Hirsutenone reduces deterioration of tight junction proteins through EGFR/Akt and ERK1/2 pathway both converging to HO-1 induction.
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.
Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Jeonbuk, South Korea.
Geom Seog
GS
Seo
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, South Korea; BK21Plus Program & Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Iksan, Jeonbuk, South Korea.
Wen-Yi
WY
Jiang
College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, South Korea.
Pil-Hoon
PH
Park
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, South Korea.
Dong Hwan
DH
Sohn
Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea; Avison Biomedical Research Center, Yonsei University College of Medicine, Seoul, South Korea. Electronic address: geniushee@yuhs.ac.
Jae Hee
JH
Cheon
Institute of Pharmaceutical Research and Development, College of Pharmacy, Wonkwang University, Iksan, Jeonbuk, South Korea; BK21Plus Program & Department of Smart Life-Care Convergence, Wonkwang University Graduate School, Iksan, Jeonbuk, South Korea. Electronic address: gsseo@wku.ac.kr.
Sung Hee
SH
Lee
D000818:Animals; D018938:Caco-2 Cells; D002396:Catechols / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D036381:Diarylheptanoids / Q000494:pharmacology*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics* / Q000378:metabolism; D062793:Occludin / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D062725:Tight Junction Proteins / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid; D062826:Zonula Occludens-1 Protein / Q000235:genetics / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000494:pharmacology
D002396:Catechols; D036381:Diarylheptanoids; D062793:Occludin; C568986:Ocln protein, mouse; D012333:RNA, Messenger; D062725:Tight Junction Proteins; D062826:Zonula Occludens-1 Protein; C508777:hirsutenone; D014302:Trinitrobenzenesulfonic Acid; D020122:tert-Butylhydroperoxide; D051547:Heme Oxygenase-1; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3
Epidermal growth factor receptor; Heme oxygenase-1; Hirsutenone; Inflammatory bowel diseases; Tight junction