Abstract
Several clinical studies have reported that Japanese herbal medicine Hangeshashinto (HST) has beneficial effects on chemotherapy-induced oral ulcerative mucositis (OUM). Our previous research demonstrated that HST improves chemotherapy-induced OUM through human oral keratinocyte (HOK) migration, which was suppressed by mitogen-activated protein kinase (MAPK) and C-X-C chemokine receptor 4 (CXCR4) inhibitors. However, the association between these molecules and HOK migration was unclear. Here, we examined the effects of HST on the expression of CXCR4/CXCR7 and C-X-C motif chemokine ligands 11 and 12 (CXCL11/CXCL12) in HOKs. Our results indicated that HST upregulated CXCL12, but not CXCR4, CXCR7, nor CXCL11 in HOKs. HST-induced expression of CXCL12 was significantly suppressed by an inhibitor of extracellular signal-regulated kinase (ERK), but not of p38 and c-Jun N-terminal kinase (JNK). In addition, HST induced phosphorylation of ERK in HOKs. These findings suggest that HST enhances HOK migration by upregulating CXCL12 via ERK.
Highlights
To elucidate the involvement of mitogenactivated protein kinase (MAPK) in HST-induced upregulation of CXCL12, we examined the effects of MAPK inhibitors on HST-induced upregulation of CXCL12 in human oral keratinocyte (HOK)
We revealed for the first time that treatment with 100 μg/ml HST activated extracellular-signal-regulated kinase (ERK) and upregulated CXCL12 in HOKs, which subsequently caused their migration
Concurring with the results of previous studies, our results demonstrated that ERK, Jun N-terminal kinase (JNK), p38, and CXCR4 inhibitors significantly suppressed HST-induced HOK migration (Figure 1)
Summary
Radiotherapy, hematopoietic stem cell transplant, or terminal care often experience severe oral ulcerative mucositis (OUM), which evokes painful inflammation and limits their basic day-to day activities, such as “eating, drinking, and talking” (McGuire et al, 1993; Sonis, 1998; Dodd et al, 2000; Dörr et al, 2002; Sonis, 2004; Duncan et al, 2005; Jones et al, 2006; Vera-Llonch et al, 2006; Barber et al, 2007; El-Housseiny et al, 2007; VeraLlonch et al, 2007; Bensinger et al, 2008; Sonis, 2010a; Sonis, 2010b; Miyano et al, 2016; Miyano et al, 2020). A recent double-blind, placebo-controlled, randomized study reported that the repetitive use of HST-containing mouthwash effectively improved chemotherapy-induced OUM in patients with colorectal cancer or gastric cancer (Matsuda et al, 2015). Our recent in vitro and in vivo studies revealed that HST directly affects OUM and enhances tissue repair through migration of HOKs, involving activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), and C-X-C chemokine receptor 4 (CXCR4) (Miyano et al, 2020). We investigated the effects of HST on the expression of endogenous CXCR4 agonists (C-X-C chemokine ligands CXCL11 and CXCL12) and the receptors CXCR4 and CXCR7 to clarify how MAPKs and CXCR4 induce HOK migration. We analyzed the effects of several MAPK inhibitors on the expression of CXCL12, and examined the effects of HST treatment on MAPK phosphorylation in migrating HOKs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
