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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-?B 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.

SUBMITTER: Crespo I

PROVIDER: S-EPMC5372951 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Crespo Irene I San-Miguel Beatriz B Mauriz José Luis JL Ortiz de Urbina Juan José JJ Almar Mar M Tuñón María Jesús MJ González-Gallego Javier J

Nutrients 20170316 3

(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 prevente ...[more]

PMID: 28300788

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Project description:The world is currently experiencing the worst health pandemic since the Spanish flu in 1918-the COVID-19 pandemic-caused by the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This pandemic is the world's third wake-up call this century. In 2003 and 2012, the world experienced two major coronavirus outbreaks, SARS-CoV-1 and Middle East Respiratory syndrome coronavirus (MERS-CoV), causing major respiratory tract infections. At present, there is neither a vaccine nor a cure for COVID-19. The severe COVID-19 symptoms of hyperinflammation, catastrophic damage to the vascular endothelium, thrombotic complications, septic shock, brain damage, acute disseminated encephalomyelitis (ADEM), and acute neurological and psychiatric complications are unprecedented. Many COVID-19 deaths result from the aftermath of hyperinflammatory complications, also referred to as the "cytokine storm syndrome", endotheliitus and blood clotting, all with the potential to cause multiorgan dysfunction. The sphingolipid rheostat plays integral roles in viral replication, activation/modulation of the immune response, and importantly in maintaining vasculature integrity, with sphingosine 1 phosphate (S1P) and its cognate receptors (SIPRs: G-protein-coupled receptors) being key factors in vascular protection against endotheliitus. Hence, modulation of sphingosine kinase (SphK), S1P, and the S1P receptor pathway may provide significant beneficial effects towards counteracting the life-threatening, acute, and chronic complications associated with SARS-CoV-2 infection. This review provides a comprehensive overview of SARS-CoV-2 infection and disease, prospective vaccines, and current treatments. We then discuss the evidence supporting the targeting of SphK/S1P and S1P receptors in the repertoire of COVID-19 therapies to control viral replication and alleviate the known and emerging acute and chronic symptoms of COVID-19. Three clinical trials using FDA-approved sphingolipid-based drugs being repurposed and evaluated to help in alleviating COVID-19 symptoms are discussed.

Project description:BackgroundThe pathogenesis of Crohn's disease (CD) is unknown; however, angiogenesis is known to play an important role in the disease. The present research suggests that microRNA-21 (miR-21) may play a positive regulatory role in disordered angiogenesis in CD.MethodsC57 wild-type mice were divided into 6 groups. On day 0, all mice in the 2,4,6-trinitrobenzenesulfonic acid (TNBS) group were given an enema at the concentration of TNBS 100 mg/kg mouse body weight (solvent 50% alcohol). In the control group, the enema was performed with 50% alcohol. On day 0, 2, 4, and 6, the mice of the agomir-21 + TNBS group and the agomir control + TNBS group were injected with 200 µL, 5 nmol agomir-21 or agomir control [dissolved in ribonuclease (RNase)-free water] by tail vein injection, while the antagomir-21 + TNBS group and the antagomir control + TNBS group were injected with 200 µL, 20 nmol antagomir-21 or antagomir control (dissolved in RNase-free water). The body weight and disease activity index (DAI) score were recorded daily. The colons were obtained to assess macro and microscopic colon damage. The inferior vena cava and the accompanying abdominal aorta were chosen to detect the protein expression of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/serine/threonine kinase (AKT)/vascular endothelial growth factor (VEGF) axis through western blotting. Serum interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The distribution and expression of neovascularization were demonstrated by cluster of differentiation 31 (CD31) immunohistochemistry.ResultsCompared with the only-TNBS group, the agomir-21 + TNBS group showed significantly severer colitis symptoms and more abnormal vascular hyperplasia, while the antagomir-21 + TNBS group showed symptom relief and reduced vascular hyperplasia. In addition, agomir-21 obviously inhibited the expression of PTEN and activated the PI3K/AKT/VEGF pathway in mice induced by TNBS, while antagomir-21 effectively antagonized this effect.ConclusionsmiR-21 can promote the progression of colitis in mice induced by TNBS and aggravate the disordered angiogenesis by regulating the PTEN/PI3K/AKT axis. Intravenous injection of miR-21 antagonists can effectively relieve the symptoms of colitis and inhibit colonic angiogenesis.

