title: 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.
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain. icreg@unileon.es.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 24071, Spain. icreg@unileon.es.
authors.forename: Irene
authors.initials: I
authors.lastname: Crespo
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain. bsanv@unileon.es.
authors.forename: Beatriz
authors.initials: B
authors.lastname: San-Miguel
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain. jl.mauriz@unileon.es.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 24071, Spain. jl.mauriz@unileon.es.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Mauriz
authors.affiliation: Pharmacy Service, Complejo Asistencial Universitario de León, 24071 León, Spain. jortiz@saludcastillayleon.es.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Ortiz de Urbina
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain. malmg@unileon.es.
authors.forename: Mar
authors.initials: M
authors.lastname: Almar
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain. mjtung@unileon.es.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 24071, Spain. mjtung@unileon.es.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Tuñón
authors.affiliation: Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain. jgonga@unileon.es.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 24071, Spain. jgonga@unileon.es.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005978:Glutathione / Q000378:metabolism; D062385:Hydroxybenzoates / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D051546:Cyclooxygenase 2; D005978:Glutathione; D062385:Hydroxybenzoates; D053583:Interleukin-1beta; D016328:NF-kappa B; D009195:Peroxidase; D017853:Phosphotransferases (Alcohol Group Acceptor); D043484:Proprotein Convertases; D050796:STAT3 Transcription Factor; D012697:Serine Endopeptidases; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C494087:Stat3 protein, mouse; C009091:protocatechuic acid; C077623:Ptgs2 protein, mouse; C115575:membrane-bound transcription factor peptidase, site 1
keywords: SphK/S1P signaling; colitis; inflammation; protocatechuic acid; sphingolipids