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Biological Neurotoxin

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1. A novel role of C-terminus in introducing a functionally flexible structure critical for the biological activity of botulinum neurotoxin (PubMed)

A novel role of C-terminus in introducing a functionally flexible structure critical for the biological activity of botulinum neurotoxin Botulinum neurotoxin (BoNT) is responsible for botulism, a clinical condition resulting in flaccid muscle paralysis and potentially death. The light chain is responsible for its intracellular toxicity through its endopeptidase activity. Available crystal structures of BoNT/A light chains (LCA) are based on various truncated versions (tLCA) of the full-length (...) . This seems to be achieved by a much stronger, more rapid binding to substrate (SNAP-25) of the fLCA compared to tLCA. These results suggest that the C-terminus of LCA plays a critical role in introducing a flexible structure, which is essential for its biological function. This is the first report of such a massive structural role of the C-terminus of a protein being critical for maintaining a functional state.

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2018 Scientific reports

2. Biological Neurotoxin

Biological Neurotoxin Biological Neurotoxin Toggle navigation Brain Head & Neck Chest Endocrine Abdomen Musculoskeletal Skin Infectious Disease Hematology & Oncology Cohorts Diagnostics Emergency Findings Procedures Prevention & Management Pharmacy Resuscitation Trauma Emergency Procedures Ultrasound Cardiovascular Emergencies Lung Emergencies Infectious Disease Pediatrics Neurologic Emergencies Skin Exposure Miscellaneous Abuse Cancer Administration 4 Biological Neurotoxin Biological (...) Neurotoxin Aka: Biological Neurotoxin , Neurotoxin From Related Chapters II. Causes: Animal Toxins See Also Sting Ciquatera Toxin ( ) Paralytic Shellfish (Saxitoxin) in Clams and Mussels Acute paralysis 30 to 120 minutes after ingestion Toxin similar to Tetradotoxin Caused by Gonyaulax species III. Causes: Plant Toxins Mushrooms See Amanita muscaria and pantherina ( ) Inocybe and Clitocybe species (parasympathetic) Coprinus atramentarius ( -like effect) Psilcybe ( ) Gyromitra esculenta or false morel

2018 FP Notebook

3. Augmentation of VAMP-catalytic activity of botulinum neurotoxin serotype B does not result in increased potency in physiological systems. (PubMed)

Augmentation of VAMP-catalytic activity of botulinum neurotoxin serotype B does not result in increased potency in physiological systems. Botulinum neurotoxins (BoNTs) are used extensively as therapeutic agents. Serotypes A and B are available as marketed products. Higher doses of BoNT/B are required to reach an efficacy similar to that of products containing BoNT/A. Advances in our understanding of BoNT/B mechanism of action have afforded the opportunity to make rational modifications (...) biological systems. In the cell-free assay, which measured light-chain activity alone, rBoNT/B1(S201P) cleaved VAMP-2 and VAMP-1 substrate with an activity 3-4-fold higher than rBoNT/B1. However, despite the enhanced catalytic activity of rBoNT/B1(S201P), there was no significant difference in potency between the two molecules in any of the in vitro cell-based assays, using either rodent spinal cord neurons or cortical neurons. Similarly in ex vivo tissue preparations rBoNT/B1(S201P

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2017 PLoS ONE

4. The Effect of Neurotoxin MPTP and Neuroprotector Isatin on the Profile of Ubiquitinated Brain Mitochondrial Proteins (PubMed)

The Effect of Neurotoxin MPTP and Neuroprotector Isatin on the Profile of Ubiquitinated Brain Mitochondrial Proteins Mitochondria are a crucial target for the actions of neurotoxins, causing symptoms of Parkinson's disease in various experimental animal models, and also neuroprotectors. There is evidence that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible (...) for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria) and neuroprotective effects of certain anti-Parkisonian agents (monoamine oxidase inhibitors) may be associated with their effects on the UPS. In this study, we have investigated the effect of the neurotoxin MPTP and neuroprotector isatin, and their combination on the profile of ubiquitinated brain mitochondrial proteins. The development of movement disorders induced by MPTP administration

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2018 Cells

5. The Expanding Therapeutic Utility of Botulinum Neurotoxins (PubMed)

The Expanding Therapeutic Utility of Botulinum Neurotoxins Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent (...) years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation

