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Cerebral endothelial and glial cells are more than bricks in the Great Wall of the brain: Insights into the way the blood-brain barrier actually works (Celebrating the centenary of Goldman's experiments)

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195725 Year: Pages: 186 DOI: 10.3389/978-2-88919-572-5 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-02-05 17:24:33
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When Ehrlich discovered the first evidence of the blood-brain barrier in 1885, he probably did not perceive the Great Wall that remained hidden from consciousness inside the central nervous system. Ehrlich had observed that acidic vital dyes did not stain the brain if they were injected into the blood stream. A century ago (1913), Goldman showed that the injection of trypan blue in the cerebrospinal fluid stained only the brain, but not the other organs. For almost a century it was thought that the blood-brain barrier (BBB) consisted in a physical barrier, resulting from the restricted permeability of the cerebral endothelial cell layer, as they are joined by tight junctions. However, as scientists are always looking for news in what is already discovered, in the end of the 20th century we had evidences that cerebral endothelial and glial cells express several drug metabolizing enzymes consisting in a second protection system: a metabolic barrier. Furthermore, the drugs and their metabolites must overcome the activity of several multidrug resistance proteins that function as ATP-dependent efflux pumps, consisting in the third line of defence: the active barrier. Therefore, the way the BBB actually works should be better explained. Several endogenous compounds, as well as xenobiotics, may be activated by enzymes of the metabolic barrier, generating reactive oxygen species that could damage neurons. Therefore, endothelial and glial cells possess endogenous protecting compounds and enzymes against oxidants, consisting in an antioxidant barrier. When all these systems fail, glial cells, mainly microglia, secrete cytokines in an attempt to crosstalk with defence cells asking for help, which consists in an immune barrier. In cerebral regions that are devoid of the physical barrier, such as circumventricular organs, the metabolic, active, antioxidant and immune barriers are reinforced. It is important to understand how cells involved in the BBB interact with one another and the dynamic mechanisms of their functions. This Research Topic published in this e-Book considers recent highlights in BBB structure, cell and molecular biology, biotransformation, physiology, pathology, pharmacology, immunology and how these basic knowledges can be applied in drug discovery and clinical researches, rewriting what is already written, and paving the way that goes to the Great Wall in the Frontiers of the Brain in this new century that is just beginning.

The changing faces of glutathione, a cellular protagonist

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195954 Year: Pages: 142 DOI: 10.3389/978-2-88919-595-4 Language: English
Publisher: Frontiers Media SA
Subject: Therapeutics --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Glutathione (GSH) has been described for a long time just as a defensive reagent against the action of toxic xenobiotics (drugs, pollutants, carcinogens), both directly and as a cofactor for GSH transferases. As a prototype antioxidant, it has been involved in cell protection from the noxious effect of excess oxidant stress, both directly and as a cofactor of glutathione peroxidases. In addition, it has long been known that GSH is capable of forming disulfide bonds with cysteine residues of proteins, and the relevance of this mechanism ("S-glutathionylation") in regulation of protein function has been well documented in a number of research fields. Rather paradoxically, it has also been highlighted that GSH—and notably its catabolites, as originated by metabolism by gamma-glutamyltransferase—can promote oxidative processes, by participating in metal ion-mediated reactions eventually leading to formation of reactive oxygen species and free radicals. Also, a fundamental role of GSH has been recognized in the storage and transport of nitric oxide (NO), in the form of S-nitrosoglutathione (GSNO). The significance of GSH as a major factor in regulation of cell life, proliferation, and death, can be regarded as the integrated result of all these roles, as well as of more which are emerging in diverse fields of biology and pathophysiology. Against this background, modulation of GSH levels and GSH-related enzyme activities represents a fertile field for experimental pharmacology in numerous and diverse perspectives of animal, plant and microbiologic research. This research topic includes 14 articles, i.e. 4 Opinion Articles, 6 Reviews, and 4 Original Research Articles. The contributions by several distinguished research groups, each from his own standpoint of competence and expertise, provide a comprehensive and updated view over the diverse roles, the changing faces of GSH and GSH-related enzymes in cell’s health, disease and death.

