Characteristics of blood-brain barrier endothelial cells in response to inflammatory stimuli PDF Download

Author: Helga Eveline de Vries
Publisher:
ISBN: 9789074538060
Category :
Languages : en
Pages : 189

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Author: Gert Fricker
Publisher: Springer
ISBN: 3662437872
Category : Science
Languages : en
Pages : 169

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Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.

Author: Ruth Lyck
Publisher: Springer
ISBN: 3319455141
Category : Medical
Languages : en
Pages : 288

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This PIR volume presents a comprehensive collection of reviews that focus on the role of the blood-brain barrier (BBB) during steady-state and inflamed conditions. Within the central nervous system (CNS) the constantly changing bloodstream is strictly separated from the CNS parenchyma by the BBB. However, viruses, bacteria, parasites and auto-aggressive immune cells can penetrate the barrier and significantly contribute to CNS inflammation. The BBB can actively contribute to neuroinflammation by presentation of chemokines, expression of cell adhesion molecules and alterations of barrier properties. As such, understanding the role of the BBB under healthy and pathological conditions is essential to the development of new drugs to efficiently combat inflammatory diseases of the CNS.

Author: Leon Smyth
Publisher:
ISBN:
Category :
Languages : en
Pages : 466

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The blood-brain barrier (BBB) is an important protective structure that restricts the free passage of blood components and circulating immune cells into the brain. The BBB is primarily composed of endothelial cells that line the inside of the vessel, and is surrounded by pericytes that perform critical roles in its formation and maintenance. In this project, I aimed to examine aspects of inflammatory signalling at the BBB using primary human brain pericytes and endothelia. Initially, pericytes were characterised in human brain tissue to develop a panel of markers for pericytes in vitro. Characterisation studies validated that in vitro cultures of pericytes recapitulated their in situ phenotype, as well as identifying two novel markers of vascular smooth muscle cell phenotype in situ and in vitro. A protocol for the isolation of primary human brain endothelia was then developed to study the interactions of pericytes and endothelia in vitro, and these cultures were shown to retain their unique brain endothelial phenotype. Using cultures of pericytes and endothelia, differences in the inflammatory response of these two cell types were identified, including unique secretions, and differential sensitivity to inflammatory stimuli. Subsequently, the role of platelet-derived growth factor-BB (PDGF-BB) was investigated in greater detail. PDGF-BB was found to cause a proliferative response in brain pericytes, as has been found previously, but also induced the expression of inflammation-related secretions. The pathways through which this inflammatory response was mediated were dissected using genetic and pharmacological inhibitors. Interestingly, it was found that PDGF-BB altered pericyteendothelial interactions, stopping pericytes from strengthening the endothelial barrier. The role of PDGF-BB was investigated further in co-cultures, incorporating astrocytes, microglia, endothelia, and pericytes. It was observed that PDGF-BB improves the formation of blood vessel-like endothelial cords in vitro due to reduced cell death and increased expression of angiogenesis-associated molecules, reminiscent of its effects in vivo. The BBB is a critical structure in the brain, but has not yet been targeted to treat disease. Together these findings provide novel insights into cell-cell signalling at the BBB, and how these interactions are modified during inflammatory conditions. Because BBB damage and neuroinflammation are critical disease processes in neurological diseases, the factors that govern neuroinflammation at the BBB present potential drug targets to prevent the progression of AD.

Author: Roy Bicknell
Publisher: Cambridge University Press
ISBN: 9780521559904
Category : Science
Languages : en
Pages : 156

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The aim of the Handbooks in Practical Animal Cell Biology is to provide practical workbooks for those involved in primary cell culture. Each volume addresses a different cell lineage, and contains an introductory section followed by individual chapters on the culture of specific differentiated cell types. The authors of each chapter are leading researchers in their fields and use their first-hand experience to present reliable techniques in a clear and thorough manner. Endothelial Cell Culture contains chapters on endothelial cells derived from 1) lung, 2) bone marrow, 3) brain, 4) mammary glands, 5) skin, 6) adipose tissue, 7) female reproductive system, and 8) synovium.

