Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways

Ashwinkumar Subramenium Ganapathy; Kushal Saha; Alexandra Wang; Priya Arumugam; Viszwapriya Dharmaprakash; Gregory Yochum; Walter Koltun; Meghali Nighot; Gary Perdew; Todd A. Thompson; Thomas Ma; Prashant Nighot

Cell Reports (Jul 2023)

Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways

Ashwinkumar Subramenium Ganapathy,
Kushal Saha,
Alexandra Wang,
Priya Arumugam,
Viszwapriya Dharmaprakash,
Gregory Yochum,
Walter Koltun,
Meghali Nighot,
Gary Perdew,
Todd A. Thompson,
Thomas Ma,
Prashant Nighot

Affiliations

Ashwinkumar Subramenium Ganapathy: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Kushal Saha: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Alexandra Wang: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Priya Arumugam: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Viszwapriya Dharmaprakash: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Gregory Yochum: Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Walter Koltun: Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Meghali Nighot: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Gary Perdew: Department of Veterinary and Biomedical Sciences and the Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA 16802, USA
Todd A. Thompson: University of New Mexico College of Pharmacy, Albuquerque, NM 87131, USA
Thomas Ma: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA
Prashant Nighot: Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA 17033, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 7
p. 112705

Abstract

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Summary: Defects in intestinal epithelial tight junctions (TJs) allow paracellular permeation of noxious luminal antigens and are important pathogenic factors in inflammatory bowel disease (IBD). We show that alpha-tocopherylquinone (TQ), a quinone-structured oxidation product of vitamin E, consistently enhances the intestinal TJ barrier by increasing barrier-forming claudin-3 (CLDN3) and reducing channel-forming CLDN2 in Caco-2 cell monolayers (in vitro), mouse models (in vivo), and surgically resected human colons (ex vivo). TQ reduces colonic permeability and ameliorates colitis symptoms in multiple colitis models. TQ, bifunctionally, activates both aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Genetic deletion studies reveal that TQ-induced AhR activation transcriptionally increases CLDN3 via xenobiotic response element (XRE) in the CLDN3 promoter. Conversely, TQ suppresses CLDN2 expression via Nrf2-mediated STAT3 inhibition. TQ offers a naturally occurring, non-toxic intervention for enhancement of the intestinal TJ barrier and adjunct therapeutics to treat intestinal inflammation.

CP: Cell biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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