Thymol ameliorates 5-fluorouracil-induced intestinal mucositis: Evidence of down-regulatory effect on TGF-β/MAPK pathways through NF-κB

J Biochem Mol Toxicol. 2022 Jan;36(1):e22932. doi: 10.1002/jbt.22932. Epub 2021 Oct 19.

Abstract

5-Fluorouracil (5-FU) is a front-line cytotoxic therapy. However, intestinal mucositis is a well-known adverse event of 5-FU, which limits its therapeutic use. Indeed, thymol, which is a monoterpene component of the essential oil derived from thymus, has a potential anti-inflammatory and immunomodulatory activity. Therefore, this study aimed to investigate the potential chemoprotective effect of thymol against 5-FU-induced intestinal mucositis. Rats were either exposed to two doses of 5-FU (150 mg/kg, ip) and/or treated with thymol (60 or 120 mg/kg). Oxidative stress and inflammatory markers, as well as pathological changes, were assessed. 5-FU-induced severe intestinal damages as were evidenced by histopathological changes as well as oxidative and inflammatory responses. Thymol pretreatment inhibited 5-FU-induced oxidative stress by reducing lipid peroxidation and increasing intestinal levels of antioxidant systems. Moreover, inflammatory response markers, such as interleukin-6, prostaglandin E2, and COX-2 were also improved. The immunoblotting analysis also showed that thymol significantly inhibited the 5-FU-induced expression of nuclear factor-κB, tumor necrosis factor-α, and transforming growth factor β-1 (TGF-β1), in addition to the suppression of p38 and phosphorylated c-Jun N-terminal kinases (p-JNK) mitogen-activated protein kinase proteins' expressions. Our study is the first to demonstrate the promising protective effect of thymol against 5-FU-induced intestinal mucositis through inhibition of oxidative, inflammatory pathways, and suppression of TGF-β/p38/p-JNK signaling.

Keywords: 5-flourouracil; NF-κB signaling; TGF-β/p38/p-JNK signaling; chemotherapy; inflammation; interleukins; intestinal mucositis; thymol.

MeSH terms

  • Animals
  • Chymases
  • Fluorouracil / adverse effects*
  • Fluorouracil / pharmacology
  • Intestinal Diseases* / chemically induced
  • Intestinal Diseases* / drug therapy
  • Intestinal Diseases* / metabolism
  • MAP Kinase Signaling System / drug effects*
  • Mucositis* / chemically induced
  • Mucositis* / drug therapy
  • Mucositis* / metabolism
  • NF-kappa B / metabolism*
  • Rats
  • Rats, Wistar
  • Thymol / pharmacology*
  • Transforming Growth Factor beta / metabolism*

Substances

  • NF-kappa B
  • Transforming Growth Factor beta
  • Thymol
  • Chymases
  • Cma1 protein, rat
  • Fluorouracil