The Role of Acetylation in the Regulation of Antimicrobial Peptide Gene Expression in the Human Intestine PDF Download

Author: Natalie Fischer
Publisher:
ISBN:
Category :
Languages : en
Pages : 0

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Book Description
Les peptides antimicrobiens (PAMs) sont des effecteurs de l'immunité innée et exercent leur activité microbicide sur un spectre de microorganismes. Au niveau de l'intestin, leur sécrétion est directement impliquée dans les processus homéostatiques existant entre un hôte et son microbiote. Ces dernières années, plusieurs études ont démontré une corrélation entre le niveau d'expression des PAMs et la susceptibilité des individus à différentes pathologies. Les PAMs peuvent être exprimés constitutivement ou de manière inductible. Dans les deux cas, les mécanismes de régulation (épi)génétique pour contrôler leur expression sont méconnus.Le but de ces travaux de thèse a été d'étudier la composante (épi)génétique des régulations contrôlant l'expression des gènes codant les PAMs. Utilisant un modèle de cellules épithéliales intestinales humaines exposées à des molécules inhibitrices de l'activité d'enzymes modifiant la chromatine, et stimulées par la bactérie Escherichia coli, nous avons identifié l'importance du processus d'acétylation dans l'expression des ces gènes. Nous avons montré que l'inhibition des enzymes de la famille des histones déacétylases augmente significativement le niveau d'induction des gènes antimicrobiens comme la béta-défensine-2, sans impacter celui des gènes pro-inflammatoires comme l'interleukine 8. Enfin, nous avons étudié le mécanisme moléculaire sous-jacent à cette observation, notamment le rôle du facteur de transcription NF- B et celui de l'histone acétyltransférase p300. Ces travaux démontrent l'existence d'un mécanisme (épi)génétique permettant de réguler différentiellement le niveau d'induction des gènes antimicrobiens et pro-inflammatoires.

Author: Yan Campbell
Publisher:
ISBN:
Category : Bile acids
Languages : en
Pages : 124

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The human cathelicidin antimicrobial peptide (CAMP) is a broad spectrum microbicidal agent and modulator of both the innate and adaptive immune system. It is induced by 1,25-dihydroxyvitamin D (1,25(OH)2D3) through activation of the vitamin D receptor (VDR) and primary bile salts through activation of the xenobiotic nuclear receptor farnesoid X receptor (FXR). Both receptors are expressed by enterohepatic and gastrointestinal (GI) tissues and play important roles in GI immunity and homeostasis. It has been demonstrated by us and others that plant polyphenol xanthohumol (XN) acts as an FXR ligand, but its regulation of CAMP gene expression has not been determined. We hypothesize that plant polyphenols obtained in the diet act as ligands for FXR and regulate expression of the CAMP gene in the GI tract thereby promoting gastrointestinal health through improved barrier defense against infection and inflammation. In this study, we demonstrate that XN induces BSEP (bile acid export pump) and human CAMP promoter activity via FXR. This activation appears to require some combination of the vitamin D response element (VDRE) site in the CAMP promoter and a potential FXR response element (FXRE) located in the third exon of the gene. In addition, XN and its metabolite 8-prenylnaringenin (8-PN) induced the mRNA expression of several FXR target genes including: BSEP, SHP (small heterodimer partner), IBABP (ileal bile acid binding protein), CAMP and FXR in biliary carcinoma cell lines. Combinations of 1,25(OH)2D3 and either XN or 8-PN cooperatively induced endogenous CAMP gene expression in cells. We conclude that the plant polyphenol XN and its metabolite 8-PN act as FXR ligands and regulate expression of the human CAMP gene alone or in combination with 1,25(OH)2D3. A second distinct project used immunohistochesmitry (IHC), Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) to characterize a transgenic mouse that carries the human CAMP gene. In the transgenic mice fed a normal diet, the human CAMP gene is expressed in immune and epithelial barrier cells and treatment of tissues with 1,25(OH)2D3, including those from the GI tract, induced expression of the human, but not the mouse gene. This study advances our understanding of human CAMP gene regulation by FXR and also helps establish the mouse as a reliable model system that can be used in future studies to determine the importance of CAMP gene expression in human health.

