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

• Published in: Journal of biochemical and molecular toxicology Vol. 36; no. 1; pp. e22932 - n/a
• Main Authors: Al‐Khrashi, Layla A., Badr, Amira M., AL‐Amin, Maha A., Mahran, Yasmen F.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2022
• Subjects: 5-Fluorouracil; 5‐flourouracil; Animals; Antioxidants; chemotherapy; Chymases; Cytotoxicity; Damage; Essential oils; Fluorouracil - adverse effects; Fluorouracil - pharmacology; Growth factors; Immunoblotting; Immunomodulation; Inflammation; Inflammatory response; Interleukins; Intestinal Diseases - chemically induced; Intestinal Diseases - drug therapy; Intestinal Diseases - metabolism; intestinal mucositis; Intestine; JNK protein; Kinases; Lipid peroxidation; Lipids; MAP kinase; MAP Kinase Signaling System - drug effects; Markers; Mucositis; Mucositis - chemically induced; Mucositis - drug therapy; Mucositis - metabolism; NF-kappa B - metabolism; NF‐κB signaling; Oxidative stress; Peroxidation; Prostaglandin E2; Protein kinase; Proteins; Rats; Rats, Wistar; Signal transduction; Signaling; TGF‐β/p38/p‐JNK signaling; Thymol; Thymol - pharmacology; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumor necrosis factor; Tumor necrosis factor-TNF; NF-κB signaling; thymol; inflammation; intestinal mucositis; 5-flourouracil; TGF-β/p38/p-JNK signaling; chemotherapy; interleukins
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.22932

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. Thymol ameliorates 5‐fluorouracil‐induced intestinal mucositis. Mechanisms include antioxidant, anti‐inflammatory activity via modulating cross‐talks of oxidative stress/nuclear factor‐κB (NF‐κB)/tumor necrosis factor‐α (TNF‐α)/transforming growth factor β (TGF‐β)/mitogen‐activated protein kinases (MAPKs). Highlights Thymol inhibited 5‐fluorouracil (5‐FU)‐induced intestinal injury in an experimental model of intestinal mucositis. Thymol increased antioxidant capacity and decreased molecular oxidative damage. Targeting of nuclear factor‐κB/tumor necrosis factor‐α/transforming growth factor β (TGF‐β) inflammatory loop with thymol significantly ameliorated intestinal mucositis induced by 5‐FU. Suppression of TGF‐β/p38/phosphorylated c‐Jun N‐terminal kinases signaling might have contributed to the antioxidant and anti‐inflammatory effects of thymol. Thymol is a potential adjuvant therapy, which may be beneficial for cancer patients treated with 5‐FU.