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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.

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

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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.

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.

The Emerging Discipline of Quantitative Systems Pharmacology

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196425 Year: Pages: 97 DOI: 10.3389/978-2-88919-642-5 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Therapeutics
Added to DOAB on : 2016-08-16 10:34:25
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In 2011, the National Institutes of Health (NIH), in collaboration with leaders from the pharmaceutical industry and the academic community, published a white paper describing the emerging discipline of Quantitative Systems Pharmacology (QSP), and recommended the establishment of NIH-supported interdisciplinary research and training programs for QSP. QSP is still in its infancy, but has tremendous potential to change the way we approach biomedical research. QSP is really the integration of two disciplines that have been increasingly useful in biomedical research; “Systems Biology” and “Quantitative Pharmacology”. Systems Biology is the field of biomedical research that seeks to understand the relationships between genes and biologically active molecules to develop qualitative models of these systems; and Quantitative Pharmacology is the field of biomedical research that seeks to use computer aided modeling and simulation to increase our understanding of the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs, and to aid in the design of pre-clinical and clinical experiments. The purpose of QSP modeling is to develop quantitative computer models of biological systems and disease processes, and the effects of drug PK and PD on those systems. QSP models allow testing of numerous potential experiments “in-silico” to eliminate those associated with a low probability of success, avoiding the potential costs of evaluating all of those failed experiments in the real world. At the same time, QSP models allow us to develop our understanding of the interaction between drugs and biological systems in a more systematic and rigorous manner. As the need to be more cost-efficient in the use of research funding increases, biomedical researchers will be required to gain the maximum insight from each experiment that is conducted. This need is even more acute in the pharmaceutical industry, where there is tremendous competition to develop innovative therapies in a highly regulated environment, combined with very high research and development (R&D) costs for bringing new drugs to market (~$1.3 billion/drug). Analogous modeling & simulation approaches have been successfully integrated into other disciplines to improve the fundamental understanding of the science and to improve the efficiency of R&D (e.g., physics, engineering, economics, etc.). The biomedical research community has been slow to integrate computer aided modeling & simulation for many reasons: including the perception that biology and pharmacology are “too complex” and “too variable” to be modeled with mathematical equations; a lack of adequate graduate training programs; and the lack of support from government agencies that fund biomedical research. However, there is an active community of researchers in the pharmaceutical industry, the academic community, and government agencies that develop QSP and quantitative systems biology models and apply them both to better characterize and predict drug pharmacology and disease processes; as well as to improve efficiency and productivity in pharmaceutical R&D.

Structure-Based Drug Design for Diagnosis and Treatment of Neurological Diseases

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889451234 Year: Pages: 204 DOI: 10.3389/978-2-88945-123-4 Language: English
Publisher: Frontiers Media SA
Subject: Therapeutics --- Neurology --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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European Cooperation in Science and Technology (COST) supports the collaboration of nationally-funded science and technology research through the creation of networks. COST is the longest-running European framework enhancing cooperation among researchers, engineers and scholars across Europe. The COST Action CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain” is a good example of the advances possible through interdisciplinary collaboration on difficult problems. COST Action CM1103 brought together 28 research groups from 18 countries to collaborate for four years on multi-target drug design for complex neuropathologies. The interdisciplinary expertise of the members is spans the range from computational enzymology to human studies, providing outstanding opportunities for the interdisciplinary development of trainees, and is reflected in the articles in this e-book. This Research Topic covers progress in multi-target drug design for the complex neuropathologies of the monoamine system that are apparent, for example, in Alzheimer’s disease. After a mini-review to introduce the topic of multi-target drug design, the other articles review the Research topic from their own perspective, two from computational approaches, three from medicinal chemistry, two from molecular pharmacology, and two from studies in whole brain. This multi-faceted approach describes new compounds, new methodology, and advances in the basic science of understanding the brain. This Ebook is based upon work from COST Action (CM1103 “Structure-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain"), supported by COST (European Cooperation in Science and Technology). COST (European Cooperation in Science and Technology) is a pan-European intergovernmental framework. Its mission is to enable break-through scientific and technological developments leading to new concepts and products and thereby contribute to strengthening Europe’s research and innovation capacities. It allows researchers, engineers and scholars to jointly develop their own ideas and take new initiatives across all fields of science and technology, while promoting multi- and interdisciplinary approaches. COST aims at fostering a better integration of less research intensive countries to the knowledge hubs of the European Research Area. The COST Association, an International not-for-profit Association under Belgian Law, integrates all management, governing and administrative functions necessary for the operation of the framework. The COST Association has currently 36 Member Countries. www.cost.eu

In Vivo Imaging in Pharmacological Research

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889452378 Year: Pages: 222 DOI: 10.3389/978-2-88945-237-8 Language: English
Publisher: Frontiers Media SA
Subject: Therapeutics --- Science (General)
Added to DOAB on : 2017-10-13 14:57:01
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The discovery and development of a biological active molecule with therapeutic properties is an ever increasing complex task, highly unpredictable at the early stages and marked, in the end, by high rates of failure. As a consequence, the overall process leading to the production of a successful drug is very costly. The improvement of the net outcome in drug discovery and development would require, amongst other important factors, a good understanding of the molecular events that characterize the disease or pathology in order to better identify likely targets of interest, to optimize the interaction of an active agent (small molecule or macromolecule of natural or synthetic origin) with those targets, and to facilitate the study of the pharmacokinetics, pharmacodynamics and toxicity of an active agent in suitable models and in human subjects. The objective of this Research Topic is to highlight new developments and applications of imaging techniques with the objective of performing pharmacological studies in vivo, in animal models and in humans. In the domain of drug discovery, the pharmacological and biomedical questions constitute the center of attention. In this sense, it is fundamental to keep in mind the strengths and limitations of each analytical or imaging technique. At the end, the judicious application of the technique with the aim of supporting the search for answers to manifold questions arising during a long and painstaking path provides a continuous role for imaging within the complex area of drug discovery and development.

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