Project description:Ulcerative colitis (UC) is a chronic immune-inflammatory disorder characterized by oxido-nitrosative stress, the release of pro-inflammatory cytokines and apoptosis. Ferulic acid (FA), a phenolic compound is considered to possess potent antioxidant, anti-apoptotic and anti-inflammatory activities. The aim is to evaluate possible mechanism of action of FA against trinitrobenzensulfonic acid (TNBS) induced ulcerative colitis (UC) in rats. UC was induced in Sprague-Dawley rats (150-200 g) by intrarectal administration of TNBS (100 mg/kg). FA was administered (10, 20 and 40 mg/kg, p.o.) for 14 days after colitis was induced. Various biochemical, molecular and histological changes were assessed in the colon. Intrarectal administration of TNBS caused significant induction of ulcer in the colon with an elevation of oxido-nitrosative stress, myeloperoxidase and hydroxyproline activity in the colon. Administration of FA (20 and 40 mg/kg) significantly decrease oxido-nitrosative stress, myeloperoxidase, and hydroxyproline activities. Up-regulated mRNA expression of TNF-α, IL-1β, IL-6, COX-2, and iNOs, as well as down-regulated IL-10 mRNA expressions after TNBS administration, were significantly inhibited by FA (20 and 40 mg/kg) treatment. Flow cytometric analysis revealed that intrarectal administration of TNBS-induced significantly enhanced the colonic apoptosis whereas administration of FA (20 and 40 mg/kg) significantly restored the elevated apoptosis. FA administration also significantly restored the histopathological aberration induced by TNBS. The findings of the present study demonstrated that FA ameliorates TNBS-induced colitis via inhibition of oxido-nitrosative stress, apoptosis, proinflammatory cytokines production, and down- regulation of COX-2 synthesis.Graphical Abstract: TNBS caused activation of T cells which interact with CD40 on antigen presenting cells i.e. dendritic cells (DC) that induce the key Interleukin 12 (IL-12)-mediated Th1 T cell immune inflammatory response. It releases interferon-γ (IFN-γ), which in turn induces macrophages (MAC) to produce TNF-α and other pro-inflammatory cytokines (e.g., IL-1β, IL-6). This inflammatory influx resulted in induction of ulcerative colitis (UC). Administration of FA may inhibit this IFN-γ induced inflammatory cascade via a decrease in the release of pro-inflammatory cytokines to ameliorate TNBS-induced colitis.

Project description:Inflammatory bowel disease (IBD) is a chronic inflammatory disorder for which the current medical therapy is not completely effective. Bovine colostrum (BC) is a biological fluid rich in bioactive molecules that may have beneficial effects on several gastrointestinal disorders. The objectives of this study were to assess the preventive effects of BC supplementation in a mouse model of 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis using a multidisciplinary approach. Specifically, the following parameters were evaluated: (i) disease activity index (DAI), (ii) histological score, (iii) expression levels of TLR4, anti- and pro-inflammatory cytokines, and (iv) count of some bacterial species of the intestinal microbiota. Mice received a daily suspension of BC (BC group, n = 12) or saline solution (control, CN group, n = 12) for 21 days before the intrarectal inoculation with 1% of TNBS solution. BC was well tolerated and did not induce any histological damage or clinical symptoms. After TNBS treatment, BC group showed a reduction of body weight (BW) loss (P<0.01) and histological score (P<0.05) compared to CN. Moreover, the expression levels of TLR4 (P<0.05), IL-1β (P<0.001), IL-8 (P<0.001), and IL-10 (P<0.001) were lower in mice administered with BC, while the concentrations of TNF-α did not show any differences between groups. Finally, the supplementation with BC resulted in a differential response to TNBS treatment in the bacterial count. In CN group, E. coli and Enterococci increased (P<0.001), while Anaerobes (P<0.01), Lactobacilli, and Bifidobacteria (P<0.001) reduced. Conversely, no significant changes in bacterial load were found after the inoculation of TNBS in BC pre-treated mice. This study confirms that TNBS-induced colitis model in mice is useful for studying the mechanisms involved in IBD pathogenesis and shows that pre-treatment with BC reduces the intestinal damages and clinical signs of the colitis. Molecular mechanisms and intestinal microflora could be involved in the protective effect of colostrum.

Dataset Information

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

Publications

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

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