Lys 40 (Ahx-HYNIC-99m Tc/EDDA)NH 2 ]-exendin-4 did not result in inferior tumor-to-organ ratios or reduced image quality. All radiopeptides tested showed a high tumor-to-background ratio, resulting in the visualization of small tumors (maximum diameter between 1.0 and 3.2 mm) by SPECT and PET. The only exception was the kidneys, which also showed high uptake. This uptake could be reduced by 49%278% using poly-glutamic acid, Gelofusine, or a combination of the 2. The estimated effective radiation dose was 3.7 mSv/MBq for [Lys 40 (Ahx-HYNIC-99m Tc/ EDDA)NH 2 ]-exendin-4, which was 8 times less than that for [Lys 40 (Ahx-DOTA-68 Ga)NH 2 ]-exendin-4 and 43 times less than that for [Lys 40 (Ahx-DOTA-111 In)NH 2 ]-exendin-4. Conclusion: These promising pharmacokinetic and imaging data show that [Lys 40 (Ahx-DOTA-68 Ga)NH 2 ]-exendin-4 and [Lys 40 (Ahx-HYNIC-99m Tc/EDDA)NH 2 ]-exendin-4 are suitable candidates for clinical GLP-1 receptor imaging studies.

- by Damian Wild and +1
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- Nuclear medicine, Positron Emission Tomography, Kidney, Mice

The Glucagon-like peptide 1 receptor (GLP-1R) has become an important target for imaging due to its elevated expression profile in pancreatic islets, insulinoma, and the cardiovascular system. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), several studies have conjugated different chelators to a more stable analog of GLP-1 (such as exendin-4) as PET or SPECT imaging agents with various advantages and disadvantages. Based on the recently developed Sarcophagin chelator, here, we describe the construction of GLP-1R targeted PET probes containing monomeric and dimeric exendin-4 subunit. The in vitro binding affinity of Bar-MalSar-exendin-4 and Mal 2 Sar-(exendin-4) 2 was evaluated in INS-1 cells, which over-express GLP-1R. Mal 2 Sar-(exendin-4) 2 demonstrated around 3 times higher binding affinity compared with BaMalSar-exendin-4. After 64 Cu labeling, microPET imaging of 64 Cu-BaMalSar-exendin-4 and 64 Cu-Mal 2 Sar-(exendin-4) 2 were performed on subcutaneous INS-1 tumors, which were clearly visualized with both probes. The tumor uptake of 64 Cu-Mal 2 Sar-(exendin-4) 2 was significantly higher than that of 64 Cu-BaMaSarl-exendin-4, which could be caused by polyvalency effect. The receptor specificity of these probes was confirmed by effective blocking of the uptake in both tumor and normal positive organs with 20-fold excess of unlabeled exendin-4. In conclusion, sarcophagine cage conjugated exendin-4 demonstrated persistent and specific uptake in INS-1 insulinoma model. Dimerization of exendin-4 could successfully lead to increased tumor uptake in vivo. Both 64 Cu-BaMalSar-exendin-4 and 64 Cu-Mal 2 Sar-(exendin-4) 2 hold a great potential for GLP-1R targeted imaging.

- by Ivan Todorov
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- Positron Emission Tomography, Western blotting, Peptides, Theranostics

We have developed a unique long-acting drug-delivery system for the GLP-1 agonist exenatide. The peptide was covalently attached to Tetra-PEG hydrogel microspheres by a cleavable β-eliminative linker; upon s.c. injection, the exenatide is slowly released at a rate dictated by the linker. A second β-eliminative linker with a slower cleavage rate was incorporated in polymer crosslinks to trigger gel degradation after drug release. The uniform 40 micron microspheres were fabricated using a flow-focusing microfluidic device and in situ polymerization within droplets. The exenatide-laden microspheres were injected subcutaneously into the rat, and serum exenatide measured over a one-month period. Pharmacokinetic analysis showed a t1/2,β of released exenatide of about seven days which represents over a 300-fold half-life extension in the rat and exceeds the half-life of any currently approved long-acting GLP-1 agonist. Hydrogel-exenatide conjugates gave an excellent Level A in vitro-in viv...

