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Author: Helga Eveline de Vries
Publisher:
ISBN: 9789074538060
Category :
Languages : en
Pages : 189
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Book Description
Author: Helga Eveline de Vries
Publisher:
ISBN: 9789074538060
Category :
Languages : en
Pages : 189
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Book Description
Author: Gert Fricker
Publisher: Springer
ISBN: 3662437872
Category : Science
Languages : en
Pages : 169
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Book Description
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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Book Description
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: Roy Bicknell
Publisher: Cambridge University Press
ISBN: 9780521559904
Category : Science
Languages : en
Pages : 156
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Book Description
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: Leon Smyth
Publisher:
ISBN:
Category :
Languages : en
Pages : 466
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Book Description
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: D. Neil Granger
Publisher: Morgan & Claypool Publishers
ISBN: 1615041656
Category : Medical
Languages : en
Pages : 99
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Book Description
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: Allan Siegel
Publisher: Springer Science & Business Media
ISBN: 0387848517
Category : Medical
Languages : en
Pages : 437
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Book Description
For many years, the immune and central nervous systems were thought to function independently with little or no interaction between the two. This view has und- gone dramatic changes over the past three decades. Indeed, we now know that there exists various feedback loops between the brain and immune systems that impact signi cantly upon different behavioral processes, including normal behavior and mental disorders. Pioneering efforts in generating this change were initiated by a number of early investigators. Included were those whose efforts were directed at establishing neuroimmune connections as well as others whose research focused upon the relationship between immunity, cytokines, and behavior. This book brings together outstanding scientists and clinicians who have made major contributions to the rapidly developing eld investigating the relationship between immunity and behavior. The book is divided into three parts. The rst part describes pathways by which the brain and immune systems communicate and int- act with each other. In the chapter “Cytokines and the Blood–Brain Barrier” p- vides insight into interactions between the blood–brain barrier and cytokines. Such interactions underlie basic communication between the immune system and brain that are present in normal as well as in disease conditions. In the chapter “Neu- chemical and Endocrine Responses to Immune Activation: The Role of Cytokines,” the neurochemical and endocrine consequences of immune challenge and cytokine administration on central neurotransmitter activity are discussed.
Author: Keith D. Rochfort
Publisher:
ISBN:
Category :
Languages : en
Pages : 364
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Book Description
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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Book Description
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: Ulrich Dirnagl
Publisher: Springer Science & Business Media
ISBN: 3662054264
Category : Medical
Languages : en
Pages : 248
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Book Description
The successful treatment of acute stroke remains one of the major challenges in clinical medicine. Over the last decades, the understanding of stroke pathophysiology has greatly improved, while the therapeutic options in stroke therapy remain very limited. Today, hyperacute mechanisms of damage, such as excitotoxicity, can be discriminated from delayed ones, such as inflammation and apoptosis. Targeting of inflammation has already been successfully applied in various stroke models, but translation into a clinically efficacious strategy has not been achieved so far. In this book, leading experts in basic cerebrovascular research as well as stroke treatment review the current evidence for and against an important role for inflammation in stroke, and explore the potential of treating or modulating inflammation in stroke therapy.
