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Coupled Enzyme Activity and Thermal Shift Screening of the Maybridge Rule of 3 Fragment Library Against Trypanosoma brucei Choline Kinase; A Genetically Validated Drug Target (Book chapter)

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ISBN: 9789535109068 Year: DOI: 10.5772/52668 Language: English
Publisher: IntechOpen Grant: Wellcome Trust - 067441
Subject: Medicine (General)
Added to DOAB on : 2019-01-17 11:47:01
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In this study we interrogate 630 compounds of the Maybridge Rule of 3 Fragment Library for compounds that interact with, and inhibit TbCK. The Maybridge Rule of 3 Fragment Library is a small collection of quantifiable diverse, pharmacophoric rich, chemical entities that comply with the following criteria; MW ≤ 300, cLogP ≤ 3, H-Bond Acceptors ≤ 3, H-Bond Donors ≤ 3, Rotatable bonds (Flexibility Index) ≤ 3, Polar Surface Area ≤ 60 Å2 and aqueous solubility ≥ 1 mM using LogS and high purity (≥ 95%). Comparisons between two different screening methods, a coupled enzyme activity assay and differential scanning fluorimetry, has allowed identification of compounds that interact and inhibit the T. brucei choline kinase, several of which possess selective trypanocidal activity. Screening of a comparatively small fragment library by two different screening methods has allowed identification of several compounds that interact with and inhibit TbCK, a genetically validated drug target against African sleeping sickness. Some of the inhibitory fragments were also selectively trypanocidal, considering these are relatively simple molecules with no optimization, finding low μΜ inhibitors is very encouraging. Moreover some of the morphological phenotypes of these trypanocidal compounds include cell-cycle arrests similar to those observed for the TbCK conditional knockout grown under permissive conditions.

Keywords

pharmacology --- toxicology

Alternatives to Animal Testing

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ISBN: 9789811324475 Year: Pages: 130 DOI: 10.1007/978-981-13-2447-5 Language: English
Publisher: Springer Nature
Subject: Medicine (General) --- Biology
Added to DOAB on : 2020-02-04 11:21:24
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This open access book presents recent advances in the pure sciences that are of significance in the quest for alternatives to the use of animals in research and describes a variety of practical applications of the three key guiding principles for the more ethical use of animals in experiments – replacement, reduction, and refinement, collectively known as the 3Rs. Important examples from across the world of implementation of the 3Rs in the testing of cosmetics, chemicals, pesticides, and biologics, including vaccines, are described, with additional information on relevant regulations. The coverage also encompasses emerging approaches to alternative tests and the 3Rs. The book is based on the most informative contributions delivered at the Asian Congress 2016 on Alternatives and Animal Use in the Life Sciences. It will be of value for those working in R&D, for graduate students, and for educators in various fields, including the pharmaceutical and cosmetic sciences, pharmacology, toxicology, and animal welfare. The free, open access distribution of Alternatives to Animal Testing is enabled by the Creative Commons Attribution license in International version 4: CC BY 4.0.

Novel Therapeutic Targets and Emerging Treatments for Fibrosis

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453726 Year: Pages: 162 DOI: 10.3389/978-2-88945-372-6 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Therapeutics
Added to DOAB on : 2018-11-16 17:17:57
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For decades we have known that the overgrowth, hardening and scarring of tissues (so-called fibrosis) represents the final common pathway and best histological predictor of disease progression in most organs. Fibrosis is the culmination of both excess extracellular matrix deposition due to ongoing or severe injury, and a failure to regenerate. An inadequate wound repair process ultimately results in organ failure through a loss of function, and is therefore a major cause of morbidity and mortality in disease affecting both multiple and individual organs.Whilst the pathology of fibrosis and its significance are well understood, until recently we have known little about its molecular regulation. Current therapies are often indirect and non-specific, and only slow progression by a matter of months. The recent identification of novel therapeutic targets, and the development of new treatment strategies based on them, offers the exciting prospect of more efficacious therapies to treat this debilitating disorder.This Research Topic therefore compromises several up-to-date mini-reviews on currently known and emerging therapeutic targets for fibrosis including: the Transforming Growth Factor (TGF)-family; epigenetic factors; Angiotensin II type 2 (AT2) receptors; mineralocorticoid receptors; adenosine receptors; caveolins; and the sphingosine kinase/sphingosine 1-phosphate and notch signaling pathways. In each case, mechanistic insights into how each of these factors contribute to regulating fibrosis progression are described, along with how they can be targeted (by existing drugs, small molecules or other mimetics) to prevent and/or reverse fibrosis and its contribution to tissue dysfunction and failure. Two additional reviews will discuss various anti-fibrotic therapies that have demonstrated efficacy at the experimental level, but are not yet clinically approved; and the therapeutic potential vs limitations of stem cell-based therapies for reducing fibrosis while facilitating tissue repair. Finally, this Research Topic concludes with a clinical perspective of various anti-fibrotic therapies for cardiovascular disease (CVD), outlining limitations of currently used therapies, the pipeline of anti-fibrotics for CVD and why so many anti-fibrotic drugs have failed at the clinical level.