- by Jeff Henise
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- Chemistry, Organic Chemistry, Drug delivery, Hydrogels
- by P.Gopalakrishnakone PON
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- Documentation, Singapore, World Wide Web, Computer communication networks

The duck-billed platypus, Ornithorhynchus anatinus, is one of the few venomous Australian mammals. 1 Envenoming by a male platypus causes immediate excruciating pain in humans, which evolves toward a long-lasting hyperalgesia. Several constituents of the venom fluid or its crural gland have been identified, including defensin-like peptides, 2 C-type natriuretic peptides (OvCNPs), 3 NGF, and hyaluronidase. OvCNP causes the relaxation of rat uterine smooth muscle, promotes histamine release from mast cells, and forms fast cation channels in lipid bilayers. Recently, an L-to-Dpeptide isomerase was identified by which D-Leu 2 in OvCNPs and D-Met JA908148Z Figure 3. Effects of 1 on Ca 2+ uptake in IMR-32 cells: (left) Increase in the f 340/f380 ratio monitored as the [Ca 2+ ]i uptake rate. The arrow indicates the time of sample injection. (right) Inhibitory effects of EGTA. Values are the mean ( standard deviation of duplicate experiments.

- by Masaki Kita
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- Calcium, Sequence alignment, Peptides, The

The Sperm-coating protein/Tpx-1/Ag5/PR-1/Sc7 (SCP/TAPS) domain is found across phyla and is a major structural feature of insect allergens, mammalian sperm proteins and parasitic nematode secreted molecules. Proteins containing this domain are implicated in diverse biological activities and may be important for chronic host/parasite interactions.

- by Ralf Schmid
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- Molecular Evolution, Biological Sciences, Phylogeny, Statistical Significance

Injuries caused by venomous animals reported by the agricultural workers from the municipality of Cuité, Curimataú region of Paraiba State, Northeast of Brazil, and the practices of folk medicine which they use to treat these cases were studied in this work from June to August 2010. The farmers studied aged from 11 to 90 years. The number of people who reported cases of injury by these animals in their families was high (89.3%). Scorpions, wasps, bees and snakes were the most cited and the extremities of the body (hands, feet, legs and head) were the most affected. The practice of folk medicine to treat these injuries includes various procedures ranging from ritualistic treatments, use of animals or parts of them, and some herbal preparations. The folk treatment was reported as effective by most of the workers injured (63.9%). Body parts of dead snakes are used in various zootherapic treatments. In the imaginary of the agricultural workers the venomous animals are considered hazardous (48.7%) or disgusting (11.3%), and several parts of such animals as the rattle, bee sting or snake leather are used as amulet. Several legends have also been reported about snakes, scorpions and bees. The need for educational activities that aim to clarify these workers about the dangers of such practices is urgent. 634 Injuries caused by venomous animals and folk medicine in farmers from Cuité, State of Paraiba, Northeast of Brazil Oliveira, H.F.A. et al. Rev Bras Epidemiol 2013; 16(3): 633-43 Injuries caused by venomous animals and folk medicine in farmers from Cuité, State of Paraiba, Northeast of Brazil Oliveira, H.F.A. et al. Rev Bras Epidemiol 2013; 16(3): 633-43 Oliveira, H.F.A. et al. Rev Bras Epidemiol 2013; 16(3): 633-43 Oliveira, H.F.A. et al. Rev Bras Epidemiol 2013; 16(3): 633-43

- by roberto sassi
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- Traditional Medicine, Brazil, Adolescent, Child

T ype 2 diabetes mellitus results from insulin resistance and defective endogenous insulin secretion. 1 The United Kingdom Prospective Diabetes Study demonstrated a progressive 4% annual decline in pancreatic β-cell function and subsequent deterioration of glycemic control in individuals with type 2 diabetes mellitus. 2 Due to the progressive nature of type 2 diabetes, escalation of treatment over time is inevitable. Achievement and maintenance of glycemic targets reduce the risk of long-term complications. 2 For this purpose, a treat-to-target approach, with ongoing evaluation of glucose levels and timely transition to appropriate regimens, is recommended in patients with diabetes. The development of multiple innovative classes of glucose-lowering medications during the past decade has broadened treatment options, but also created a therapeutic dilemma for healthcare providers in choosing the optimal agents at different stages of disease progression. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) issued an evidence-based consensus algorithm to guide the selection of various interventions. 3 Clearly, the addition of basal insulin remains the most effective regimen for lowering hyperglycemia. However, concerns regarding hypoglycemia and weight gain with insulin therapy represent significant barriers to both providers and patients.

