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Thymol ameliorates 5-fluorouracil-induced intestinal mucositis: Evidence of down-regulatory effect on TGF-β/MAPK pathways through NF-κB
Journal of Biochemical and Molecular Toxicology ( IF 3.6 ) Pub Date : 2021-10-19 , DOI: 10.1002/jbt.22932
Layla A Al-Khrashi 1 , Amira M Badr 1, 2 , Maha A Al-Amin 1 , Yasmen F Mahran 2
Affiliation  

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.

中文翻译:

百里酚改善 5-氟尿嘧啶诱导的肠粘膜炎:通过 NF-κB 下调 TGF-β/MAPK 通路的证据

5-氟尿嘧啶 (5-FU) 是一种一线细胞毒疗法。然而,肠粘膜炎是众所周知的 5-FU 不良事件,这限制了其治疗用途。事实上,百里酚是源自胸腺的精油的单萜成分,具有潜在的抗炎和免疫调节活性。因此,本研究旨在探讨百里酚对 5-FU 诱导的肠粘膜炎的潜在化学保护作用。大鼠要么暴露于两剂 5-FU (150 mg/kg, ip) 和/或用百里酚 (60 或 120 mg/kg) 治疗。评估了氧化应激和炎症标志物以及病理变化。组织病理学变化以及氧化和炎症反应证明了 5-FU 诱导的严重肠道损伤。百里酚预处理通过减少脂质过氧化和增加抗氧化系统的肠道水平来抑制 5-FU 诱导的氧化应激。此外,炎症反应标志物,如白细胞介素6、前列腺素E2和COX-2也得到了改善。免疫印迹分析还表明,除了抑制 p38 和磷酸化外,百里酚还显着抑制 5-FU 诱导的核因子-κB、肿瘤坏死因子-α 和转化生长因子 β-1 (TGF-β1) 的表达。 c-Jun N-末端激酶 (p-JNK) 丝裂原活化蛋白激酶蛋白的表达。我们的研究首次证明了百里酚通过抑制氧化、炎症途径和抑制 TGF-β/p38/p-JNK 信号传导对 5-FU 诱导的肠粘膜炎具有良好的保护作用。
更新日期:2021-10-19
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