Author: Chi Hin Cho
Publisher: Academic Press
ISBN: 0128143207
Category : Science
Languages : en
Pages : 188

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Book Description
Antimicrobial peptides (AMPs), including cathelicidins and defensins are host defence peptides that carry out multiple roles in the gastrointestinal (GI) tract. Antimicrobial Peptides in Gastrointestinal Diseases presents knowledge about the physiological functions and pharmacological actions of AMPs in inflammation, cancer, and further infection of the GI tract. The book provides coverage from the basic research to clinical application for GI diseases. Current research and development of AMPs is presented, opening the way for further work on these peptides, not only in the context of GI diseases, but also for similar pathologies in other organs. AMPs are key to the regulation of human microbiome and second line defence in the GI mucosa, prevent colonization of pathogens and modulation of innate response to invading pathogens, and modify immunological reactions during inflammatory processes and oncogenic development in the GI mucosa. More importantly, AMPs possess diversified anti-microbial actions against various infectious diseases in the GI tract. With these physiological functions and pharmacological actions, AMPs have significant potential as therapeutic agents for the treatment of inflammation, cancer and further infection in the GI tract. Provides an overview of AMPs, particularly cathelicidin and defensin, in different diseases Covers inflammation and ulcer repair in the stomach and colon and carcinogenesis in the GI tract Presents AMP information and knowledge in a concise manner Gives useful information on all aspects of AMPs Promotes research on AMPs and their development as drugs, from bench, to clinical application

Author: Patricia A. Castillo
Publisher:
ISBN: 9781321805703
Category :
Languages : en
Pages :

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Book Description
Intestinal epithelial cells provide a protective barrier from resident commensal microbes that reside in the lumen, as well as from pathogens that often contaminate ingested food or water. In the small intestine, Paneth cells are an epithelial cell lineage residing in the crypts of Lieberkühn that produce and store in their secretory granules high quantities of antimicrobial peptides, including [alpha]-defensins. Paneth cells release these stored antimicrobial peptides into the lumen, where they function to help shape the composition of the colonizing microbiota, as well as a defend from invading pathogens. The repertoire of [alpha]-defensins in Paneth cells varies between species. For example, humans express two Paneth cell [alpha]-defensins, human defensin (HD)-5 and HD6, where as mice express numerous [alpha]-defensins termed cryptdins (for crypt defensins). Aside from their general homoeostatic and protective roles in innate immunity, human Paneth cell [alpha]-defensins are of particular interest because of their link to small intestinal Crohn's disease. Resent investigations have implicated a reduced expression of HD5 and HD6 as a contributing factor in the pathophysiology of the chronic inflammation that characterizes Crohn's disease. In vitro studies have shown that most [alpha]-defensins, including HD5 and mouse cryptdins, kill bacteria by a mechanism that involves an initial charge interaction with the bacterial membrane (that is an attraction of the cationic peptide with anionic membrane), which then leads to pore formation through interaction of the hydrophobic residues of the peptide with the core of the bacterial membrane. An exception to this general rule is found with the [alpha]-defensin HD6, which does not kill bacteria, but rather binds to bacterial surface proteins and agglutinates the bacteria through HD6-HD6 interactions. In the human small intestine, the agglutinating activity of HD6 likely complements the antimicrobial activity of HD5 to provide effective innate immunity of this vital mucosal surface. In vivo studies using mouse models have given us great insight into the physiological functions of these molecules. Studies of mice that lack the enzyme matrix metalloproteinase 7 (matrilysin), the enzyme responsible for proteolytic processing of procryptdins into their mature forms, showed that the knockout mice were susceptible to enteric pathogens. In addition, these mice lacking mature cryptdins show a shift in the composition of their colonizing microbiota. In other models, where HD5 or HD6 were transgenically expressed in mouse Paneth cells showed that both of these human [alpha]-defensins serve important roles in host defense, but through different mechanisms. HD5 transgenic mice were protected from S. typhimurium invasion due to the direct bacterial killing by HD5 in the intestinal lumen leading to a decrease of pathogen burden. On the other hand, HD6 mice were protected by decreasing the number of S. typhimurium that invaded intestinal cells and translocation to systemic sites, through a mechanism involving the ability of HD6 to bind, self-assemble and agglutinate (not kill) bacteria. In addition, transgenic expression of HD5 in mouse Paneth cells influenced the composition of the microbiota, whereas no change in microbiota was observed in the HD6 transgenic mice. Further understanding of how Paneth cell [alpha]-defensins contribute to host defense, and elucidation of detail on their association with pathogenesis of chronic inflammation, requires more knowledge on their expression and biochemical regulation in the small intestine. This investigation was aimed to develop new tools to analyze the complex patterns of [alpha]-defensin expression in C57BL/6 mice, the most common laboratory strain of mice (Chapter 1), and to elucidate the biochemical steps important in the post-translational activation of HD6 (Chapter 2). To investigate the expression of Paneth cell [alpha]-defensins (cryptdins) along the intestinal tract in C57BL/6 mice under various experimental conditions, we developed a quantitative real time PCR (qRT-PCR) approach to determine the abundance of cryptdin-encoding Defa mRNA. For this approach, we cloned the collection of cDNAs encoding the Paneth cell cryptdins, and then used these cDNAs as external template standards with a series of Defa specific PCR primers to generate standard curves for each of the eight subgroups of Defa genes in C57BL/6 mice. Defa mRNA expression was first determined in 3 cm adjacent sections along the length of the small intestine. A difference in both the total number of Defa mRNA transcripts, and in the abundance of the eight subgroups of Defa mRNA was observed when comparing the proximal to distal segments. We next determined Defa expression in the proximal and distal segments of small intestine from several treatment groups. The data suggest that as compared to control mice, there is little or no difference in Defa mRNA expression in streptomycin-treated mice, or in mice with genetic deletions of either the Infar1 gene or with deletions of both the Nod1 and Nod2 genes. Although no differences in Defa mRNA expression in these experimental conditions, the experimental approach developed here should be valuable in future experiments aimed to identify potential genetic and environmental influences on Paneth cell [alpha]-defensin expression. Previous studies have shown that HD5 is stored in Paneth cell secretory granules as a propeptide (aa 20-94), and that a mature proteolytically cleaved HD5 (aa 63-94) is found in the lumen. Paneth cells express two isoforms of the enzyme trypsin, which are hypothesized to mediate the proteolytic processing of HD5 upon or after secretion. To our knowledge, nothing has been published on the biochemical forms of HD6 isolated from small intestinal tissue or lumen. We used human tissue biopsies and ileal fluid to determine the biochemical forms of HD6 present in these samples. Our results show that HD6 is stored in Paneth cell secretory granules as a propeptide (aa 20-100), and exists in the ileal lumen as a proteolytically cleaved mature peptide (aa 69-100). The processing site (Arg68) is consistent with proteolytic cleavage by trypsin. In vitro bacterial agglutination assays indicate that proHD6 is inactive, whereas upon trypsin cleavage the mature HD6 peptide can agglutinate both Gram-negative and Gram-positive bacteria. These data provide a clearer picture of the post-translational regulatory steps of Paneth cell [alpha]-defensin physiology.The studies reported in this dissertation advance our understanding on the expression of Paneth cell [alpha]-defensins in the small intestine. New experimental tools were developed to analyze [alpha]-defensin expression in the small intestine of the most common mouse strain used in current investigations - C57BL/6 mice. In addition, the studies reported here identified the biochemical forms of HD6 that exist in the human intestine. HD6, along with HD5, are the most abundantly expressed antimicrobial peptides of human Paneth cells. Defects in expression of HD5 and HD6 have been linked to ileal Crohn's disease and may contribute to disease pathogenesis. Therefore, advancing our understanding on how [alpha]-defensins are expressed and regulated provides further information on how they maintain homeostasis in the small intestine.