- by Linda Jaber and +1
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- Peptides, Oral Hypoglycemic Agents, Combination drug therapy, Venoms

Exenatide is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). Exenatide lowers blood glucose through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying. The current formulation of exenatide requires twice-daily dosing (exenatide BID), and an extended-release formulation of exenatide is now in development for use as a once-weekly injection (exenatide QW). The purpose of this report is to review the most current clinical data on the development of exenatide QW for the treatment of T2DM. In clinical trials, exenatide QW significantly improved glycemic control, resulted in patient weight loss, and was well tolerated in patients with T2DM. In a head-to-head clinical trial, exenatide QW caused greater improvements in glycemic control and was better tolerated than exenatide BID. Given the rapidly increasing prevalence of diabetes and obesity worldwide, exenatide QW is a promising development candidate for the treatment of T2DM.

- by James Malone
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- Treatment Outcome, Peptides, Venoms, Type 2 Diabetes Mellitus

Introduction Glucagon-like peptide-1 (GLP-1) is produced and secreted from L-cells, an open-type intestinal epithelial endocrine cell, following the entry of nutrients in the gut lumen. GLP-1 is a member of the incretin family and as such, upon its binding to the GLP-1 receptor expressed at the surface of pancreatic cells, potentiates glucosedependent insulin secretion from pancreatic islet 1 . Several studies have demonstrated that GLP-1 secretion and action are reduced in T2DM and Vilsbøll et al. demonstrated that infusion of GLP-1 at supraphysiological doses in T2DM patients restored insulin levels comparable to non-diabetic controls. 2-4 However, the rapid inactivation of native GLP-1 by the dipeptidyl Significant findings of the study: Treatment with GLP-1Ra was not associated with any modifications in the occurrence of bone fractures in type 2 diabetes mellitus.

- by Guillaume Mabilleau
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- Diabetes, Treatment Outcome, Peptides, Oral Hypoglycemic Agents

The complete amino acid sequence of a small, basic protein with cardiotoxic activity is described. This toxin, designated Naja naja F8, was isolated from the venom of Naja naja, of Cambodian origin, by gel filtration on Sephadex G-75 followed by gradient ion exchange chromatography on Bio-Rex 70. The cardiotoxin F8, molecular weight 6727 from amino acid composition, consists of 60 amino acids in a single peptide chain cross-linked by four disulfide bridges and is devoid of histidine, tryptophan, and glutamic acid. The chymotryptic and tryptic peptides from c o b r a venoms contain many small basic proteins representing several different pharmacological activities (Lee, 197 I ) and immunological classes . The Naja naja cardiotoxin F8 described below is serologically related to the Naja nigricollis toxin y and is distinct from all the curariform neurotoxins tested . Cardiotoxin F8 is similar in sequence to the cardiotoxin from Naja naja atra venom (Narita and Lee, 1970), Naja nigricollis toxin y (Fryklund and Eaker, 1975), the Naja naja cytotoxins I ) and I I , the lytic protein 12B from Haemachatus haemachates venom . the two cytotoxins from Naje naje annulifera (Weise et al., 1973). the major cytotoxin from Naja melanoleuca (Carlsson and Joubert, 1974), and Naja mossamhica mossamhica .