Good Research Practice in Non-Clinical Pharmacology and Biomedicine

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Book Series: Handbook of Experimental Pharmacology ISBN: 9783030336561 Year: Pages: 423 DOI: 10.1007/978-3-030-33656-1 Language: English
Publisher: Springer Nature
Subject: Medicine (General) --- Neurology
Added to DOAB on : 2020-06-16 23:59:54
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This open access book, published under a CC BY 4.0 license in the Pubmed indexed book series Handbook of Experimental Pharmacology, provides up-to-date information on best practice to improve experimental design and quality of research in non-clinical pharmacology and biomedicine.

Mind the gap! Gap junction channels and their importance in pathogenesis

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192380 Year: Pages: 252 DOI: 10.3389/978-2-88919-238-0 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Medicine (General) --- Therapeutics --- Science (General)
Added to DOAB on : 2015-11-16 15:44:59
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"Cells live together, but die singly", this sentence wrote the German physiologist Theodor Engelmann in 1875 and although he had no particular knowledge of gap junction channels (their structure was discovered around 100 years later) he described their functions very well: gap junction channels are essential for intercellular communication and crucial for the development of tissue and organs. But besides providing an opportunity for cells to communicate gap junction channels might also prevent intercellular communication by channel closure thereby preserving the surrounding healthy tissue in case of cellular necrosis. According to today’s understanding gap junction channels play an important role during embryonic development, during growth, wound healing and cell differentiation and are also involved in the process of learning. In the past decades most intensive research was done not only to unravel the physiological role of gap junction channels but also to extend our knowledge of the contribution of these channels in pathogenesis. A new frontier emerges in the field "pharmacology of gap junctions" with the aim to control growth, differentiation, or electrical coupling via targeting gap junction channels pharmacologically. As we know today disturbances in gap junction synthesis, assembly and cellular distribution may account for various organic disorders from most different medical fields, such as the Charcot-Marie-Tooth neuropathy, epilepsy, Chagas-disease, Naxos-syndrome, congenital cardiac malformations, arrhythmias, cancer and as a very common disease in industrial countries atherosclerosis. Point mutations in gap junction channels have been found to cause hereditary diseases like the congenital deafness or the Charcot-Marie-Tooth neuropathy but the exact molecular mechanisms of gap junction malfunction from most of the mentioned illnesses are not fully understood. Moreover, in the last few years research has expanded on the role and function of connexin hemichannels and on a relatively new field the pannexins. The purpose of this volume is to give a comprehensive overview of the involvement of gap junction channels, hemichannels and pannexins on pathogenesis of inborn and acquired diseases and on emerging pharmacological strategies to target these channels. We welcome our colleagues to contribute their findings on the influence of gap junctions on pathogenesis and to unravel the secrets of intercellular communication. Take the lid off!

