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The long-term goal of this study is to develop mode of treatment for inflammation in the oral cavity. To this end, we sought to investigate both (1) the mechanism regulating the integrity of the mucosal barrier, as well as (2) the epigenetic mechanisms by which inflammatory response is elicited and regulated. Epithelial tissue serves as an important barrier against infection. In response to physical injury or infection, this tissue undergoes significant phenotypic changes for eliciting its barrier function. For example, epithelial cells, major components of epithelial tissue, upregulate the expression of TGF- when the tissue is encountered by inflammation or injury in the human oral cavity. TGF- induces cellular proliferation and differentiation, and also initiates a reversible process known as epithelial-mesenchymal transition (EMT) for wound healing processes. During EMT, epithelial cells exhibit phenotypic changes, loss of cell-cell adhesion, enhanced migratory capacity, and disruption of epithelial integrity. We have demonstrated that transcription factors Grainyhead-like 2 (GRHL2) and p63 regulate epithelial proliferation and differentiation, and may regulate EMT in human keratinocytes. Thus, to explore the molecular mechanism of TGF- -dependent EMT, we investigated the effects of p63 and Grainyhead-like 2 (GRHL2) modulation on epithelial plasticity. We found that TGF- leads to downregulation of GRHL2 and p63 expression, and facilitation of EMT molecular phenotype. Knockdown of all p63 isoforms by transfection of p63 Si-RNA was sufficient to induce EMT phenotype in normal human keratinocytes (NHK), and EMT in NHK accompanied loss of GHRL2 and miR-200 family gene expression, both of which play crucial roles in determining epithelial phenotype. Modulation of GRHL2 in NHK also led to congruent changes in p63 expression. Lastly, conditional knockout of GRHL2 resulted in significant phenotypic changes affecting the epithelial barrier and led to enhanced Porphyromonas gingvalis (P.g.) bacterial load within the bloodstream. These findings indicate that GRHL2 and p63 play an important role in inhibiting TGF- -dependent EMT in epithelial cells, and that loss of GRHL2 expression induces phenotypic changes altering epithelial barrier function and facilitates accumulation of P.g. bacteria in the bloodstream. These bacteria are known to release lipoglycan endotoxin lipopolysaccharide (LPS) that triggers the expression of pro-inflammatory cytokines. Although previous literature has identified an association between dynamic demethylation of distinct histone marks and cytokine transcriptional activation, the role of histone lysine demethylases in the epigenetic regulation of inflammatory response is not well understood. Thus, to explore the epigenetic regulation of P.g. lipopolysaccharide (P.g. LPS) induced inflammatory response, we discovered a novel histone lysine demethylase KDM3C that regulates pro-inflammatory cytokine induction and inflammatory response. We found that P.g. LPS culture led to KDM3C upregulation and enrichment on the promoter regions of several inflammatory cytokines, driving their transcriptional activation by demethylating H3K9me2. Overexpression of histone methyltransferase G9a maintained the H3K9me2 repressive mark and prevented inflammatory cytokine induction. Knockout of KDM3C also prevented induction of inflammatory signaling molecules, including pro-inflammatory cytokines, by P.g. LPS. These findings indicate that KDM3C plays an important functional role in the epigenetic regulation of inflammatory response. Collectively, these data demonstrate the effect that injury or infection in the oral cavity can have on epithelial integrity and resistance against pathogenic bacteria, and the epigenetic mechanisms that trigger the inflammatory response to these bacteria. As a result, we have identified the potential of KDM3C as novel anti-inflammatory therapeutic target, and our understanding of the mechanisms regulating epithelial barrier function and inflammatory response will be useful in the management and treatment of inflammatory diseases affecting oral tissues.
Advances in Stem Cells and Their Niches addresses stem cells during development, homeostasis, and disease/injury of the respective organs, presenting new developments in the field, including new data on disease and clinical applications. Video content illustrates such areas as protocols, transplantation techniques, and work with mice. Explores not only reviews of research, but also shares methods, protocols, and transplantation techniques Contains video content to illustrate such areas as protocols, transplantation techniques, and work with mice Each volume concentrates on one organ, making this a unique publication
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.