Author: Wang Jiajun
Publisher: Frontiers Media SA
ISBN: 2832502059
Category : Science
Languages : en
Pages : 189

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Author: Mark Lyte
Publisher: Springer
ISBN: 1493908979
Category : Science
Languages : en
Pages : 440

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Book Description
The field of microbial endocrinology is expressly devoted to understanding the mechanisms by which the microbiota (bacteria within the microbiome) interact with the host (“us”). This interaction is a two-way street and the driving force that governs these interactions are the neuroendocrine products of both the host and the microbiota. Chapters include neuroendocrine hormone-induced changes in gene expression and microbial endocrinology and probiotics. This is the first in a series of books dedicated to understanding how bi-directional communication between host and bacteria represents the cutting edge of translational medical research, and hopefully identifies new ways to understand the mechanisms that determine health and disease.​

Author: Naheed Mojgani
Publisher: Springer Nature
ISBN: 9811602239
Category : Science
Languages : en
Pages : 373

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Book Description
This book covers all aspects of probiotic bacteria and their metabolites, as well as their role and significance in human and animal health. Given the role of probiotic bacterial strains in the production of short chain fatty acids, butyrate etc probiotics may be considered as an alternative approach for the prevention or treatment of intestinal dysbiosis, cancers, cardiovascular diseases, hypertensions. Additionally, the significance of probiotics added in aquaculture systems for improving health, performance and growth of aquatic organisms has been highlighted. In this book, the multi-functional role of probiotics and their post-biotic metabolites in improving overall health status of man and animals, is discussed. It is a comprehensive compilation useful for researchers, academics, veterinarians and students in the field of microbiology, food technology and biotechnology.

Author: Masato Kusunoki
Publisher: Springer
ISBN: 4431555226
Category : Medical
Languages : en
Pages : 151

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Book Description
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.

Author: Marcela A. Hermoso
Publisher: Frontiers Media SA
ISBN: 2889634353
Category :
Languages : en
Pages : 222

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Author:
Publisher:
ISBN:
Category : Medicine
Languages : en
Pages : 2160

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Vols. for 1963- include as pt. 2 of the Jan. issue: Medical subject headings.