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Modulation Of The Aryl Hydrocarbon Receptor By Endogenous And Exogenous Ligands
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Book Synopsis Modulation of the Aryl Hydrocarbon Receptor by Endogenous and Exogenous Ligands by : Ashley Joan Parks
Download or read book Modulation of the Aryl Hydrocarbon Receptor by Endogenous and Exogenous Ligands written by Ashley Joan Parks and published by . This book was released on 2013 with total page 350 pages. Available in PDF, EPUB and Kindle. Book excerpt: Abstract: This year it is estimated that over 34,000 American women will be diagnosed with triple-negative breast cancer (TNBC), an aggressive disease resistant to current targeted therapies. Consequently, development of new therapeutics that can be used to combat TNBC is an area of intense medical research.The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates many biological processes. Dysregulation of normal AhR expression and function is observed in breast cancers and promotes tumor growth. It is likely that AhR activation is involved in many steps of mammary tumor progression; however, the endogenous AhR ligand(s) driving these functions in mammary tissue remains a mystery.Here, we surveyed tryptophan metabolites to identify endogenous AhR agonists in mammary epithelial cells. Several metabolites, including 6-formylindolo[3,2-b]carbazole (FICZ), xanthurenic acid, indoxyl sulfate and kynurenic acid were found to activate the AhR in a mammary epithelial cell line and to bind directly to human AhR. Untargeted metabolomic studies identified indoxyl sulfate in cell extracts and strongly suggested that serum added to cultures is its source. The common presence of an efficacious AhR agonist in human sera and in serum used in our studies suggests the intriguing possibility that AhR activity in vivo is controlled, at least in part, by production of this bacteria-derived metabolite, potentially linking the microbiome to AhR-mediated mammalian cell function.Given the potential role of the AhR in mammary tumorigenesis, we sought to develop a new method for high throughput identification of novel AhR modulators for therapeutic applications. By screening of structure-guided chemical libraries, we identified CB7993113 as a pure, competitive AhR antagonist. In vivo, CB7993113 inhibited the acute toxicity associated with exposure to 7,12-dimethylbenz[a]anthracene, a prototypic AhR agonist. Additionally, CB7950998 was discovered to be a non-toxic AhR agonist that is able to decrease cell proliferation in human ER - breast cancer cells. These results are the first steps in the preclinical investigation for these AhR modulators.These studies advance the understanding of the endogenous agonists that drive endogenous AhR activation in mammary cells, and present two novel exogenous AhR ligands to be investigated for their therapeutic potential through modulation of AhR activity.
Author :Monica Antenos Publisher :National Library of Canada = Bibliothèque nationale du Canada ISBN 13 :9780612916548 Total Pages :430 pages Book Rating :4.9/5 (165 download)
Book Synopsis Molecular Identification of Novel Aryl Hydrocarbon Receptor Modulators [microform] by : Monica Antenos
Download or read book Molecular Identification of Novel Aryl Hydrocarbon Receptor Modulators [microform] written by Monica Antenos and published by National Library of Canada = Bibliothèque nationale du Canada. This book was released on 2004 with total page 430 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Aryl hydrocarbon Receptor (AhR) is a ligand dependent basic helix-loop-helix Per-ARNT-Sim transcription factor that regulates the expression of genes in a wide range of species and tissues. The best-characterized AhR ligands are environmental contaminants, which include polycyclic and halogenated aromatic hydrocarbons (dioxin). The molecular mechanism of AhR signaling has been extensively investigated in the induction of drug metabolizing enzymes. However, the involvement of AhR in biological processes remains obscure. The objective of this thesis was to identify novel endogenous modulators that may influence the mechanism of AhR action. Competitive binding assays performed with a panel of the most frequent oxysterols in blood revealed that 7-ketocholesterol displaced radiolabeled-dioxin from AhR. The search for additional partners of AhR was further pursued using a yeast two-hybrid screen where Nedd8 and Ubc9 were identified as potential AhR-interacting proteins. Initially the three novel, yet distinct modulators were validated for their independent interaction with AhR. Each modulator was found within an AhR multi-protein complex; however 7-ketocholesterol and Ubc9 independently functioned to attenuate the transactivational properties of the receptor, while Nedd8 augmented AhR signaling. These findings provided novel evidence for interactions between AhR and important cell signaling molecules. The molecular mechanism of AhR action within a specific cell type, organ or tissue as well as developmental stage may be dependent on the presence or absence of these specific modulators. Alteration of the AhR signaling pathway with these modulators may serve as potential therapeutic targets to inhibit the toxicity of dioxin and dioxin-like compounds. Additionally, the identification of these proteins may reveal the importance of AhR signaling in a non-toxicological context.