- by Linda Fryklund
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- Biochemistry, Snake venoms, Methods, Heart

Herein, we report evidence of an envenomation apparatus (EA) in two different species of extinct "giant" shrews, Beremendia and an indeterminate soricine (Mammalia, Eulipotyphla, Soricidae), documented by very well preserved fossil specimens recovered from two Early Pleistocene cave deposits of the Sierra de Atapuerca in Burgos, Spain. The two soricine taxa from Atapuerca have evolved specialized teeth as EAs, which differ from those of recently reported mammals of the Paleocene age, being more similar to the ones described in the modern Solenodon. This discovery reveals the first instance of shrews possessing what appears to be an EA, an evolutionary adaptation that, in these species, was probably related to an increase in body mass and hunting of a larger-sized prey. The Atapuerca specimens would have a highly specialized EA, one of the very few reported for an extinct or living mammal of any time. In addition to the presence of a gutterlike groove along the medial side of the crown of the lower incisors, these two species also present stout jaws and a modified mandibular symphysis with a conspicuous cavity, which in life would likely contain large amounts of connective tissue. The strong mandible architecture of these large shrews would be, in this way, reinforced by a more immovable symphysis, increasing the bite force exerted over a potential prey. This adaptation, together with the grooved incisors, would ensure a rapid and efficient transmission of the poisonous saliva to paralyze relatively large-sized prey.

- by Gloria Cuenca-Bescós
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- Multidisciplinary, Bite force, Shrews, Connective tissue
- by Masaki Kita
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- Multidisciplinary, Shrews, P-glycoprotein, Amino Acid Sequence

Therapeutic approaches based on the actions of the incretin hormone GLP-1 have been widely established in the management of T2DM. Nevertheless, much less research has been aimed at elucidating the role of GLP-1 in lipid metabolism and in particular postprandial dyslipidemia. Exenatide and liraglutide are two GLP-1 receptor agonists which are currently available as subcutaneously administered treatment for T2DM but their chronic effects on postprandial lipaemia have not been well investigated. The aim of this study is to examine the effect of treatment with either liraglutide or exenatide for two weeks on postprandial lipaemia in obese subjects with T2DM. This study was a single-center, two-armed, randomized, controlled 2-week prospective intervention trial in 20 subjects with T2DM. Patients were randomized to receive either liraglutide or exenatide treatment and underwent a standardized meal tolerance test early in the morning after 10 h fast at baseline (visit 1, beginning of treatment) and after a two-week treatment period (visit 2). Exenatide and liraglutide both appear to be equally effective in lowering postprandial lipaemia after the first administration and after a two-week treatment. The mechanisms which lead to this phenomenon, which seem to be independent of gastric emptying, are yet to be studied.

- by Nicholas Tentolouris
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- Diabetes, Treatment Outcome, Prospective studies, Peptides

- by Humberto González
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- Snakes, Rats, Lethal Dose, Venoms

Classified into 16 superfamilies, conopeptides are the main component of cone snail venoms that attract growing interest in pharmacology and drug discovery. The conventional approach to assigning a conopeptide to a superfamily is based on a consensus signal peptide of the precursor sequence. While this information is available at the genomic or transcriptomic levels, it is not present in amino acid sequences of mature bioactives generated by proteomic studies. As the number of conopeptide sequences is increasing exponentially with the improvement in sequencing techniques, there is a growing need for automating superfamily elucidation. To face this challenge we have defined distinct models of the signal sequence, propeptide region and mature peptides for each of the superfamilies containing more than 5 members (14 out of 16). These models rely on two robust techniques namely, Position-Specific Scoring Matrices (PSSM, also named generalized profiles) and hidden Markov models (HMM). A total of 50 PSSMs and 47 HMM profiles were generated. We confirm that propeptide and mature regions can be used to efficiently classify conopeptides lacking a signal sequence. Furthermore, the combination of all three-region models demonstrated improvement in the classification rates and results emphasise how PSSM and HMM approaches complement each other for superfamily determination. The 97 models were validated and offer a straightforward method applicable to large sequence datasets.

- by Silja Laht and +2
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- Computational Biology, Biological Sciences, Markov chains, Physical sciences

- by Brian Finan
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- Treatment Outcome, Adolescent, Rodentia, Biological Sciences
- by Bronwen Martin
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- Genetics, Research Design, Diabetes, Immunohistochemistry
- by Lourival Possani
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- Brazil, Mice, SCORPIONS, Amino Acids

Glucagon like peptide-1 receptor (GLP-1R) Positron emission tomography (PET) Introduction: Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [ 68 Ga]Ga-DO3A-VS-Cys 40 -Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma. Methods: [ 68 Ga]Ga-DO3A-VS-Cys 40 -Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficient mice at two different doses of peptide: 2.5 μg/kg (baseline) and 100 μg/kg (block). In vivo imaging of [ 68 Ga]Ga-DO3A-VS-Cys 40 -Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [ 11 C]5-hydroxy-tryptophan ([ 11 C]5-HTP). Results: GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [ 68 Ga]Ga-DO3A-VS-Cys 40 -Exendin-4 showed significant uptake (p ≤ 0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [ 11 C]5-HTP. Conclusion: [ 68 Ga]Ga-DO3A-VS-Cys 40 -Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo.