The Physiology and Pharmacology of Leucine-rich Repeat GPCRs

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889199587 Year: Pages: 115 DOI: 10.3389/978-2-88919-958-7 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Internal medicine
Added to DOAB on : 2016-01-19 14:05:46
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G protein-coupled receptors (GPCRs) represent a large and physiologically important class of cell surface receptors. There are approximately 750 known GPCRs present in the human genome that can be subdivided into general classes based upon sequence homology within their transmembrane domains. Therapeutically, GPCRs represent a fertile source for the development of therapies as they are a significant percentage of our current pharmacopeia. Among the three subclasses of GPCRs, the Class A (rhodopsin-like) receptors are by far the most prevalent and extensively studied. However, within the Class A receptors, sub-families of receptors can be distinguished based upon common sequence motifs within the transmembrane domains as well as extracellular and intracellular domains. One such family of Class A receptors is characterized by multiple leucine- rich repeats within their amino- terminal domains (the Leucine-rich Repeat family (LRR)). This family of GPCRs are best represented by the glycoprotein hormone receptors (LHR, FSHR and TSHR) which have been studied extensively but also includes receptors for the peptide hormone relaxin (RXFP1 and RXFP2 (RXFP2 also binds insulin-like peptide 3)) and three other receptors (LGR4, LGR5 and LGR6). LGR4-6 were, until recently, considered orphan receptors. However, emerging data have revealed that these proteins are the receptors for a family of growth factors called R-spondins. Over the last 20 years much has been learned about LRR receptors, including the development of synthetic agonists and antagonists, new insights into signaling (including signaling bias) and the physiological role these receptors play in regulating the function of many tissues. This topic will focus on what is known concerning the regulation of these receptors, their signaling pathways, functional consequences of activation and pharmacology.

Keywords

GPCR --- Leucine- rich repeat --- LH --- FSH --- TSH --- Relaxin --- R-spondin --- LRR --- Pharmacology

Molecular and Biotechnological Advancements in Hypericum Species

Authors: --- ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889451173 Year: Pages: 159 DOI: 10.3389/978-2-88945-117-3 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Botany
Added to DOAB on : 2017-07-06 13:27:36
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Hypericum is an important genus of the family Hypericaceae and includes almost 500 species of herbs, shrubs and trees. Being the home for many important bioactive compounds, these species have a long traditional value as medicinal plants. Currently, several species of this genus have been used in ailments as knowledge-based medicine in many countries. In the recent past, several pharmacological studies have been performed using crude extracts to evaluate the traditional knowledge. Results of those studies have revealed that Hypericum extract exert multiple pharmacological properties including antidepressant, antimicrobial, antitumor and wound healing effects. Phytochemical analyses revealed that these species produce a broad spectrum of valuable compounds, mainly naphthodianthrones (hypericin and pseudohypericin), phloroglucinols (hyperforin and adhyperforin), flavonoids (hyperoside, rutin and quercitrin), benzophenones/xanthones (garcinol and gambogic acid), and essential oils. Noticeably, Hypericum perforatum extracts have been used to treat mild to moderate depression from ancient to present times and the antidepressant efficacy of Hypericum extracts has been attributed to its hyperforin content, which is known to inhibit the re-uptake of aminergic transmitters such as serotonin and noradrenaline into synaptic nerve endings. Neurodegenerative diseases and inflammatory responses are also linked with Reactive Oxygen Species (ROS) production. A wide range of flavonoids present in Hypericum extracts, namely, rutin, quercetin, and quercitrin exhibit antioxidant/free radical scavenging activity. Hypericin, beside hyperforin, is the active molecule responsible for the antitumor ability of Hypericum extracts and is seen as a potent candidate to treat brain tumor. Recent attempts of using hypericin in patients with recurrent malignant brain tumors showed promising results. Collectively, Hypericum species contain multiple bioactive constituents, suggesting their potential to occupy a huge portion of the phytomedicine market. Today, studies on medicinal plants are rapidly increasing because of the search for new active molecules, and for the improvement in the production of plants and molecules for the herbal pharmaceutical industries. In the post genomic era, application of molecular biology and genomic tools revolutionized our understanding of major biosynthetic pathways, phytochemistry and pharmacology of Hypericum species and individual compounds. This special issue mainly focuses on the recent advancements made in the understanding of biosynthetic pathways, application of biotechnology, molecular biology, genomics, pharmacology and related areas.

Making Medicines in Africa: The Political Economy of Industrializing for Local Health

Authors: --- --- ---
ISBN: 9781137571335 9781137546470 Year: Pages: 360 DOI: 10.1057/9781137546470 Language: English
Publisher: Palgrave Macmillan
Subject: Political Science --- Therapeutics
Added to DOAB on : 2015-12-16 18:20:38
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This book is open access under a CC-BY license. The importance of the pharmaceutical industry in Sub-Saharan Africa, its claim to policy priority, is rooted in the vast unmet health needs of the sub-continent. Making Medicines in Africa is a collective endeavour, by a group of contributors with a strong African and more broadly Southern presence, to find ways to link technological development, investment and industrial growth in pharmaceuticals to improve access to essential good quality medicines, as part of moving towards universal access to competent health care in Africa. The authors aim to shift the emphasis in international debate and initiatives towards sustained Africa-based and African-led initiatives to tackle this huge challenge. Without the technological, industrial, intellectual, organisational and research-related capabilities associated with competent pharmaceutical production, and without policies that pull the industrial sectors towards serving local health needs, the African sub-continent cannot generate the resources to tackle its populations' needs and demands.