Book Synopsis Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor by : Troy Hubbard
Download or read book Ligand Selectivity and Evolutionary Divergence of the Human Aryl Hydrocarbon Receptor written by Troy Hubbard and published by . This book was released on 2017 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor of the basic region helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) homology super family. The AHR was first identified as the primary mediator of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity and regulator of xenobiotic metabolism. Further investigation revealed AHR possesses a promiscuous ligand binding domain (LBD) that is able to bind to an array of exogenous compounds, such as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs). Following ligand-binding, the AHR forms a functional heterodimeric transcription factor with AHR nuclear translocator (ARNT) and regulates expression of target genes via binding of dioxin response elements (DREs) within their promoters.The physiological activity of the AHR has expanded to include pivotal roles within immune regulation, mucosal barrier function, cell cycle progression, organogenesis, circadian rhythm, and cellular differentiation pathways. However, these functions often require the ligand activated form of the receptor and are known to occur in the absence of exogenous ligand. This finding led to the premise and eventual characterization of endogenous AHR ligands. The catabolism of the amino acid tryptophan by commensal microorganisms, endogenous enzymes, and radical oxidation is a known source of numerous AHR ligands.The studies presented in here build upon previously published data establishing microbial metabolism as a reservoir of endogenous ligand production. In our research we have identified the microbial tryptophan metabolite indole as a human AHR selective agonist through SAR studies and in silico modeling of AHR-ligand molecular docking. In silico molecular docking models support observations of differential indole responsiveness between species through a unique bi-molecular (2:1) binding stoichiometry that is sterically permissive within the human AHR, but not its mouse homolog. The capacity for host cells to sense microbial indole through the AHR may be paramount to the establishment of an inter-kingdom signaling pathway that affects maintenance of intestinal homeostasis.Molecular functionalities of the AHR, such as heterodimerization with ARNT and binding of DREs, are conserved among vertebrate and invertebrate species. However, ligand specificity of the AHR can vary between species. Comparative studies have shown that the human AHR displays reduced binding capacity with regard to prototypical PAH agonists when compared to rodent homologs. Such differences suggest that divergence of the AHR ligand binding domain (LBD) structure during the course of mammalian evolution facilitated interspecies variation in ligand selectivity. Here we present evidence supporting the hypothesis that selective desensitization of the human AHR to PAHs arose during speciation of Homo sapiens. Interspecies AHR analyses, through utilization of ligand binding assay, DNA binding assay, and AHR-dependent gene expression identified a single amino acid substitution (A381V) as the determinant in reduced PAH affinity exhibited by H. sapiens relative to their Homo neanderthalensis (Neanderthal) and primate counterparts. Notably, H. sapiens AHR responsiveness to endogenous ligands derived from tryptophan and indole metabolism remains unperturbed. These findings reveal that a functionally significant mutation in the AHR occurred uniquely in humans that would attenuate the response to many environmental pollutants, including chemicals present in smoke.
