Diosmetin Maintains Barrier Integrity by Reducing the Expression of ABCG2 in Colonic Epithelial Cells

Abstract

Crohn’s disease (CD) is a relapsing and chronic inflammatory bowel disease. Recent advances have highlighted that dysfunction of the barrier function formed by a polarized monolayer of columnar epithelial cells plays a crucial role in the pathophysiology of CD. At present, we reported that diosmetin increased cell viability by reducing the levels of TNFα and IL-6 in lipopolysaccharide (LPS)-treated colonic epithelial Caco-2 cells. Meanwhile, diosmetin conferred a direct effect on maintaining barrier integrity by reducing epithelial permeability and increasing the expression of proteins associated with tight junctions, including zonula occludens-l (ZO-1), occludin, and claudin-1, in LPS-treated Caco-2 cells and in 2,4,6-trinitrobenzene sulfonic acid-induced CD mice. Additionally, diosmetin decreased the protein content of adenosine triphosphate-binding cassette efflux transporter G2 (ABCG2) in vitro and in vivo. Over-expression of ABCG2 had an important impact on the epithelial permeability and barrier-related protein levels induced by LPS in Caco-2 cells. At the same time, Ko143, a specific ABCG2 inhibitor, dramatically enhanced the role of diosmetin in ZO-1 and occludin proteins in LPS-treated Caco-2 cells. Mechanically, diosmetin significantly attenuated the role of LPS in the phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (PKB/AKT), and cAMP-response element binding protein (CREB) in Caco-2 cells. The AMPK inhibitor Compound C obviously prevented the effect of diosmetin on ZO-1 and occludin expression in LPS-treated Caco-2 cells. Taken together, the results of this study suggest that AMPK/AKT/CREB-mediated ABCG2 expression plays a crucial role in diosmetin, improving the barrier dysfunction in CD.

Diosmin alleviates ulcerative colitis in mice by increasing Akkermansia muciniphila abundance, improving intestinal barrier function, and modulating the NF-κB and Nrf2 pathways

“…The initial pathological change that strengthens injury and inflammation is thought to be functional loss of epithelial cell barrier integrity, which results in the migration of luminal antigens into the submucosa, exposing lamina propria immune cells to these antigens and eliciting an inflammatory response in the intestine [ 72 ]. One of A. muciniphila 's key mechanisms is based on its regulation of the host intestinal barrier via promotion of TJ protein expression (ZO-1 and Claudin-1 mRNA) [ 73 ], thereby inhibiting the entry of intestinal bacteria-borne endotoxin into the blood and relieving chronic inflammation in vivo [ 71 ]. Several studies have found that A. muciniphila could improve intestinal barrier integrity [ 74 ].…”

Anti-Inflammatory Properties of the Citrus Flavonoid Diosmetin: An Updated Review of Experimental Models

“…It has been demonstrated that elucidating the mechanisms underlying barrier dysfunction and permeability defects has great potential in the treatment of CD [108]. Liu et al discovered that in LPS-treated colorectal adenocarcinoma (Caco-2) cells and TNBS-induced CD model mice, Dios treatment was effective in decreasing epithelial permeability and improving the expression of proteins related to barrier integrity (such as ZO-1, occludin, and claudin-1) [53]. This indicated that Dios has great potential in the treatment of CD.…”