Neuropsychopharmacology of Psychosis: Relation of Brain Signals, Cognition and Chemistry

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193356 Year: Pages: 276 DOI: 10.3389/978-2-88919-335-6 Language: English
Publisher: Frontiers Media SA
Subject: Psychiatry --- Medicine (General)
Added to DOAB on : 2016-03-10 08:14:32
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Previous research over the past decades has identified diverse neurobiological underpinnings of psychosis. In particular, by combining a variety of different neuroimaging modalities, it has been shown that psychotic states and the actual transition phase from a clinical high-risk state to established psychosis is characterized by structural, functional and neurochemical changes across different brain regions.Further evidence revealed that maybe not only focal brain abnormalities are characteristic for psychosis but specifically also an abnormal functional integration among various brain areas. Some evidence also suggests that dysfunctional brain connectivity proceeds during the development of psychosis when subjects perform a cognitive task. Notably, altered brain connectivity during cognitive challenges was often found to be associated with psychopathological measures, suggesting a mechanistic relation between functional network integrity and the clinical expression of psychosis.Several works proposed that disordered brain connectivity in psychosis results from abnormal N-methyl- D -aspartate receptor (NMDAR)-dependent synaptic plasticity, which can be mediated by other neurotransmitter systems such as dopamine or serotonin. Specific chemically mediated changes in synaptic plasticity may contribute to abnormal functional integration among brain regions and in consequence to impaired learning performances and inferences. Model-based connectivity investigations on synaptic signalling demonstrated for example that manipulation of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor system altered synaptic plasticity in healthy volunteers, which was predictive for subjects’ cognitive performance and psychopathology. In patients with psychosis, the activity in the prefrontal cortex during the processing of prediction errors, a specific form of learning, which is conveyed via synaptic connections, was linked with individuals’ formation of delusions. These results fit well with many works suggesting that psychotic symptoms or also drug-induced psychosis-like experiences can be explained by disturbances within a hierarchically organized neuronal network, leading to maladaptive integrations of new incoming evidence and thereby to false formations of prediction errors and false beliefs.In this research topic, we like to cover the most recent neurobiological correlates for early stage psychosis and in particular for the prediction of psychosis by using different neurophysiological measures (e.g. structural and functional MRI, EEG, DTI or PET). Studies exploring effective connectivity or complex brain networks such as small-world properties with techniques like dynamic causal modelling, structural equation modelling, or graph theory analysis are highly appreciated. Very welcome are studies proving a link between clinical features such as psychopathology and cognition, brain signals, and chemistry (also in regard of antipsychotic treatments or substance-induced psychotic states). Moreover, environmental factors that may influence psychosis onset or its’ developmental processes will be brought together with a diversity of different research modalities. We also collect critical reviews, mini-reviews or theoretical reflections from leading international researcher and clinicians in this field. The purpose of our research topic is intended to provide a state-of-the-art cognitive perspective to consider developing psychosis, which might shed more lights into the pathophysiological and neurobiological mechanisms of psychosis.

Neural and Synaptic Defects in Autism Spectrum Disorders

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196289 Year: Pages: 285 DOI: 10.3389/978-2-88919-628-9 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2016-08-16 10:34:25
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Autism spectrum disorders (ASDs) are a group of genetically and clinically heterogeneous neurodevelopmental disorders characterized by impaired reciprocal social interactions and communication, and restricted and repetitive patterns of behaviors and interests. Studies in genetics, neurobiology and systems biology are providing insights into the pathogenesis of ASDs. Investigation of neural and synaptic defects in ASDs not only sheds light on the molecular and cellular mechanisms that govern the function of the central nervous system, but may lead to the discovery of potential therapeutic targets for autism and other cognitive disorders. Our Research Topic which constitutes this e-book documents the recent development and ideas in the study of pathogenesis and treatment of ASDs, with an emphasis on syndromic disorders such as fragile X and Rett syndromes. In addition, model systems and methodological approaches with translational relevance to autism are covered herein. We hope that the Research Topic will enhance the global knowledge base in the autism research community and foster new research directions in autism related biology.

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