A polyphenol-rich açaí seed extract protects against 5-fluorouracil-induced intestinal mucositis in mice through the TLR-4/MyD88/PI3K/mTOR/NF-κBp65 signaling pathway

Nutr Res. 2024 May:125:1-15. doi: 10.1016/j.nutres.2024.01.017. Epub 2024 Feb 3.

Abstract

Açaí seed extract (ASE) is obtained from Euterpe oleracea Mart. (açaí) plant (Amazon region) has high nutritional and functional value. ASE is rich in polyphenolic compounds, mainly proanthocyanidins. Proanthocyanidins can modulate the immune system and oxidative stress by inhibiting the toll-like receptor-4 (TLR-4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor-κB (NF-κB) pathway. A great deal of evidence suggests that inflammatory cytokines and oxidative stress contribute to the pathogenesis of intestinal mucositis, and these events can lead to intestinal dysmotility. We hypothesized that ASE acts as an anti-inflammatory and antioxidant compound in intestinal mucositis induced by 5-fluorouracil (5-FU) through modulation of the TLR-4/MyD88/phosphatidylinositol-3-kinase α/mechanistic target of rapamycin/NF-κBp65 pathway. The animals were divided into linear 5-FU (450 mg/kg) and 5-FU + ASE (10, 30, and 100 mg/kg) groups. The weight loss of the animals was evaluated daily. Samples from duodenum, jejunum, and ileum were obtained for histopathological, biochemical, and functional analyses. ASE reduced weight loss, inflammatory parameters (interleukin-1β; tumor necrosis factor-α; myeloperoxidase activity) and the gene expression of mediators involved in the TLR-2/MyD88/NF-κB pathway. ASE prevented histopathological changes with beneficial effects on gastrointestinal transit delay, gastric emptying, and intestinal absorption/permeability. In conclusion, ASE protects the integrity of the intestinal epithelial barrier by inhibiting the TLR/MyD88/PI3K/mechanistic target of rapamycin/NF-κBp65 pathway.

Keywords: 5-fluorouracil; Inflammation; Intestinal mucositis; Oxidative stress; Polyphenol-rich açaí seed extract.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Antioxidants / pharmacology
  • Euterpe* / chemistry
  • Fluorouracil*
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Male
  • Mice
  • Mucositis* / chemically induced
  • Mucositis* / drug therapy
  • Mucositis* / metabolism
  • Mucositis* / prevention & control
  • Myeloid Differentiation Factor 88* / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress / drug effects
  • Phosphatidylinositol 3-Kinases / metabolism
  • Plant Extracts* / pharmacology
  • Polyphenols* / pharmacology
  • Seeds* / chemistry
  • Signal Transduction* / drug effects
  • TOR Serine-Threonine Kinases* / metabolism
  • Toll-Like Receptor 4* / metabolism
  • Transcription Factor RelA / metabolism

Substances

  • Toll-Like Receptor 4
  • Myeloid Differentiation Factor 88
  • TOR Serine-Threonine Kinases
  • Fluorouracil
  • Plant Extracts
  • Myd88 protein, mouse
  • Polyphenols
  • mTOR protein, mouse
  • Tlr4 protein, mouse
  • Transcription Factor RelA
  • Antioxidants
  • Phosphatidylinositol 3-Kinases
  • Anti-Inflammatory Agents
  • Rela protein, mouse
  • NF-kappa B