Anti-Inflammatory Effects of β-Cryptoxanthin on 5-Fluorouracil-Induced Cytokine Expression in Human Oral Mucosal Keratinocytes

Abstract

Oral mucositis is a typical adverse effect of chemotherapy, causing oral pain that significantly reduces the patient’s quality of life. β-cryptoxanthin (β-cry) is a carotenoid abundant in citrus fruits with antioxidant and anti-inflammatory effects. However, the β-cry effect on oral mucositis remains unclear. We investigated the effects of 5-fluorouracil (5-FU) and β-cry on human normal oral mucosal keratinocytes (hOMK). hOMK was seeded on a culture plate and cultured with 5-FU and β-cry. The cell number, mRNA expression of inflammatory cytokines and matrix metalloproteinases (MMPs), and production of inflammatory cytokines in hOMK were evaluated. Additionally, the cell count and inflammatory cytokine production were analyzed when hOMK was co-stimulated with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) in addition to 5-FU. The numbers of hOMK significantly reduced with 5-FU stimulation, whereas it increased with β-cry treatment. mRNA expression of interleukin (IL)-6, IL-8, metalloproteinase (MMP)-2, and MMP-9 and protein production of IL-6 and IL-8 in hOMK were augmented on 5-FU stimulation. Simultaneously, β-cry treatment significantly suppressed IL-8 and MMP-9 mRNA expression, and IL-8 production was induced on 5-FU stimulation. Co-stimulation with P. gingivalis LPS and 5-FU enhanced IL-6 and IL-8 production in hOMK. β-cry could enhance cell proliferation and suppress 5-FU-induced expression of inflammatory cytokines and MMP in hOMK. Thus, β-cry can alleviate the symptoms of chemotherapy-induced oral mucositis, and its combination with oral care is effective in managing oral mucositis.

Application of In Situ Mucoadhesive Hydrogel with Anti-Inflammatory and Pro-Repairing Dual Properties for the Treatment of Chemotherapy-Induced Oral Mucositis

“…59,61 Studies have indicated that 5-FU induces an increase in MMP-9 expression in the oral mucosa, leading to significant apoptosis in both epithelial and connective tissues, ultimately resulting in tissue damage. 62,63 In the context of in vivo experiments, the immunofluorescence analysis revealed the expression pattern of MMP-9 in tissue cells (Figure 7C). Notably, by day 3, a noticeable decrease in the relative fluorescence intensity of MMP-9 was observed in the Col/HA-E/Alg hydrogel group, as illustrated in Figure 7D.…”

The Role of the Innate Immune Response in Oral Mucositis Pathogenesis

“…Importantly, the transcription factor NF-κB is a key component activated by TLR signaling and is known to contribute to numerous inflammatory signals, including those leading to OM [58,59]. During ulcerative mucositis, PAMPs, such as lipopolysaccharides, can interact with TLRs expressed on innate immune cells of the oral mucosa to trigger an inflammatory response [60]. In addition, release of DAMPs, such as HMGB1, from cells undergoing necrosis or oxidative stress also contributes to innate immune activation via detection by TLRs.…”