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2018 Toxins

6. Botulinum neurotoxin formulations: overcoming the confusion (PubMed)

Botulinum neurotoxin formulations: overcoming the confusion Botulinum toxin A is produced by anaerobic spore-forming bacteria and is used for various therapeutic and cosmetic purposes. Botulinum toxin A injections are the most popular nonsurgical procedure worldwide. Despite an increased demand for botulinum toxin A injections, the clinical pharmacology and differences in formulation of commonly available products are poorly understood. The various products available in the market are unique (...) and vary in terms of units, chemical properties, biological activities, and weight, and are therefore not interchangeable. For safe clinical practice and to achieve optimal results, the practitioners need to understand the clinical issues of potency, conversion ratio, and safety issues (toxin spread and immunogenicity). In this paper, the basic clinical pharmacology of botulinum toxin A and differences between onabotulinum toxin A, abobotulinum toxin A, and incobotulinum toxin A are discussed.

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2018 Clinical, cosmetic and investigational dermatology

7. Novel Botulinum Neurotoxins: Exploring Underneath the Iceberg Tip (PubMed)

Novel Botulinum Neurotoxins: Exploring Underneath the Iceberg Tip Botulinum neurotoxins (BoNTs), the etiological agents of botulism, are the deadliest toxins known to humans. Yet, thanks to their biological and toxicological features, BoNTs have become sophisticated tools to study neuronal physiology and valuable therapeutics for an increasing number of human disorders. BoNTs are produced by multiple bacteria of the genus Clostridium and, on the basis of their different immunological properties (...) , were classified as seven distinct types of toxin. BoNT classification remained stagnant for the last 50 years until, via bioinformatics and high-throughput sequencing techniques, dozens of BoNT variants, novel serotypes as well as BoNT-like toxins within non-clostridial species have been discovered. Here, we discuss how the now “booming field” of botulinum neurotoxin may shed light on their evolutionary origin and open exciting avenues for future therapeutic applications.

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2018 Toxins

8. Distribution of oxidized DJ-1 in Parkinson’s disease-related sites in the brain and in the peripheral tissues: effects of aging and a neurotoxin (PubMed)

Distribution of oxidized DJ-1 in Parkinson’s disease-related sites in the brain and in the peripheral tissues: effects of aging and a neurotoxin DJ-1 plays an important role in antioxidant defenses, and a reactive cysteine at position 106 (Cys106) of DJ-1, a critical residue of its biological function, is oxidized under oxidative stress. DJ-1 oxidation has been reported in patients with Parkinson's disease (PD), but the relationship between DJ-1 oxidation and PD is still unclear (...) -type mice, oxDJ-1 levels in the OB, striatum, and heart tended to decrease, while those in the skeletal muscle increased significantly. Expression of dopamine-metabolizing enzymes significantly increased in the SN and OB of aged DJ-1-/- mice, accompanied by a complementary increase in glutathione peroxidase 1. MPTP treatment concordantly changed oxDJ-1 levels in PD-related brain sites and heart. These results indicate that the effects of physiological metabolism, aging, and neurotoxin change oxDJ-1

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2018 Scientific reports

9. Response to Commentary by W. Jost on: Pharmaceutical, Biological, and Clinical Properties of Botulinum Neurotoxin Type A Products (PubMed)

Response to Commentary by W. Jost on: Pharmaceutical, Biological, and Clinical Properties of Botulinum Neurotoxin Type A Products 25851380 2015 12 07 2018 12 03 1179-6901 15 2 2015 Jun Drugs in R&D Drugs R D Response to Commentary by W. Jost on: Pharmaceutical, Biological, and Clinical Properties of Botulinum Neurotoxin Type A Products. 217-8 10.1007/s40268-015-0091-y Frevert Jürgen J Merz Pharmaceuticals GmbH, Potsdam, Germany, juergen.frevert@merz.de. eng Letter Comment New Zealand Drugs R D

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2015 Drugs in R&D

10. Dual-route targeted vaccine protects efficiently against botulinum neurotoxin A complex (PubMed)

Dual-route targeted vaccine protects efficiently against botulinum neurotoxin A complex Clostridium botulinum readily persists in the soil and secretes life-threatening botulinum neurotoxins (BoNTs) that are categorized into serotypes A to H, of which, serotype A (BoNT/A) is the most commonly occurring in nature. An efficacious vaccine with high longevity against BoNT intoxication is urgent. Herein, we developed a dual-route vaccine administered over four consecutive weeks by mucosal (...) induced robust protection against BoNT/A lethal intoxication. Together, a targeted vaccine employing local and systemic administrative routes may represent a novel formulation eliciting protective B cell responses with remarkable longevity against threatening biologic agents such as BoNTs.Copyright © 2017 Elsevier Ltd. All rights reserved.