Book Synopsis Translational Immunotherapy of Brain Tumors by : John H. Sampson
Download or read book Translational Immunotherapy of Brain Tumors written by John H. Sampson and published by Academic Press. This book was released on 2017-02-06 with total page 406 pages. Available in PDF, EPUB and Kindle. Book excerpt: Translational Immunotherapy of Brain Tumors gives researchers and practitioners an up-to-date and comprehensive overview of the field. Chapters include adoptive immunotherapy, immunosuppression, CAR therapy of brain tumors, and dendritic cell therapy for brain tumors. Very few agents have been shown to be efficacious in the treatment of malignant gliomas. Recently, there have been a number of studies demonstrating the potential success of immunotherapy for brain tumors. Immunotherapeutics are becoming the most frequent drugs to be used in cancer therapy. These new breakthroughs, now approved by the FDA, are a part of multiple phase III international trials and ongoing research in malignant glioma, meaning that the information in this cutting-edge book will be of great importance to practitioners and researchers alike. Comprehensive overview, providing an update on immunology, translational immunotherapy, and clinical trials relating to malignant gliomas Edited by a prominent neurosurgeon with contributions by leading researchers in the field Ideal resource for researchers and practitioners interested in learning about mechanisms that use the immune system to treat brain tumors
Book Synopsis Normal and Malignant B-Cell by : Mourad Aribi
Download or read book Normal and Malignant B-Cell written by Mourad Aribi and published by BoD – Books on Demand. This book was released on 2020-02-26 with total page 163 pages. Available in PDF, EPUB and Kindle. Book excerpt: Normal and Malignant B-Cell is a collection of harmonious chapters contributed by different authors. This book sets out to describe the B-cell during different stages of ontogeny and the molecular mechanisms of its antigen receptor diversity. It also discusses the main clinical and etiopathogenic aspects when it is transformed into a malignant cell. The book will be interesting and useful for clinicians, biologists, researchers, teachers, and graduate students of both doctoral and master's degrees in the field of immunology.
Book Synopsis The Search for Endogenous Agonists of the Aryl Hydrocarbon Receptor by : Linh Nguyen (Phuang)
Download or read book The Search for Endogenous Agonists of the Aryl Hydrocarbon Receptor written by Linh Nguyen (Phuang) and published by . This book was released on 2007 with total page 232 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Download or read book Xenobiotics in Fish written by D.J. Smith and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 226 pages. Available in PDF, EPUB and Kindle. Book excerpt: Aquaculture is rapidly becoming a major source of fish protein used to meet the nutritional needs of humans. As the aquaculture industry grows, exposure of farmed fish to environmental contaminants, and the need for chemical therapeutic agents for fish, will increase. This book is designed to bring together authorities worldwide on the regulation of environmental contaminants and food chemicals and researchers investigating the metabolism and disposition of foreign chemicals (xenobiotics) in fish species.
Book Synopsis Modulation of the Aryl Hydrocarbon and Androgen Receptors by the Nuclear Receptor Coactivator 4 by : Alexandra Kollara
Download or read book Modulation of the Aryl Hydrocarbon and Androgen Receptors by the Nuclear Receptor Coactivator 4 written by Alexandra Kollara and published by . This book was released on 2007 with total page 400 pages. Available in PDF, EPUB and Kindle. Book excerpt: Coactivators are regulatory proteins that are able to modulate the transcriptional activity of multiple steroid receptors by affecting receptor downstream targets that might be involved in cancer initiation, progression and/or development. Coactivators may also be involved in crosstalk between different receptor signaling pathways due to lack of coactivator specificity for a particular receptor. Nuclear receptor coactivator 4 (NcoA4) is a steroid receptor coactivator that interacts with and increases the transcriptional activity of multiple steroid receptors including the androgen receptor (AR). In this thesis, the differential interaction of both NcoA4 isoforms with the aryl hydrocarbon receptor (AhR) and modulation of the transcriptional activity of the receptor is demonstrated. The involvement of NcoA4 in the cross-talk of these receptors is also examined as it is shown that both receptors are able to compete for NcoA4 availability. To examine the modulation of AR signaling by AhR ligands, a cell model system (PC-3(AR)) was validated. PC-3(AR) cells are shown to produce and secrete endogenous prostate specific antigen (PSA) only under androgenic stimulation and were used to examine AR signaling modulation by AhR ligands. The three AhR agonists (TCDD, BaP and DMBA) and one partial agonist (alpha-NF) examined exhibited antiandrogenic effects as evidenced by suppression of androgen-induced PSA secretion. However, this effect is not mediated directly through AR or through competition for coactivators such as NcoA4 and SRC1 availability. The NcoA4-interacting proteins (AR and AhR) are known to play a role in embryo development, therefore, the expression of NcoA4 during embryo development and organogenesis was also examined. A dynamic expression profile for NcoA4 during development, particularly in cardiac, liver and lung tissue is also demonstrated. The expression of a novel mouse NcoA4 isoform was also detected during development and in some adult tissues. The important impact of NcoA4 on AR and AhR transactivation was also examined. Overall, this study indicates that receptor and coactivator availability can alter receptor action, resulting in effects on the downstream receptor targets.
Book Synopsis Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications by : Joel Faintuch
Download or read book Microbiome and Metabolome in Diagnosis, Therapy, and other Strategic Applications written by Joel Faintuch and published by Academic Press. This book was released on 2019-01-03 with total page 506 pages. Available in PDF, EPUB and Kindle. Book excerpt: Microbiome and Metabolome in Diagnosis, Therapy, and Other Strategic Applications is the first book to simultaneously cover the microbiome and the metabolome in relevant clinical conditions. In a pioneering fashion, it addresses not only the classic intestinal environment, but also the oral, gastric, lung, skin and vaginal microbiome that is in line with the latest investigations. Nonbacterial microbiomes, such as fungi and viruses are not overlooked, and the plasma microbiome is also discussed. As plasma, brain, placenta, tumor cells, and other sterile fluids and tissues, are increasingly recognized to potentially host a microbiome, albeit a limited one, this is a timely resource. The book's editors were fortunate to have the input of renowned collaborators from nearly all continents. This is truly an international effort that brings the latest in the field to students and professionals alike. - Provides comprehensive coverage on diagnosis, therapy, pharmacotherapy and disease prevention in context of the microbiome and metabolome - Focuses on the proposed physiological or pathological conditions - Presents an up-to-date, useful reference
Book Synopsis The Role of Crosstalk Between the Aryl Hydrocarbon Receptor and Translocator Protein in Modulation of Gene Expression and Cellular Homeostasis by : Michelle Megan Steidemann
Download or read book The Role of Crosstalk Between the Aryl Hydrocarbon Receptor and Translocator Protein in Modulation of Gene Expression and Cellular Homeostasis written by Michelle Megan Steidemann and published by . This book was released on 2023 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: The complexity of biological cells requires the use of multiple proteins and pathways to maintain a level of homeostasis in changing environments. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that binds to numerous aromatic environmental pollutants, including 2,3,7,8-tetrachlorodibenzo-Σ-dioxin (TCDD). The AHR regulates the expression of a battery of genes, most notably drug metabolizing enzymes. While environmental sensing has long been the most studied activity of AHR, there has always been the assumption that AHR could have another function mediated by an endogenous ligand(s). Proposed endogenous ligands of the AHR include cholesterol-related, heme-related, and tryptophanrelated molecules. Growing evidence for AHR to be partially localized to mitochondria leads to the hypothesis that AHR could have an impact on this organelle's activity. Interestingly, another mitochondrial protein, translocator protein (TSPO) is associated with many of the putative AHR endogenous ligands. Due to the shared mitochondrial localization and ligands, the goal of this research was to determine if AHR and TSPO exhibited signaling crosstalk. Transmission electron microscopy was employed to visualize mito-AHR at a high magnification to confirm the suborganellar location. CRISPR technology was used to knock out AHR and TSPO individually in mouse cell lines; BV-2 (microglia), Hepa1c1c7 (liver), and MLE-12 (lung). The influence of AHR and TSPO was studied by treating MLE-12 cells with an AHR ligand (TCDD), TSPO ligand (PK 11195), or both and then collecting the RNA for comparison. RNA-sequencing demonstrated that loss of either AHR or TSPO altered the expression of nuclear-encoded mitochondrial genes including Micu2, which is a component of mitochondrial calcium transport. AHR and TSPO both also influenced the expression of mitochondrial-encoded genes for the electron transport system.℗
Book Synopsis 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, "dioxin"). by :
Download or read book 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, "dioxin"). written by and published by . This book was released on 1984 with total page 36 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Allergy Prevention and Exacerbation by : Carsten B. Schmidt-Weber
Download or read book Allergy Prevention and Exacerbation written by Carsten B. Schmidt-Weber and published by Springer. This book was released on 2018-01-25 with total page 251 pages. Available in PDF, EPUB and Kindle. Book excerpt: Allergy is developing into one of the most prevalent diseases affecting individuals in the very early days of life. While the cause of this epidemic is still unclear, it appears that the westernized life style is playing an important role, which includes nutrition, possibly air pollution as well as hygienic conditions. While epidemiologic studies were able to narrow down these factors, basic research discovered novel mechanisms that control the organism ́s tolerance against allergens. Particularly interesting is the role of microorganisms that colonize or infect a host and thereby cause damage and immunological activation followed by sensitization or exacerbation of already existing sensitizations. However at the same time microbial activation of the immune system can help to generate a protective immunity that prevents allergen sensitization. The current book is collecting these evidences and connects epidemiologic and clinical mechanistic knowledge. Only the synthesis of this knowledge will help to find solutions to the ongoing allergy epidemic in terms of public health activities, prevention and therapy.
