Abstract
(1) Background: The present study aimed to investigate whether beneficial effects of protocatechuic acid (PCA) are associated with inhibition of the SphK/S1P axis and related signaling pathways in a 2,4,6-trinitrobenzenesulfonic acid (TNBS) model of inflammatory bowel disease; (2) Methods: Colitis was induced in male Balb/c mice by intracolonic administration of 2 mg of TNBS. PCA (30 or 60 mg/kg body wt) was given intraperitoneally daily for five days; (3) Results: Administration of PCA prevented the macroscopic and microscopic damage to the colonic mucosa, the decrease in body weight gain and the increase in myeloperoxidase activity induced by TNBS. PCA-treated mice exhibited a lower oxidized/reduced glutathione ratio, increased expression of antioxidant enzymes and Nrf2 and reduced expression of proinflammatory cytokines. Following TNBS treatment mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production and expression of S1P receptor 1 and S1P phosphatase 2 were significantly elevated. However, there was a decreased expression of S1P lyase. Furthermore, TNBS-treated mice exhibited increased phosphorylation of AKT and ERK, and a higher expression of pSTAT3 and the NF-κB p65 subunit. PCA administration significantly prevented those changes; (4) Conclusions: Data obtained suggest a contribution of the SphK/S1P system and related signaling pathways to the anti-inflammatory effect of PCA.
Highlights
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder encompassing ulcerative colitis and Crohn’s disease
Severe macroscopic damage of the colon was observed at day five after trinitrobenzenesulfonic acid (TNBS) rectal administration, the macroscopic damage was significantly lower in mice received protocatechuic acid (PCA) at both doses reducing the presence of mucosal edema and hemorrhagic ulcerations
The histopathological features of TNBS-treated mice included crypt destruction and submucosal edema characterized by inflammatory cell infiltration in mucosa and submucosa
Summary
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder encompassing ulcerative colitis and Crohn’s disease. Immunologic reactions promote release of different pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α. These mediators initiate pathways that activate key inflammatory transcription factors, including nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription (STAT), resulting in the chronic tissue inflammation that characterizes human IBD [2]. Different studies have shown that both SphK and S1P are upregulated in colonic tissues and S1P modulation shows effectiveness for alleviating multiple aspects of chronic intestinal inflammation [5,6]. Targeting S1P signaling may represent a novel strategy in treating IBD
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