This book provides readers with an up-to-date and comprehensive view on the resolution of inflammation and on new developments in this area, including pro-resolution mediators, apoptosis, macrophage clearance of apoptotic cells, possible novel drug developments.
New updated edition first published with Cambridge University Press. This new edition includes 29 chapters on topics as diverse as pathophysiology of atherosclerosis, vascular haemodynamics, haemostasis, thrombophilia and post-amputation pain syndromes.
This book offers a comprehensive study of C-reactive protein (CRP) belonging to the pentraxin family, including a brief history of CRP, its structure, synthesis and evolution. Focusing on the emerging role of CRP and its clinical application in the field of disease biology, it details the pathophysiological role of CRP in a host of diseases such as cardiovascular disease, diabetes, cancers, rheumatoid arthritis and infectious diseases and others. It also discusses the role of innate immunity and acute phase response (APR) and their key mediators in the host body in response to tissue injury, infection, trauma or surgery, immunological disorders or neoplastic growth. CRP’s significance in inflammation is highlighted, and its importance as a clinical marker in cardiovascular disease, its functional significance in Leishmania and Plasmodium infections, its association with the development of insulin resistance in type 2 diabetes mellitus, and its role in cancer are discussed in detail. The book also includes clinical data studies and presents the latest research advances to further readers’ understanding of CRP.
The enteric nervous system (ENS) is a complex neural network embedded in the gut wall that orchestrates the reflex behaviors of the intestine. The ENS is often referred to as the “little brain” in the gut because the ENS is more similar in size, complexity and autonomy to the central nervous system (CNS) than other components of the autonomic nervous system. Like the brain, the ENS is composed of neurons that are surrounded by glial cells. Enteric glia are a unique type of peripheral glia that are similar to astrocytes of the CNS. Yet enteric glial cells also differ from astrocytes in many important ways. The roles of enteric glial cell populations in the gut are beginning to come to light and recent evidence implicates enteric glia in almost every aspect of gastrointestinal physiology and pathophysiology. However, elucidating the exact mechanisms by which enteric glia influence gastrointestinal physiology and identifying how those roles are altered during gastrointestinal pathophysiology remain areas of intense research. The purpose of this e-book is to provide an introduction to enteric glial cells and to act as a resource for ongoing studies on this fascinating population of glia. Table of Contents: Introduction / A Historical Perspective on Enteric Glia / Enteric Glia: The Astroglia of the Gut / Molecular Composition of Enteric Glia / Development of Enteric Glia / Functional Roles of Enteric Glia / Enteric Glia and Disease Processes in the Gut / Concluding Remarks / References / Author Biography
As the number of patients with colitis-associated cancer (CAC) is on the increase, the purpose of this book is to review the latest topics concerning management of the disease. In recent years, the diagnostic power of endoscopy and molecular pathology has also grown tremendously, as a result of which they now have a far greater influence on the treatment of CAC. At the moment, appropriate monitoring programs for ulcerative colitis and Crohn’s disease remain uncertain. At the same time, the latest findings on DNA methylation and microRNAs hold the promise of making revolutionary changes in these areas. Moreover, recent drug advances in the treatment of inflammatory bowel diseases have changed surgical indications. On the other hand, the indication of mucosectomy on colorectal cancer in ulcerative colitis and prophylactic abdominoperineal resection for Crohn’s disease remain controversial. This book provides the latest information on the remaining issues of CAC from the point of view of expert surgeons.
Arrest chemokines are a small group of chemokines that promote leukocyte arrest from rolling by triggering rapid integrin activation. Arrest chemokines have been described for neutrophils, monocytes, eosinophils, naïve lymphocytes and effector memory T cells. Most arrest chemokines are immobilized on the endothelial surface by binding to heparin sulfate proteoglycans. Whether soluble chemokines can promote integrin activation and arrest is controversial (Alon-Gerszten). Many aspects of the signaling pathway from the GPCR chemokine receptor to integrin activation are the subject of active investigation. Leukocyte adhesion deficiency III is a human disease in which chemokine-triggered integrin activation is defective because of a mutation in the cytoskeletal protein kindlin-3. About 10 different such mutations have been described. The defects seen in patients with LAD-III elucidate the importance of rapid integrin activation for host defense in humans. We welcome reports that help clarifying this crucial first step in the process of leukocyte transendothelial migration.