A novel gastroprotective effect of zeaxanthin against stress-induced gastritis in male rats targeting the expression of HIF-1α, TFF-1 and MMP-9 through PI3K/Akt/JNK signaling pathway

Life Sci. 2021 May 15:273:119297. doi: 10.1016/j.lfs.2021.119297. Epub 2021 Mar 6.

Abstract

Stress-induced gastritis is a common problem in the intensive care unit. Zeaxanthin (ZE), a non-provitamin A carotenoid has been known to exert antioxidant and anti-inflammatory effects. In this study, we examined the effect of ZE on water avoidance stress (WAS)-induced gastritis in rats. 24 Sprague' Dawley male rats were divided into four groups; control, ZE, WAS and WAS+ZE. In the stressed rats, treatment with ZE effectively downregulated the gastric levels of total oxidant status (TOS), myeloperoxidase (MPO) and malondialdehyde (MDA), with significant upregulation of the antioxidant enzymes' activities and gastric levels of prostagladin-E2 (PGE2) as compared to the untreated stressed one. As noticed in the present study, ZE significantly decrease the gastric levels of interleukin-1 β (IL-1β) and IL-6 as well as suppression of nuclear transcription factor kappa-B (NF-κB) immunohistochemical expression together with upregulation of trefoil factor-1 (TFF-1) gene expression. Moreover, in the untreated WAS-induced gastritis group, gastrin and corticosterone levels were significantly increased together with upregulation of the gene expression of hypoxia inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), PI3K, Akt and JNK in the gastric tissues, which significantly improved by ZE administration. These all positive effects of ZE reflected on reduction of microscopic gastric mucosal damage and inflammatory cell infiltration with improvement of ulcer score. Our results discover that ZE has a new gastroprotective effect against stress-induced gastritis in rats, primarily through its antioxidative and anti-inflammatory effects, which are expressed in the regulation of the MMP-9 and HIF-1α signaling pathways.

Keywords: Akt; HIF-1α; JNK; MMP-9; NF-κB; PI3K; TFF-1; WAS.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Biomarkers / analysis*
  • Cytokines / metabolism
  • Gastritis / drug therapy*
  • Gastritis / etiology
  • Gastritis / metabolism
  • Gastritis / pathology
  • Gene Expression Regulation / drug effects*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protective Agents / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Stress, Physiological*
  • Trefoil Factor-1 / genetics
  • Trefoil Factor-1 / metabolism
  • Zeaxanthins / pharmacology*

Substances

  • Antioxidants
  • Biomarkers
  • Cytokines
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Protective Agents
  • Tff1 protein, rat
  • Trefoil Factor-1
  • Zeaxanthins
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 4
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat