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  1. Article ; Online: RNA Polymerase II Transcription Attenuation at the Yeast DNA Repair Gene,

    Whalen, Courtney / Tuohy, Christine / Tallo, Thomas / Kaufman, James W / Moore, Claire / Kuehner, Jason N

    G3 (Bethesda, Md.)

    2018  Volume 8, Issue 6, Page(s) 2043–2058

    Abstract: Termination of RNA Polymerase II (Pol II) activity serves a vital cellular role by separating ubiquitous transcription units and influencing RNA fate and function. In the ... ...

    Abstract Termination of RNA Polymerase II (Pol II) activity serves a vital cellular role by separating ubiquitous transcription units and influencing RNA fate and function. In the yeast
    MeSH term(s) Base Sequence ; Chromosomal Proteins, Non-Histone/genetics ; Chromosomal Proteins, Non-Histone/metabolism ; Codon/genetics ; DNA Helicases/metabolism ; DNA Repair/genetics ; Genes, Reporter ; Mutation/genetics ; Open Reading Frames/genetics ; Plasmids/metabolism ; Polyadenylation/genetics ; Promoter Regions, Genetic/genetics ; RNA Helicases/metabolism ; RNA Polymerase II/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Transcription Termination, Genetic ; Transcription, Genetic
    Chemical Substances Chromosomal Proteins, Non-Histone ; Codon ; DEF1 protein, S cerevisiae ; RNA, Messenger ; Saccharomyces cerevisiae Proteins ; RNA Polymerase II (EC 2.7.7.-) ; SEN1 protein, S cerevisiae (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; RNA Helicases (EC 3.6.4.13)
    Language English
    Publishing date 2018-05-31
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2629978-1
    ISSN 2160-1836 ; 2160-1836
    ISSN (online) 2160-1836
    ISSN 2160-1836
    DOI 10.1534/g3.118.200072
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Gut microbiota regulation of P-glycoprotein in the intestinal epithelium in maintenance of homeostasis.

    Foley, Sage E / Tuohy, Christine / Dunford, Merran / Grey, Michael J / De Luca, Heidi / Cawley, Caitlin / Szabady, Rose L / Maldonado-Contreras, Ana / Houghton, Jean Marie / Ward, Doyle V / Mrsny, Randall J / McCormick, Beth A

    Microbiome

    2021  Volume 9, Issue 1, Page(s) 183

    Abstract: Background: P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical ... ...

    Abstract Background: P-glycoprotein (P-gp) plays a critical role in protection of the intestinal epithelia by mediating efflux of drugs/xenobiotics from the intestinal mucosa into the gut lumen. Recent studies bring to light that P-gp also confers a critical link in communication between intestinal mucosal barrier function and the innate immune system. Yet, despite knowledge for over 10 years that P-gp plays a central role in gastrointestinal homeostasis, the precise molecular mechanism that controls its functional expression and regulation remains unclear. Here, we assessed how the intestinal microbiome drives P-gp expression and function.
    Results: We have identified a "functional core" microbiome of the intestinal gut community, specifically genera within the Clostridia and Bacilli classes, that is necessary and sufficient for P-gp induction in the intestinal epithelium in mouse models. Metagenomic analysis of this core microbial community revealed that short-chain fatty acid and secondary bile acid production positively associate with P-gp expression. We have further shown these two classes of microbiota-derived metabolites synergistically upregulate P-gp expression and function in vitro and in vivo. Moreover, in patients suffering from ulcerative colitis (UC), we find diminished P-gp expression coupled to the reduction of epithelial-derived anti-inflammatory endocannabinoids and luminal content (e.g., microbes or their metabolites) with a reduced capability to induce P-gp expression.
    Conclusion: Overall, by means of both in vitro and in vivo studies as well as human subject sample analysis, we identify a mechanistic link between cooperative functional outputs of the complex microbial community and modulation of P-gp, an epithelial component, that functions to suppress overactive inflammation to maintain intestinal homeostasis. Hence, our data support a new cross-talk paradigm in microbiome regulation of mucosal inflammation. Video abstract.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Animals ; Gastrointestinal Microbiome/genetics ; Homeostasis ; Humans ; Intestinal Mucosa ; Mice
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1
    Language English
    Publishing date 2021-09-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Video-Audio Media
    ZDB-ID 2697425-3
    ISSN 2049-2618 ; 2049-2618
    ISSN (online) 2049-2618
    ISSN 2049-2618
    DOI 10.1186/s40168-021-01137-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Intestinal P-glycoprotein exports endocannabinoids to prevent inflammation and maintain homeostasis.

    Szabady, Rose L / Louissaint, Christopher / Lubben, Anneke / Xie, Bailu / Reeksting, Shaun / Tuohy, Christine / Demma, Zachary / Foley, Sage E / Faherty, Christina S / Llanos-Chea, Alejandro / Olive, Andrew J / Mrsny, Randall J / McCormick, Beth A

    The Journal of clinical investigation

    2018  Volume 128, Issue 9, Page(s) 4044–4056

    Abstract: Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from ...

    Abstract Neutrophil influx into the intestinal lumen is a critical response to infectious agents, but is also associated with severe intestinal damage observed in idiopathic inflammatory bowel disease. The chemoattractant hepoxilin A3, an eicosanoid secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2), mediates this neutrophil influx. Information about a possible counterbalance pathway that could signal the lack of or resolution of an apical inflammatory signal, however, has yet to be described. We now report a system with such hallmarks. Specifically, we identify endocannabinoids as the first known endogenous substrates of the apically restricted multidrug resistance transporter P-glycoprotein (P-gp) and reveal a mechanism, which we believe is novel, for endocannabinoid secretion into the intestinal lumen. Knockdown or inhibition of P-gp reduced luminal secretion levels of N-acyl ethanolamine-type endocannabinoids, which correlated with increased neutrophil transmigration in vitro and in vivo. Additionally, loss of CB2, the peripheral cannabinoid receptor, led to increased pathology and neutrophil influx in models of acute intestinal inflammation. These results define a key role for epithelial cells in balancing the constitutive secretion of antiinflammatory lipids with the stimulated secretion of proinflammatory lipids via surface efflux pumps in order to control neutrophil infiltration into the intestinal lumen and maintain homeostasis in the healthy intestine.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/deficiency ; ATP Binding Cassette Transporter, Subfamily B/genetics ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Animals ; Biological Transport, Active ; Cell Line ; Disease Models, Animal ; Endocannabinoids/metabolism ; Female ; Homeostasis ; Humans ; Inflammatory Bowel Diseases/metabolism ; Inflammatory Bowel Diseases/pathology ; Inflammatory Bowel Diseases/prevention & control ; Intestinal Mucosa/cytology ; Intestinal Mucosa/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Biological ; Multidrug Resistance-Associated Proteins/metabolism ; Neutrophil Infiltration/physiology ; Receptor, Cannabinoid, CB2/deficiency ; Receptor, Cannabinoid, CB2/genetics ; Receptor, Cannabinoid, CB2/metabolism ; Signal Transduction
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Endocannabinoids ; Multidrug Resistance-Associated Proteins ; Receptor, Cannabinoid, CB2 ; multidrug resistance-associated protein 2 (4AF605U6JN) ; multidrug resistance protein 3 (9EI49ZU76O)
    Language English
    Publishing date 2018-08-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI96817
    Database MEDical Literature Analysis and Retrieval System OnLINE

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