KIM, MI RI Cho, Su-yeon Lee, Hee Ju Kim, Joo Yeon Nguyen, Tran Tu Uyen Ngoc Minh, Ha CHOI, KI YOUNG Cha, Kwang Hyun Kim, Jeong-Ho Kim, Won Kyu Kang, Kyungsu 2024-01-12T03:01:15Z 2024-01-12T03:01:15Z 2022-05-31 2022-08 0944-7113 https://pubs.kist.re.kr/handle/201004/76656 Background: Leaky gut symptoms and inflammatory bowel disease (IBD) are associated with damaged intestinal mucosa, intestinal permeability dysfunction by epithelial cell cytoskeleton contraction, disrupted intercellular tight junction (TJ) protein expression, and abnormal immune responses and are intractable diseases. Purpose: We evaluated the effects of schisandrin C, a dibenzocyclooctadiene lignan from Schisandra chinensis, on intestinal inflammation and permeability dysfunction in gut mimetic systems: cultured intestinal cells, intestinal organoids, and a Caenorhabditis elegans model. Methods: Schisandrin C was selected from 9 lignan compounds from S. chinensis based on its anti-inflammatory effects in HT-29 human intestinal cells. IL-113 and Pseudomonas aeruginosa supernatants were used to disrupt intestinal barrier formation in vitro and in C. elegans, respectively. The effects of schisandrin C on transepithelial electrical resistance (TEER) and intestinal permeability were evaluated in intestinal cell monolayers, and its effect on intestinal permeability dysfunction was tested in mouse intestinal organoids and C. elegans by measuring fluorescein isothiocyanate (FITC)-dextran efflux. The effect of schisandrin C on TJ protein expression was investigated by western blotting and fluorescence microscopy. The signaling pathway underlying these effects was also elucidated. Results: Schisandrin C ameliorated intestinal permeability dysfunction in three IBD model systems and enhanced epithelial barrier formation via upregulation of ZO-1 and occludin in intestinal cell monolayers and intestinal organoids. In Caco-2 cells, schisandrin C restored IL-113-mediated increases in MLCK and p-MLC expression, in turn blocking cytoskeletal contraction and subsequent intestinal permeabilization. Schisandrin C inhibited NF-KB and p38 MAPK signaling, which regulates MLCK expression and structural reorganization of the TJ complex in Caco-2 cells. Schisandrin C significantly improved abnormal FITC-dextran permeabilization in both intestinal organoids and C. elegans. English Elsevier BV Schisandrin C improves leaky gut conditions in intestinal cell monolayer, organoid, and nematode models by increasing tight junction protein expression Article 10.1016/j.phymed.2022.154209 1 Phytomedicine, v.103 Phytomedicine 103 Y scie scopus 000811864300001 Plant Sciences Chemistry, Medicinal Integrative & Complementary Medicine Pharmacology & Pharmacy Plant Sciences Pharmacology & Pharmacy Integrative & Complementary Medicine Article EPITHELIAL BARRIER IN-VITRO MITOCHONDRIAL BIOGENESIS TOPOISOMERASE INHIBITOR KINASE MECHANISM MODULATION EXTRACT ELEGANS LIGNANS Tight junction Intestinal permeability MLCK Caenorhabditis elegans Schisandrin C