Protective Effect of Protocatechuic Acid on TNBS-Induced Colitis in Mice Is Associated with Modulation of the SphK/S1P Signaling Pathway

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.

The Effects and Mechanisms of Cyanidin-3-Glucoside and Its Phenolic Metabolites in Maintaining Intestinal Integrity

“…Rats, mice, macrophages Treatment with PCA increased T-AOC [31], catalase [33], SOD [33] and GPx [33][34][35][36] levels, but decreased ROS [35], MDA [31] and hydroperoxides [31] levels.…”

“…Anti-inflammatory Mice, macrophages PCA decreased IL-6 [33,37,39], TNF-α [33,39], IL-1β [33,39] and PGE 2 production [39], and inhibited ERK, NF-κB p65 activation [33].…”

“…PCA can increase the antioxidant capacity of cells potentially by increasing the activity of antioxidant enzymes, such as catalase (CAT) in hypertensive rats or arthritis-model rats [31,32], superoxide dismutase (SOD) [33], and glutathione peroxidase (GPx) in mice or macrophages [33][34][35][36], and thus attenuate lipid peroxidation. Meanwhile, PCA has been reported to inhibit the production of inflammatory mediators, such as interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-1β, and prostaglandin E 2 (PGE 2 ) [37][38][39], potentially by suppressing the activation of nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase (ERK) [33,38] in murine BV2 microglia cells and colitis-model mice. PGA has also shown an inhibitory effect on inflammation potentially by modulating the production of IL-1β, IL-6, and IL-10 [40] in human whole blood cultures, although there are few reports about the molecular mechanisms.…”

“…PCA, VA, and FA can suppress the production of ICAM-1, and thus, alleviate inflammatory infiltration and damage in vascular endothelial cells [52,96]. In a mouse colitis model, PCA can decrease both mRNA levels and protein concentration of Sphingosine kinases (SphK), which induces the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P), but increase the expression of S1P lyase (S1PL) which irreversibly degrade S1P, and thus, inhibit SphK/S1P pathway-mediated activation of the NF-κB pathway through S1P receptors (S1PR) [33]. The main mechanism of VA on inflammation is that it can down-regulate the MAPK pathway by suppressing the phosphorylation of ERK, JNK, and p38 [47].…”

Combination therapy of mesenchymal stromal cells and sulfasalazine attenuates trinitrobenzene sulfonic acid induced colitis in the rat: The S1P pathway

“…Several studies have reported high levels of S1P expression accompanied with dysregulated of SphKs pattern in inflammation sites, such as inflamed mouse and human intestine (Crespo et al, 2017;Karuppuchamy et al, 2017;Suh & Saba, 2015). On the other hand, SPL is highly expressed in normal intestine but downregulated in the colon of IBD and colorectal cancer patients as well as the murine experimental colitis (Crespo et al, 2017;Nielsen et al, 2017). In IBD, activation of STAT-and NF-κB-mediated pathways markedly increases the risk of malignant cell growth and tumor formation (Wollny et al, 2017).…”