Honokiol Ameliorates DSS-Induced Mouse Colitis by Inhibiting Inflammation and Oxidative Stress and Improving the Intestinal Barrier

Abstract

Ulcerative colitis (UC) is a multifactor intestinal disease with increased morbidity. Recently, pleiotropic drugs with exact biosafety have been urgently needed. Honokiol (HKL) is the major bioactive component of traditional Chinese medicine “Houpu,” with almost no toxic effects and approved anti-inflammation, antioxidant, antispasmodic, etc. effects. This study examined the therapeutic effect of HKL in dextran sulfate sodium- (DSS-) induced experimental colitis. In vivo, C57BL/6 mice received 3% DSS for seven days to generate UC, and HKL was pretreated for five days and given during the whole DSS-induced period. In vitro, RAW264.7 macrophages were stimulated with lipopolysaccharide (LPS) to induce inflammation, and mouse colon epithelial cells (MCEC) were treated with HKL or pretreated with HKL and then stimulated with LPS-induced macrophage supernate to investigate the barrier enhancement roles. HKL significantly ameliorated disease activity index (DAI), colon length, and histopathological scores in DSS-induced colitis. The inflammatory mediators of interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX2) were decreased, and the tight conjunction proteins were increased in the HKL-treated group both in vivo and in vitro. Above all, HKL can relieve experimental UC through anti-inflammation, antioxidant, and epithelial barrier enhancement roles. These effects were associated with peroxisome proliferator-activated receptor γ (PPARγ)/nuclear factor-κB (NF-κB) p65, sirtuin3 (SIRT3)/adenosine 5 ′ -monophosphate- (AMP-) activated protein kinase (AMPK), and nuclear factor erythroid 2-related factor 2 (NRF2)/heme oxygenase 1 (HO1) signaling pathways. In conclusion, after further clinical studies, HKL may be a promising drug for UC.

Endoplasmic reticulum stress related genome-wide Mendelian randomization identifies therapeutic genes for ulcerative colitis and Crohn’s disease

“…The activated PERK promotes Nrf2 phosphorylation and transcription ( Cullinan et al, 2003 ). Activation of the Nrf2 pathway is known to help maintain the integrity of the intestinal epithelial barrier, involving mechanisms such as Zonula Occludens-1, claudin and MUC2 ( Wen et al, 2019 ; Yuan et al, 2019 ; Wang and Wang, 2022 ). Interestingly, there seems to be a cycle, as activated Nrf2 increases GPX1 and GSH expression to improve cellular stress resistance ( Yin et al, 2015 ; Chen et al, 2019 ; Liang et al, 2021 ).…”

The role of Nrf2 in the pathogenesis and treatment of ulcerative colitis

“…Current research confirms the indispensable involvement of Nrf2 in preventing UC. Activation of Nrf2 in animal models of UC exerts a regulatory effect on the expression of tight junction proteins located in the intestinal epithelium, specifically Zonula Occludens-1 (ZO-1) and claudin, thus safeguarding the integrity of the gut barrier (85)(86)(87). In DSS-induced mouse colitis models, tight junction protein expression was significantly lower than in the control group, resulting in increased intestinal permeability (88,89).…”