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2017 Vaccine

11. Sequence-specific backbone resonance assignments and microsecond timescale molecular dynamics simulation of human eosinophil-derived neurotoxin (PubMed)

Sequence-specific backbone resonance assignments and microsecond timescale molecular dynamics simulation of human eosinophil-derived neurotoxin Eight active canonical members of the pancreatic-like ribonuclease A (RNase A) superfamily have been identified in human. All structural homologs share similar RNA-degrading functions, while also cumulating other various biological activities in different tissues. The functional homologs eosinophil-derived neurotoxin (EDN, or RNase 2) and eosinophil (...) cationic protein (ECP, or RNase 3) are known to be expressed and secreted by eosinophils in response to infection, and have thus been postulated to play an important role in host defense and inflammatory response. We recently initiated the biophysical and dynamical investigation of several vertebrate RNase homologs and observed that clustering residue dynamics appear to be linked with the phylogeny and biological specificity of several members. Here we report the 1H, 13C and 15N backbone resonance

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2017 Biomolecular NMR assignments

12. Embryonic Stem Cell-Derived Neurons Grown on Multi-Electrode Arrays as a Novel In vitro Bioassay for the Detection of Clostridium botulinum Neurotoxins (PubMed)

Embryonic Stem Cell-Derived Neurons Grown on Multi-Electrode Arrays as a Novel In vitro Bioassay for the Detection of Clostridium botulinum Neurotoxins Clostridium botulinum neurotoxins (BoNTs) are the most poisonous naturally occurring protein toxins known to mankind and are the causative agents of the severe and potentially life-threatening disease botulism. They are also known for their application as cosmetics and as unique bio-pharmaceuticals to treat an increasing number of neurological (...) and non-neurological disorders. Currently, the potency of biologically active BoNT for therapeutic use is mainly monitored by the murine LD50-assay, an ethically disputable test causing suffering and death of a considerable number of mice. The aim of this study was to establish an in vitro assay as an alternative to the widely used in vivo mouse bioassay. We report a novel BoNT detection assay using mouse embryonic stem cell-derived neurons (mESN) cultured on multi-electrode arrays (MEAs). After 21

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2017 Frontiers in pharmacology

13. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology (PubMed)

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far (...) and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.Copyright ©

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2017 Pharmacological reviews

14. Sensitive immunoassay for detection and quantification of the neurotoxin, tetramethylenedisulfotetramine (TETS) (PubMed)

Sensitive immunoassay for detection and quantification of the neurotoxin, tetramethylenedisulfotetramine (TETS) Tetramethylenedisulfotetramine (TETS, tetramine) is a formerly used and highly neurotoxic rodenticide. Its lethality, recent history of intentional use for mass poisoning, and the absence of a known antidote raise public health concerns. Therefore, rapid, high throughput, and sensitive methods for detection and quantification of TETS are critical. Instrumental analysis method (...) analysis. The immunoassay was then used to quantify TETS concentration in the serum of mice exposed to 2× LD50 dose of TETS and to monitor kinetics of TETS clearance from blood over a short period of time. TETS concentration in the serum reached 150 ng/mL without significant change over 4 h post-treatment. Results obtained with the immunoassay had good correlation with GC/MS analysis. Overall, this immunoassay is an important tool to rapidly detect and quantify levels of TETS from biological samples

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2017 Analytical chemistry

15. Regulation of Botulinum Neurotoxin Synthesis and Toxin Complex Formation by Arginine and Glucose in Clostridium botulinum ATCC 3502 (PubMed)

Regulation of Botulinum Neurotoxin Synthesis and Toxin Complex Formation by Arginine and Glucose in Clostridium botulinum ATCC 3502 Botulinum neurotoxin (BoNT), produced by neurotoxigenic clostridia, is the most potent biological toxin known and the causative agent of the paralytic disease botulism. The nutritional, environmental, and genetic regulation of BoNT synthesis, activation, stability, and toxin complex (TC) formation is not well studied. Previous studies indicated that growth and BoNT (...) of the regulation of C. botulinum growth and BoNT and TC formation should be valuable in defining requirements for BoNT formation in foods and clinical samples, improving the quality of BoNT for pharmaceutical preparations, and elucidating the biological functions of BoNTs for the bacterium.IMPORTANCE Botulinum neurotoxin (BoNT) is a major food safety and bioterrorism concern and is also an important pharmaceutical, and yet the regulation of its synthesis, activation, and stability in culture media, foods

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2017 Applied and environmental microbiology

