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

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-FUinduced intestinal mucositis through inhibition of oxidative, inflammatory pathways, and suppression of TGF-β/p38/p-JNK signaling.

Paraprobiotics and Postbiotics of Lactobacillus delbrueckii CIDCA 133 Mitigate 5-FU-Induced Intestinal Inflammation

“…The anti-inflammatory or pro-inflammatory property of this immunoregulatory factor occurs through cellular and environmentally dependent contexts [ 48 , 49 ]. Increased TGFβ levels were observed in the 5-FU-induced inflammation model [ 50 , 51 , 52 ]. On the other hand, IL10 cytokine levels were reduced [ 30 , 53 , 54 , 55 ].…”

A mixture of organic acids and thymol protects primary chicken intestinal epithelial cells from Clostridium perfringens infection in vitro

“…All the reported effects of CPA and PFOA on cells seem to be mainly connected to the NF-κB activation which is reported to be actively inhibited by thymol ( Liang et al, 2014 ; Chen et al, 2020 ; Rossi et al, 2020 ; Al-Khrashi et al, 2022 ). Together with the 2 organic acids used, thymol forms a blend that has strong antimicrobial power against CP, reducing the bacterial load, and thus protecting against the inflammation and oxidative stress caused by the challenge.…”

“…Starting from there, a blend of thymol, citric acid, and dodecanoic acid was created to combine the antimicrobial power of organic acids with the antimicrobial and anti-inflammatory capabilities of thymol. Thymol is a well-studied anti-inflammatory that acts by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells ( Nf-kB ) pathway, MAPKs, and iNOS ( Liang et al, 2014 ; Chen et al, 2020 ; Rossi et al, 2020 ; Al-Khrashi et al, 2022 ). Thymol is also an effective antioxidant, which could scavenge free radicals and it can prevent oxidative stress increasing glutathione and superoxide dismutase levels through the Nrf2 pathway ( Saleh et al, 2021 ).…”

TLR4/Inflammasomes Cross-Talk and Pyroptosis Contribute to N-Acetyl Cysteine and Chlorogenic Acid Protection against Cisplatin-Induced Nephrotoxicity

“…Then, protein concentrations were determined using the Direct Detect quantification assay technique. Protein extraction and quantification were fully described previously [ 90 ]. Separated protein gels were transferred to polyvinylidene difluoride (PVDF) membranes (0.2 μm, Immun-Blot ® , Bio-Rad, Hercules, CA, USA).…”