- by Irina Velikyan
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- Radiochemistry, Positron Emission Tomography, Mice, Peptides
- by Janet McGill
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- Treatment Outcome, Clinical Practice, Insulin, Peptides

Glucagon-like peptide-1 (GLP-1) has shown to influence the oxidative stress status in a number of in vitro, in vivo and clinical studies. Well-known effects of GLP-1 including better glycemic control, decreased food intake, increased insulin release and increased insulin sensitivity may indirectly contribute to this phenomenon, but glucose-independent effects on ROS level, production and antioxidant capacity have been suggested to also play a role. The potential 'antioxidant' activity of GLP-1 along with other proposed glucose-independent modes of action related to ameliorating redox imbalance remains a controversial topic but could hold a therapeutic potential against micro- and macrovascular diabetic complications. This review discusses the presently available knowledge from experimental and clinical studies on the effects of GLP-1 on oxidative stress in diabetes and diabetes-related complications.

- by Kirsten Raun
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- Evidence Based Practice, Oxidative Stress, Reactive Oxygen Species, Peptides

Aims Exenatide is an incretin mimetic whose effect on glycaemic control in patients with Type 2 diabetes is currently under investigation. This study assessed the effect of injection time relative to a standardized meal on postprandial... more

- by Michael Trautmann
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- Type 2 Diabetes, Blood Glucose, Insulin, Peptides

The surgical removal of insulinomas is hampered by difficulties to localize it using conventional radiological procedures. Recently these tumors were shown to exhibit a very high density of glucagon-like peptide-1 receptors (GLP-1R) in... more

- by Martyn Caplin
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- Endocrinology, Nutrition, Magnetic Resonance Imaging, Localization
- by Karen Moreno
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- Evolutionary Biology, Zoology, Paleontology, Arsenic

Introduction: Obesity is a major worldwide health threat in Western World because of its high incidence and prevalence and its association with metabolic and cardiovascular disease as well as cancer. The reduction of food intake in obese patients can be achieved only transiently (generally for no longer than 6 months), in the absence of concomitant pharmacological therapy. Only bariatric surgery provides a mean to increase satiety and/ or decrease nutrients absorption in obese patients, in the long term.

- by franco folli
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- Bariatric Surgery, Obesity, Peptides, Eating

The aim of this study was to evaluate the effect of exenatide compared to glimepiride on body weight, glycemic control and insulin resistance in type 2 diabetic patients taking metformin. One hundred and eleven patients with uncontrolled type 2 diabetes mellitus and intolerant to metformin at the highest dosages (2500-3000 mg/day) were enrolled in this study. Patients were randomized to receive exenatide 5 μg twice a day or glimepiride 1 mg three times a day and titrated after 1 month to exenatide 10 μg twice a day or glimepiride 2 mg three times a day for 12 months in a randomized, single-blind, controlled study. We evaluated at the baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), HbA 1c , glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR) index, adiponectin, tumor necrosis factor-α, and high sensitivity-C reactive protein. Both treatments gave a similar improvement of glycemic control, without any differences between the two groups. Only exenatide gave a decrease of BMI, insulin resistance parameters such as fasting plasma insulin, HOMA-IR, and adiponectin and a decrease of inflammatory parameters such as tumor necrosis factor-α, and high sensitivity-C reactive protein. Furthermore, the values obtained with exenatide were significantly better than the values recorded with glimepiride. We can conclude that exenatide was better than glimepiride in improving insulin resistance and inflammatory state. Furthermore, adiponectin increase, and tumor necrosis factor-α reduction seem to be related to weight loss obtained with exenatide.

- by Aldo Bonaventura
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- Inflammation, Preventive medicine, Insulin Resistance, Metformin