Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction.

Abstract

Oxidative stress-induced disruption of epithelial tight junctions (TJ) plays a critical role in the pathogenesis of intestinal disorders, including inflammatory bowel disease (IBD). The current study investigated the protective effect of hirsutenone against disruption of the intestinal barrier in vitro and in a mouse model of colitis. Caco-2 cells were stimulated with tert-butyl hydroperoxide (t-BH). Hirsutenone prevented the t-BH-induced increase in permeability by inhibiting the reduction in zonula occludens-1 (ZO-1) expression, and rapidly stimulated tyrosine phosphorylation of the epidermal growth factor receptor (EGFR). Hirsutenone-mediated protection against the loss of ZO-1 depends on the activation of both ERK1/2 and Akt signaling pathways. Interestingly, hirsutenone-mediated activation of Akt, but not ERK1/2, signaling was EGFR-dependent. Hirsutenone increased heme oxygenase-1 (HO-1) expression through both EGFR/Akt- and ERK1/2-dependent pathways, contributing to the protective effects against TJ dysfunction. Colitis was induced in mice by intrarectal administration of 2,4,6,-trinitrobenzene sulfonic acid (TNBS). Hirsutenone administration improved the clinical parameters and tissue histological appearance, increased HO-1 expression, attenuated reduction of ZO-1 and occludin mRNA, and promoted BrdU incorporation in the colonic epithelium of TNBS-treated mice. Taken together, our results demonstrate that hirsutenone reverse disordered intestinal permeability by activating EGFR/Akt and ERK1/2 pathways, which are involved in the regulation of HO-1 expression. These findings highlight the potential of hirsutenone for clinical applications in the treatment of IBD.

• Authors: Geom Seog Seo, Wen-Yi Jiang, Pil-Hoon Park, Dong Hwan Sohn, Jae Hee Cheon, Sung Hee Lee
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 90 Issue 2 Pg. 115-25 (Jul 15 2014) ISSN: 1873-2968 [Electronic] England
• PMID: 24853984 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Catechols
• Diarylheptanoids
• Occludin
• Ocln protein, mouse
• RNA, Messenger
• Tight Junction Proteins
• Zonula Occludens-1 Protein
• hirsutenone
• Trinitrobenzenesulfonic Acid
• tert-Butylhydroperoxide
• Heme Oxygenase-1
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Caco-2 Cells
• Catechols (pharmacology)
• Colitis (chemically induced, drug therapy, genetics, pathology)
• Diarylheptanoids (pharmacology)
• Disease Models, Animal
• ErbB Receptors (genetics, metabolism)
• Gene Expression Regulation
• Heme Oxygenase-1 (biosynthesis, genetics)
• Humans
• Intestinal Mucosa (drug effects, metabolism, pathology)
• Mice
• Mitogen-Activated Protein Kinase 3 (genetics, metabolism)
• Occludin (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Tight Junction Proteins (metabolism)
• Trinitrobenzenesulfonic Acid
• Zonula Occludens-1 Protein (genetics, metabolism)
• tert-Butylhydroperoxide (pharmacology)