Abstract
BackgroundIntestinal mucositis is a common side effect of chemotherapy and radiotherapy. Very few drugs can efficiently ameliorate it. Tertiary butylhydroquinone (TBHQ) is a widely used food preservative with known immunomodulatory activity. Whether it has an effect on intestinal mucositis remains unknown. In this study, we investigated the role and mechanism of action of TBHQ on 5-fluorouracil-induced (5-FU-induced) human intestinal epithelial cell (HIEC) injury and intestinal mucositis in mice.MethodsWe established a cell model of HIEC injury and a mouse model of intestinal mucositis via treatment with 5-FU. Cell death, Cell Counting Kit-8, and lactate dehydrogenase (LDH) release were assessed for the HIECs. Diarrhea, body weight, intestinal length, mucosal damage, and the levels of IL-6, TNF-α, IL-1β, glutathione, reactive oxygen species, and malondialdehyde were determined for the mice. Additionally, we performed immunohistochemical analysis, immunofluorescence, western blotting, quantitative real-time PCR, and ELISA to examine the effects of TBHQ. Finally, HIECs were transfected with an Nrf2 gene silencer to verify its role in ferroptosis. All data were analyzed using one-way analysis of variance or paired t-tests.ResultsTBHQ markedly decreased LDH release and cell death and improved the proliferative ability of 5-FU-treated HIECs. The TBHQ-treated mice showed reduced weight loss, a lower diarrhea score, and longer colons than the 5-FU-treated mice. The in vivo expressions of IL-1β, IL-6, and TNF-α were suppressed by TBHQ treatment. Ferroptosis was shown to be involved in 5-FU-induced intestinal mucositis, and TBHQ markedly hampered its activation. Mechanistically, TBHQ activated Nrf2 effectively and selective Nrf2 knockdown significantly reduced the anti-ferroptotic functions of TBHQ in 5-FU-treated HIECs.ConclusionsTBHQ attenuates ferroptosis in 5-FU-induced intestinal mucositis, making it a potential novel protective agent against intestinal mucositis.
Highlights
Intestinal mucositis is a common side effect of chemotherapy and radiotherapy
We found that Tertiary butylhydroquinone (TBHQ) alleviated 5-FU-induced cell death in human intestinal epithelial cell (HIEC) (Fig. 1E, F)
TBHQ treatment (10 μM) was not cytotoxic and did not induce intestinal epithelial cell injury (Additional file 1: Fig. S1A–D). These results indicate that 10 μM of TBHQ effectively alleviates 5-FUinduced intestinal epithelial cell injury in vitro
Summary
Intestinal mucositis is a common side effect of chemotherapy and radiotherapy. Very few drugs can efficiently ameliorate it. Tertiary butylhydroquinone (TBHQ) is a widely used food preservative with known immunomodulatory activity Whether it has an effect on intestinal mucositis remains unknown. A major adverse effect of chemotherapy drugs is their impact on the intestinal mucosa. They kill rapidly differentiating intestinal mucosal cells, leading to a type of injury called intestinal mucositis [1, 2]. Ferroptosis is a non-apoptotic form of cell death It is defined as an iron-dependent regulatory necrosis that is caused by a large amount of lipid peroxidation-mediated membrane damage [5]. It may play a key role in the occurrence and development of various diseases [6–9]. Xu et al [12] found that ferroptosis is involved in intestinal epithelial cell death in ulcerative colitis and suggested it as a potential therapeutic target for that disease
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