Author: D. Neil Granger
Publisher: Morgan & Claypool Publishers
ISBN: 1615041656
Category : Medical
Languages : en
Pages : 99

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The microcirculation is highly responsive to, and a vital participant in, the inflammatory response. All segments of the microvasculature (arterioles, capillaries, and venules) exhibit characteristic phenotypic changes during inflammation that appear to be directed toward enhancing the delivery of inflammatory cells to the injured/infected tissue, isolating the region from healthy tissue and the systemic circulation, and setting the stage for tissue repair and regeneration. The best characterized responses of the microcirculation to inflammation include impaired vasomotor function, reduced capillary perfusion, adhesion of leukocytes and platelets, activation of the coagulation cascade, and enhanced thrombosis, increased vascular permeability, and an increase in the rate of proliferation of blood and lymphatic vessels. A variety of cells that normally circulate in blood (leukocytes, platelets) or reside within the vessel wall (endothelial cells, pericytes) or in the perivascular space (mast cells, macrophages) are activated in response to inflammation. The activation products and chemical mediators released from these cells act through different well-characterized signaling pathways to induce the phenotypic changes in microvessel function that accompany inflammation. Drugs that target a specific microvascular response to inflammation, such as leukocyte-endothelial cell adhesion or angiogenesis, have shown promise in both the preclinical and clinical studies of inflammatory disease. Future research efforts in this area will likely identify new avenues for therapeutic intervention in inflammation. Table of Contents: Introduction / Historical Perspectives / Anatomical Considerations / Impaired Vasomotor Responses / Capillary Perfusion / Angiogenesis / Leukocyte-Endothelial Cell Adhesion / Platelet-Vessel Wall Interactions / Coagulation and Thrombosis / Endothelial Barrier Dysfunction / Epilogue / References

Author: Keith D. Rochfort
Publisher:
ISBN:
Category :
Languages : en
Pages : 364

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Introduction: Within the central nervous system, the cerebral endothelial cells have highly specialised structural and functional properties. Compared to the endothelium of the periphery, brain endothelial cells are phenotypically unique in that they have enhanced inter-endothelial junction complexes that provide a highly restrictive yet controlled paracellular barrier for the brain from the constituents of the circulation, effectively embodying a blood-brain barrier. Disruption of the proteins that form these junctional complexes (i.e. occludin, claudin-5, VE-cadherin and ZO-1) has therefore been implicated in several CNS disease states. Endothelial functions can be modulated by both local and systemic environmental factors. The ability of the endothelium to sense its humoral and biomechanical environment and modify its functional phenotype accordingly plays a pivotal role in the maintenance of vascular homeostasis or the development of vascular pathology. However, much remains unknown about how anti- and pro- inflammatory stimuli modulate blood-brain barrier phenotype at the molecular level, thus framing the context of this thesis. In the current study, in view of the opposing physiological and pathophysiological actions demonstrated thus far in similar yet distinctly different in vivo and in vitro endothelial models, we propose to investigate how anti-inflammatory laminar shear stress and pro-inflammatory cytokines can differentially modulate BBB phenotype, with functional consequences for endothelial homeostasis, particularly with regards to the coordination and maintenance of the BBB interendothelial junction complex. Results: Exposure of cultured human brain microvascular endothelial cells (HBMvECs) to physiological levels of laminar shear stress (8 dynes cm-2) resulted in a reduction in monolayer permeability. The transcription and translation of occludin, claudin-5, VE-cadherin and ZO-1 were all upregulated, with an enhanced localisation of said proteins at the cell-cell junctions. Moreover, our studies demonstrated laminar shear stress caused a substantial reduction in pTyr and pThr levels on each protein, with functional consequences for barrier integrity as determined using dephostatin and genistein. In addition, laminar shear stress promoted a number of anti-inflammatory mechanisms, which, in the presence of inflammatory cytokines, could partially ameliorate the injurious effects of the latter. Sophisticated co-IP techniques, coupled with mass spectrometry analysis, identified several isoforms of the 14-3-3 family of proteins as intracellular binding partners to the interendothelial junction complex. This family of proteins was implicated in contributing to the protective, barrier- stabilising effect of laminar shear, whilst inhibition of their activity exacerbated cytokine injury. In parallel studies, exposure of cultured HBMvECs to pathophysiological levels of inflammatory cytokines, TNF-alpha and IL-6, resulted in an increase in monolayer permeability, an effect directly attributable to the reduction in the transcription and translation of the aforementioned tight and adherens junction proteins. Moreover, each cytokine caused a substantial increase in pTyr/Thr levels on each protein. Noteworthy, all cytokine effects were dose- and time-dependent. This increase in injury can be possibly attributed to a correlative reduction in anti-inflammatory mechanisms coupled with a correlative increase in the production and release of inflammatory mediators such as ROS and other cytokines such as IL-6 into the local environment. Conclusions: Physiological levels of laminar shear stress and pathophysiological levels of inflammatory cytokines, TNF-alpha and IL-6, modulate the expression and post-translational properties of BBB tight and adherens junction proteins in an opposing manner. Inflammatory cytokines mediate their effects in part through the induced release of injury potentiating agents such as ROS and IL-6. A novel role for 14-3-3 isoforms in the modulation of interendothelial junction assembly is also implicated in these studies.

