## 4 Discussion  
Oral mucositis, as a side effect of chemotherapy with CDDP or radiochemotherapy, causes pain or swallowing pain in the oral cavity, which reduces the nutritional state of patients, makes conversations difficult, and markedly affects quality of life. In addition, oral mucositis-related susceptibility to infection deteriorates the general condition of some patients or necessitates the reduction in number of doses of chemotherapeutic agents. Oral mucositis also affects the admission period and survival rate [26; 27; 28]. CDDP inhibits cellular DNA replication or transcription, thereby inducing apoptosis. The present study showed that CDDP inhibited the proliferation of oral mucosa-derived epithelial cells and fibroblasts, whereas \(\beta\)-cry significantly increased the proliferation of both cell types, promoting oral mucosa-derived cell proliferation. CDDP significantly increased IL-8 production in hOMK and IL-6 production in hOMF. Regarding cytokine expression in skin-derived cells, a previous study reported that the ROS-mediated expression of IL-6 and IL-8 was up-regulated under redox stress conditions [29], and that chemotherapeutic agents and inflammatory cytokines affected the expression of MMPs, potentially contributing to the onset and severity of oral mucositis [30]. Among cytokine-associated MMPs that regulate inflammatory cytokine expression or activity, MMP-2 is responsible for maintaining homeostasis in the immune system, while the  
Figure 5: Effects of CDDP and \(\beta\)-cry on cellular senescence in hOMK and hOMF. (**A**) Images for \(\beta\)-GAL staining and DAPI of hOMK and hOMF in each group. Magnification \(\times 100\). (**B**) The percentages of \(\beta\)-GAL-positive cells were significantly higher in CDDP-treated hOMK and hOMF and in CDDP+\(\beta\)-cry-treated hOMK and hOMF than in control cells. Values are means \(\pm\) S.D. \(n\) = 4 * \(p\) < 0.05, ** \(p\) < 0.01 vs. control. production of MMP-9 is increased by inflammation. MMP-9 itself may also promote inflammation [31]. In the present study, MMP-9 production significantly increased in oral mucosa-derived cells. This result suggests that oral mucosa-derived cells produced IL-6, an inflammatory cytokine, and MMP-9 in the presence of CDDP, inducing an inflammatory response in the oral mucosa, which is consistent with the findings reported by [PERSON] et al. [32]. Pathogenic microorganisms, such as _Candida albicans_, affect the basement membrane proteins through MMP-2 and MMP-9 [33]. Therefore, MMPs produced by oral mucosal epithelial cells or fibroblasts in response to CDDP in the present study may have directly induced tissue damage. In addition, \(\beta\)-cry was shown to inhibit these cytokines and MMP produced by oral mucosa-derived cells in response to CDDP, exerting anti-inflammatory effects. These results are consistent with previous findings showing \(\beta\)-cry-induced reductions in IL-6/IL-8 production by periodontal ligament cells under mechanical stress or in the presence of periodontal pathogens [22] and the inhibition of IL-8/MMP-2 expression induced by oral mucosa-derived epithelial cells in the presence of 5-FU [23]. In the present study, we examined the mRNA expression and protein production of inflammatory cytokines and MMPs. Although each result did not completely match, similar changes were observed. These results provide support for the effects of CDDP and \(\beta\)-cry on oral mucosal cells. CDDP-induced inflammation up-regulates the expression of IL-6/IL-8 mediated by the transcription factor nuclear factor-\(\kappa\)B (NF-\(\kappa\)B) in ovarian cancer cells or the activation of TNF-\(\alpha\) through the activation of the MAPK pathway [34]. When NF-\(\kappa\)B is activated, senescence-associated secretory phenotype factor is secreted [35]. Further studies are needed to investigate cell signaling in normal oral mucosa-derived cells. Cellular senescence is induced in normal cells by stress [36]. ROS affects cellular components, such as lipids, protein, and DNA in vivo [37; 38].