Book Synopsis Investigation and Modulation of the Aryl Hydrocarbon Receptor Nuclear Translocator-dependent Signaling Mechanisms by : Kyle Andrew Jensen
Download or read book Investigation and Modulation of the Aryl Hydrocarbon Receptor Nuclear Translocator-dependent Signaling Mechanisms written by Kyle Andrew Jensen and published by . This book was released on 2006 with total page 424 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Numerical Simulations by : Lutz Angermann
Download or read book Numerical Simulations written by Lutz Angermann and published by BoD – Books on Demand. This book was released on 2010-12-30 with total page 454 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book will interest researchers, scientists, engineers and graduate students in many disciplines, who make use of mathematical modeling and computer simulation. Although it represents only a small sample of the research activity on numerical simulations, the book will certainly serve as a valuable tool for researchers interested in getting involved in this multidisciplinary field. It will be useful to encourage further experimental and theoretical researches in the above mentioned areas of numerical simulation.
Book Synopsis Immune Response Activation and Immunomodulation by : Rajeev Tyagi
Download or read book Immune Response Activation and Immunomodulation written by Rajeev Tyagi and published by BoD – Books on Demand. This book was released on 2019-04-17 with total page 180 pages. Available in PDF, EPUB and Kindle. Book excerpt: Immune Response Activation and Immunomodulation has been written to address the perceived needs of both medical school and undergraduate curricula and to take advantage of new understandings in immunology. We have tried to achieve several goals and present the most important principles governing the function of the immune system. Our fundamental objective has been to synthesize the key concepts from the vast amount of experimental data that have emerged in the rapidly advancing field of immunology. The choice of what is most important is based on what is most clearly established by experimentation, what our students find puzzling, and what explains the wonderful efficiency and economy of the immune system. Inevitably, however, such a choice will have an element of bias, and our bias is toward emphasizing the cellular interactions in immune response by limiting the description of many of the underlying biochemical and molecular mechanisms to the essential facts. This book gives an insight into the role of cytokines in activating immune response during pathogenic invasion. Immunomodulation, aryl hydrocarbons, the role of the protein defensin and nucleated cells in provoking immune response, Bcl protein/gene-based apoptotic pathways, and plant-derived phytochemical-mediated immune response are all central themes of this book.
Author :United States. Public Health Service. Office of the Surgeon General Publisher : ISBN 13 : Total Pages :728 pages Book Rating :4.:/5 (318 download)
Book Synopsis How Tobacco Smoke Causes Disease by : United States. Public Health Service. Office of the Surgeon General
Download or read book How Tobacco Smoke Causes Disease written by United States. Public Health Service. Office of the Surgeon General and published by . This book was released on 2010 with total page 728 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.
Book Synopsis Skin Stress Response Pathways by : Georg T. Wondrak
Download or read book Skin Stress Response Pathways written by Georg T. Wondrak and published by Springer. This book was released on 2016-08-22 with total page 454 pages. Available in PDF, EPUB and Kindle. Book excerpt: It is now established that the interplay between environmental exposure and molecular stress response pathways plays a critical role in skin health and disease, and a refined mechanistic understanding of this phenomenon at the molecular level promises to open new avenues for targeted therapeutic strategies that may benefit patients in the near future. Coauthored by recognized international leaders in molecular and clinical biomedical sciences, this novel book provides a comprehensive perspective on environmental exposure-induced skin stress response pathways. Focusing on molecular opportunities targeting skin stress response pathways that are involved in cutaneous barrier function and repair, antimicrobial defense, immune regulation, inflammation, and malignant progression, the book is essential reading for students, basic researchers, and biomedical health care professionals interested in skin health and disease with implications for small molecule therapeutic development.
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