Author: Michel Félétou
Publisher: Morgan & Claypool Publishers
ISBN: 1615041230
Category : Science
Languages : en
Pages : 309

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The endothelium, a monolayer of endothelial cells, constitutes the inner cellular lining of the blood vessels (arteries, veins and capillaries) and the lymphatic system, and therefore is in direct contact with the blood/lymph and the circulating cells. The endothelium is a major player in the control of blood fluidity, platelet aggregation and vascular tone, a major actor in the regulation of immunology, inflammation and angiogenesis, and an important metabolizing and an endocrine organ. Endothelial cells controls vascular tone, and thereby blood flow, by synthesizing and releasing relaxing and contracting factors such as nitric oxide, metabolites of arachidonic acid via the cyclooxygenases, lipoxygenases and cytochrome P450 pathways, various peptides (endothelin, urotensin, CNP, adrenomedullin, etc.), adenosine, purines, reactive oxygen species and so on. Additionally, endothelial ectoenzymes are required steps in the generation of vasoactive hormones such as angiotensin II. An endothelial dysfunction linked to an imbalance in the synthesis and/or the release of these various endothelial factors may explain the initiation of cardiovascular pathologies (from hypertension to atherosclerosis) or their development and perpetuation. Table of Contents: Introduction / Multiple Functions of the Endothelial Cells / Calcium Signaling in Vascular Cells and Cell-to-Cell Communications / Endothelium-Dependent Regulation of Vascular Tone / Conclusion / References

Author: Thomas Heinbockel
Publisher: BoD – Books on Demand
ISBN: 1839627964
Category : Medical
Languages : en
Pages : 176

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‘Connectivity and Functional Specialization in the Brain’ is a topic that describes nerve cells in terms of their anatomical and functional connections. The term connectome refers to a comprehensive map of neural connections, like a wiring diagram of an organism’s nervous system. Connectomics, the study of connectomes, can be applied to individual neurons and their synaptic connections, as well as to connections between neuronal populations or to functional and structural connectivity of different brain regions. This book addresses neural connectivity at these various scales in health and disease. The chapters review novel findings related to neuroanatomy and cell biology, neurophysiology, neural plasticity, changes of connectivity in neurological disorders, and sensory system connectivity. The book provides the reader with an overview of the current state-of-the-art of research of neural connectivity and focuses on the most important evidence-based developments in this area. Individual chapters focus on recent advances in specific areas of neural connectivity and in different brain regions. All chapters represent recent contributions to the rapidly developing field of neural connectivity.

Author: Sarah Y. Yuan
Publisher: Biota Publishing
ISBN: 1615041214
Category : Medical
Languages : en
Pages : 160

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Book Description
The vascular endothelium lining the inner surface of blood vessels serves as the first interface for circulating blood components to interact with cells of the vascular wall and surrounding extravascular tissues. In addition to regulating blood delivery and perfusion, a major function of vascular endothelia, especially those in exchange microvessels (capillaries and postcapillary venules), is to provide a semipermeable barrier that controls blood–tissue exchange of fluids, nutrients, and metabolic wastes while preventing pathogens or harmful materials in the circulation from entering into tissues. During host defense against infection or tissue injury, endothelial barrier dysfunction occurs as a consequence as well as cause of inflammatory responses. Plasma leakage disturbs fluid homeostasis and impairs tissue oxygenation, a pathophysiological process contributing to multiple organ dysfunction associated with trauma, infection, metabolic disorder, and other forms of disease. In this book, we provide an updated overview of microvascular endothelial barrier structure and function in health and disease. The discussion is initiated with the basic physiological principles of fluid and solute transport across microvascular endothelium, followed by detailed information on endothelial cell–cell and cell–matrix interactions and the experimental techniques that are employed to measure endothelial permeability. Further discussion focuses on the signaling and molecular mechanisms of endothelial barrier responses to various stimulations or drugs, as well as their relevance to several common clinical conditions. Taken together, this book provides a comprehensive analysis of microvascular endothelial cell and molecular pathophysiology. Such information will assist scientists and clinicians in advanced basic and clinical research for improved health care.