Methotrexate mediates the integrity of intestinal stem cells partly through nitric oxide-dependent Wnt/β-catenin signaling in methotrexate-induced rat ileal mucositis

J Pharmacol Sci. 2022 Mar;148(3):281-285. doi: 10.1016/j.jphs.2022.01.002. Epub 2022 Jan 13.

Abstract

This study aimed to elucidate the role of nitric oxide (NO) in intestinal stem cells in methotrexate-induced ileal mucositis in rats. Methotrexate induced the mRNA expressions of the Wnt/β-catenin target genes Wnt3a, Sox9, and Lgr5 and the Wnt-antagonist gene sFRP-1 and the protein expressions of Lgr5 and sFRP-1. Methotrexate also induced Lgr5+ cells and lysozyme+ cells. A non-selective NO inhibitor inhibited the methotrexate induction of Wnt/β-catenin target genes and Lgr5+ cells but enhanced that of sFRP-1 expression. Thus, methotrexate mediates the integrity of intestinal stem cells partly through NO-dependent Wnt/β-catenin signaling and may enhance tolerability to methotrexate-induced injury.

Keywords: Methotrexate-induced mucositis; Nitric oxide; Wnt/β-catenin target genes.

MeSH terms

  • Animals
  • Gene Expression / drug effects
  • Ileum*
  • Intestines / cytology*
  • Intestines / drug effects*
  • Male
  • Methotrexate / adverse effects*
  • Mucositis / chemically induced
  • Mucositis / genetics*
  • Mucositis / pathology*
  • Nitric Oxide / metabolism
  • Nitric Oxide / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics*
  • Stem Cells / drug effects*
  • Stem Cells / pathology*
  • Wnt Proteins / metabolism*
  • beta Catenin / metabolism*

Substances

  • RNA, Messenger
  • Wnt Proteins
  • beta Catenin
  • Nitric Oxide
  • Methotrexate