Impact of Lipid Peroxidation on the Physiology and Pathophysiology of Cell Membranes

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889450824 Year: Pages: 88 DOI: 10.3389/978-2-88945-082-4 Language: English
Publisher: Frontiers Media SA
Subject: Physiology --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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The general process of lipid peroxidation consists of three stages: initiation, propagation, and termination. The initiation phase of lipid peroxidation includes hydrogen atom abstraction. Several species can abstract the first hydrogen atom and include the radicals: hydroxyl, alkoxyl, peroxyl, and possibly HO* 2. The membrane lipids, mainly phospholipids, containing polyunsaturated fatty acids are predominantly susceptible to peroxidation because abstraction from a methylene group of a hydrogen atom, which contains only one electron, leaves at the back an unpaired electron on the carbon. The initial reaction of *OH with polyunsaturated fatty acids produces a lipid radical (L*), which in turn reacts with molecular oxygen to form a lipid hydroperoxide (LOOH). Further, the LOOH formed can suffer reductive cleavage by reduced metals, such as Fe++, producing lipid alkoxyl radical (LO*). Peroxidation of lipids can disturb the assembly of the membrane, causing changes in fluidity and permeability, alterations of ion transport and inhibition of metabolic processes. In addition, LOOH can break down, frequently in the presence of reduced metals or ascorbate, to reactive aldehyde products, including malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), 4-hydroxy-2-hexenal (4-HHE) and acrolein. Lipid peroxidation is one of the major outcomes of free radical-mediated injury to tissue mainly because it can greatly alter the physicochemical properties of membrane lipid bilayers, resulting in severe cellular dysfunction. In addition, a variety of lipid by-products are produced as a consequence of lipid peroxidation, some of which can exert beneficial biological effects under normal physiological conditions. Intensive research performed over the last decades have also revealed that by-products of lipid peroxidation are also involved in cellular signalling and transduction pathways under physiological conditions, and regulate a variety of cellular functions, including normal aging. In the present collection of articles, both aspects (adverse and benefitial) of lipid peroxidation are illustrated in different biological paradigms. We expect this eBook may encourage readers to expand the current knowledge on the complexity of physiological and pathophysiological roles of lipid peroxidation.

Molecular Pharmacology and Pathology of Strokes

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ISBN: 9783038975410 / 9783038975427 Year: Pages: 152 DOI: 10.3390/books978-3-03897-542-7 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Medicine (General) --- Therapeutics --- Cardiovascular
Added to DOAB on : 2019-02-11 11:33:53
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Stroke, a progressively non-communicable disease, is the second leading cause of death after coronary heart disease in developed countries. The present treatment options for stroke are adapting lifestyle practices, diabetes treatment, drugs, and the management of other factors, but no cure is yet available, despite new insights into molecular and therapeutic targets. Discoveries related to explicating the molecular pharmacology in cerebrovascular function and thrombosis have led to significant advancements in the current treatment paradigm for patients with stroke. Hence, this Special Issue invited scientific papers and reviews from researchers to provide solid evidence from a molecular point of view to scrutinize the molecular pharmacology and pathology of strokes. Platelet activation plays a major role in cardio and cerebrovascular diseases. Platelets also play a key role in the hemostatic process and are associated with various pathological events, such as arterial thrombosis and atherosclerosis. While the currently used anti-platelet drugs such as aspirin and clopidogrel demonstrate efficacy in many patients, they exert undesirable side effects. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a significant priority. Recently, precious metal drugs have conquered the subject of metal-based drugs, and several investigators have moved their attention to the synthesis of various ruthenium (Ru) and iridium (Ir) complexes due to their prospective therapeutic values. We have published this e-book about the “Molecular Pharmacology and Pathology of Strokes” and anticipate that readers will find this book useful regarding the significant challenges and current advances that are presently being made in stroke research, with the possibility of inspiring the application of novel drug development to enrich the devotion and treatment of patients with cardiovascular diseases.

Mitochondrial Dysfunction in Ageing and Diseases

ISBN: 9783038422518 9783038422525 Year: Pages: XXVI, 516 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Added to DOAB on : 2016-08-16 07:37:51
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The past decade has witnessed an explosion of knowledge regarding how mitochondrial dysfunction may translate into ageing and disease phenotypes, as well as how it is modulated by genetic and lifestyle factors. Impairment of the mitochondria may be caused by mutations or deletions in nuclear or mitochondrial DNA. Hallmarks of mitochondrial dysfunction include decreased ATP production, decreased mitochondrial membrane potential, swollen mitochondria, damaged cristae, increased oxidative stress, and decreased mitochondrial DNA copy number. In addition to energy production, mitochondria play an important role in regulating apoptosis, buffering calcium release, retrograde signaling to the nuclear genome, producing reactive oxygen species (ROS), participating in steroid synthesis, signaling to the immune system, as well as controlling the cell cycle and cell growth. Dysfunctional mitochondria have been implicated in ageing and in several diseases, many of which are age-related, including mitochondrial diseases, cancers, metabolic diseases and diabetes, inflammatory conditions, neuropathy, and neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease. Additionally, a possible link between mitochondrial metabolism and the ubiquitin-proteasome and autophagy-lysosome systems is emerging as a novel factor contributing to the progression of several human diseases. This special issue calls for original research, mini and full reviews, and perspectives that address the progress and current standing in the vast field of mitochondrial biology. These include, but are not limited to: ageingneurodegenerative diseasesmitochondrial diseasesmetabolic diseasesprotein homeostasiscell/retrograde signalingoxidative stresspaincancerimmune systemtherapies to counteract mitochondrial dysfunction

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

Antioxidants and Second Messengers of Free Radicals

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ISBN: 9783038975335 / 9783038975342 Year: Pages: 194 DOI: 10.3390/books978-3-03897-534-2 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology --- Medicine (General) --- Chemistry (General)
Added to DOAB on : 2019-01-17 09:35:49
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The history of science can teach modern men that our understanding of life is to a great extent based on the accuracy of the analytical methods that we use and, on our readiness to oppose dogmatic opinions, which are based on outdated methods and black/white approaches to the major questions raised by mankind in the past. The recent decades have brought a lot of new insights into the fundamentals of the active principles of reactive oxygen species that are necessary for living cells, but which also cause dangerous pathophysiological processes. Accordingly, although they were previously considered to be the most undesired toxic compounds generated as the final products of the oxidative degradation of lipids, reactive aldehydes are now considered to play important roles both in health and in major diseases. Represented mostly by 4-hydroxynonenal (HNE), a substance discovered only fifty years ago, reactive aldehydes are the focus of research not only because of their toxicity but also because of their positive effects regulating the most important metabolic processes such as growth of living cells or the death of cells. Better understanding the interactions between reactive aldehydes and natural or synthetic antioxidant substances might eventually help us to better monitor, prevent and control modern diseases, thus building pillars for the development of the modern, multidisciplinary life sciences and integrative medicine of the 21st century.

Metal Metabolism in Animals

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ISBN: 9783038428435 9783038428442 Year: Pages: X, 356 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2018-04-20 14:25:48
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Through evolution of life, animals have adapted to the ubiquitous presence of metals in the biosphere. They utilize the more frequent ones as essential constituents of their biochemical machinery. In fact, about 40% of all proteins present in animal cells are so-called metalloproteins. On the other hand, animals have invented regulatory and detoxifying mechanisms to protect themselves from critical concentrations of both essential and non-essential metal concentrations. Metallomics is a modern approach applying cellular, biochemical, molecular and analytical methods to investigate the relationships of metals in their cellular context. The present edition contains a number of original articles and reviews dealing with various aspects of metallomics in animals, published as Special Issues of the International Journal of Molecular Sciences in 2016 and 2017. The book addresses subjects such as metal definition in biology, metabolism of metals in invertebrate and vertebrate animals, metal detoxification and regulation strategies, supplementation of essential trace elements, metal behavior in pregnancy and embryonic development, as well as metal toxicology and emerging medical implications.

Mercury and Methylmercury Toxicology and Risk Assessment

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ISBN: 9783038979708 / 9783038979715 Year: Pages: 142 DOI: 10.3390/books978-3-03897-971-5 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Technology (General) --- Chemical Engineering
Added to DOAB on : 2019-06-26 08:44:06
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Mercury is a global pollutant that affects the health of both humans and ecosystems. This Special Issue collects three review papers and six research articles that report on the latest findings on the mechanisms of mercury toxicology and its impacts on environmental health. This collection of papers provides useful, new information on the mechanisms of mercury toxicity and methods of improving the risk assessment of mercury exposure.

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