The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis

Kanako Miyano,Ayane Hirano,Yasuhito Uezono,Takashi Matsumoto,Kentaro Ono,Noriho Asai,Kaori Nagabuchi,Hideaki Fujii,Seiya Hasegawa,Suzuro Hitomi,Yuji Omiya,Yoshikazu Higami,Atsushi Kaneko,Toru Kono,Miaki Uzu,Miki Nonaka,Moeko Eto

doi:10.1038/s41598-019-57192-2

Abstract

Chemotherapy often induces oral ulcerative mucositis (OUM) in patients with cancer, characterized by severe painful inflammation. Mouth-washing with the Japanese herbal medicine hangeshashinto (HST) ameliorates chemotherapy-induced OUM in patients with colorectal cancer. Previously, we demonstrated that HST decreased interleukin 1β-induced prostaglandin E2 production in human oral keratinocytes (HOKs) and OUM-induced mechanical or spontaneous pain in rats. However, HST effects on tissue repair functions in HOKs remain unclear. Here, we examined the effects of HST on scratch-induced wound healing in vitro and in vivo. In vitro, HST enhanced wound healing mainly through scratch-induced HOK migration. Screening of the seven constituent medicinal herbs and their major components revealed that Scutellaria root, processed ginger, and Glycyrrhiza components mainly induced the scratch-induced HOK migration. Pharmacokinetic analyses indicated that the active ingredient concentrations in rat plasma following oral HST administration were below the effective doses for HOK migration, suggesting direct effects of HST in OUM. Mitogen-activated protein kinase and C-X-C chemokine receptor 4 inhibitors significantly suppressed HST-induced HOK migration. Moreover, HST enhanced tissue repair in our OUM rat model. Thus, HST likely enhanced OUM tissue repair through oral keratinocyte migration upon MAPK and CXCR4 activation and may be useful in patients with cancer-associated OUM.

Highlights

Chemotherapy often induces oral ulcerative mucositis (OUM) in patients with cancer, characterized by severe painful inflammation
To reveal the intracellular signalling mechanism of HST during scratch-induced human oral keratinocytes (HOKs) migration, we investigated the effects of inhibitors of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38) and of CXCR4, which constitutes a www.nature.com/scientificreports crucial mediator of cell migration, on scratch-induced HOK migration
HST enhanced the growth of HOKs, this effect was smaller than the wound healing effect (Fig. 1)

Summary

Introduction

Chemotherapy often induces oral ulcerative mucositis (OUM) in patients with cancer, characterized by severe painful inflammation. HST enhanced wound healing mainly through scratch-induced HOK migration. HST likely enhanced OUM tissue repair through oral keratinocyte migration upon MAPK and CXCR4 activation and may be useful in patients with cancer-associated OUM. The effects of HST on the wound-induced migration of oral keratinocytes or OUM healing (tissue repair) remain unclear. We analysed the effects of HST on scratch-induced wound healing using human oral keratinocytes (HOKs) and identified the active medicinal herbs in HST and their ingredients by screening the seven constituents and their major components. To reveal the actions of these active ingredients via the blood, we evaluated their pharmacokinetics rat plasma along with the effects of several inhibitors, such as against intracellular signalling molecules, on HST-mediated scratch-induced wound healing. We examined the effects of HST on OUM healing using an OUM rat model

Methods

Results

Conclusion