16. Prediction of presynaptic and postsynaptic neurotoxins by combining various Chou’s pseudo components (PubMed)

some useful information in a timely manner. In this study, we described four algorithms for predicting presynaptic and postsynaptic neurotoxins from sequence driven features by using Increment of Diversity (ID), Multinomial Naive Bayes Classifier (MNBC), Random Forest (RF), and K-nearest Neighbours Classifier (IBK). Each protein sequence was encoded by pseudo amino acid (PseAA) compositions and three biological motif features, including MEME, Prosite and InterPro motif features. The Maximum (...) Prediction of presynaptic and postsynaptic neurotoxins by combining various Chou’s pseudo components Presynaptic and postsynaptic neurotoxins are two groups of neurotoxins. Identification of presynaptic and postsynaptic neurotoxins is an important work for numerous newly found toxins. It is both costly and time consuming to determine these two neurotoxins by experimental methods. As a complement, using computational methods for predicting presynaptic and postsynaptic neurotoxins could provide

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2017 Scientific reports

17. Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease. (PubMed)

Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease. Pioneering work in the 1950s by Christian Anfinsen on the folding of ribonuclease has shown that the primary structure of a protein "encodes" all of the information necessary for a nascent polypeptide to fold into its native, physiologically active, three-dimensional conformation (for his classic review, see [Science 181 (1973) 223]). In Alzheimer's disease (AD), the amyloid beta-protein (...) (Abeta) appears to play a seminal role in neuronal injury and death. Recent data have suggested that the proximate effectors of neurotoxicity are oligomeric Abeta assemblies. A fundamental question, of relevance both to the development of therapeutic strategies for AD and to understanding basic laws of protein folding, is how Abeta assembly state correlates with biological activity. Evidence suggests, as argued by Anfinsen, that the formation of toxic Abeta structures is an intrinsic feature

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2017 Neurobiology of Aging

18. Development of Germline-Humanized Antibodies Neutralizing Botulinum Neurotoxin A and B (PubMed)

Development of Germline-Humanized Antibodies Neutralizing Botulinum Neurotoxin A and B Botulinum neurotoxins (BoNTs) are counted among the most toxic substances known and are responsible for human botulism, a life-threatening disease characterized by flaccid muscle paralysis that occurs naturally by food poisoning or colonization of the gastrointestinal tract by BoNT-producing clostridia. To date, 7 serologically distinct serotypes of BoNT (serotype A-G) are known. Due to the high toxicity (...) of BoNTs the Centers for Disease Control and Prevention (CDC) have classified BoNTs as category A agent, including the six biological agents with the highest potential risk of use as bioweapons. Well tolerated antibodies neutralizing BoNTs are required to deal with the potential risk. In a previous work, we described the development of scFv and scFv-Fc (Yumab) from macaque origin (Macaca fascicularis) neutralizing BoNT/A and B by targeting the heavy and light chain of each serotype. In the present

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2016 PloS one

19. Selection of RNA aptamers against botulinum neurotoxin type A light chain through a non-radioactive approach (PubMed)

Selection of RNA aptamers against botulinum neurotoxin type A light chain through a non-radioactive approach Botulinum neurotoxin (BoNT), a category A agent, is the most toxic molecule known to mankind. The endopeptidase activity of light chain domain of BoNT is the cause for the inhibition of the neurotransmitter release and the flaccid paralysis that leads to lethality in botulism. Currently, antidotes are not available to reverse the flaccid paralysis caused by BoNT. In the present study (...) , a non-radioactive-based systematic evolution of ligands by exponential enrichment (SELEX) process is developed by utilizing surface plasmon resonance to monitor the binding enrichment. Two RNA aptamers have been identified as strong binders against light chain of botulinum neurotoxin type A. These two aptamers showed strong inhibition activity on LCA, with IC50 in nanomolar range. Inhibition kinetic studies reveal mid nanomolar KI and non-competitive nature of their inhibition, suggesting

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2016 Applied biochemistry and biotechnology

20. Use of Botulinum Neurotoxin in Ophthalmology (PubMed)

Use of Botulinum Neurotoxin in Ophthalmology Botulinum neurotoxin (BoNT) is the first biological toxin used in the treatment of ophthalmic diseases and to decrease skin wrinkles as an aesthetic agent. When used appropriately, it weakens the force of muscular contraction and/or inhibits glandular secretion. The most common areas for botulinum toxin treatment are the upper face, including the glabella, forehead, brows, and lateral canthal lines, or crow's feet. By relaxing the muscles causing

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2016 Turkish Journal of Ophthalmology

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