The Japanese Herbal Medicine Hangeshashinto Induces Oral Keratinocyte Migration by Mediating the Expression of CXCL12 Through the Activation of Extracellular Signal-Regulated Kinase.

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.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Novel microvascular endothelial model utilizing a collagen vitrigel membrane and its advantages for predicting histamine-induced microvascular hyperpermeability.

INTRODUCTION: The evaluation of microvascular permeability is crucial for drug development. Nonetheless, there are few reliable test methods in vitro due to the lack of vascular endothelial models suitable for quantitative analyses. The purpose of this study is to construct a novel microvascular endothelial model with the high endothelial barrier function and sensitivity to physiological stimuli utilizing a collagen vitrigel membrane (CVM) composed of high-density collagen fibrils. METHODS: Human microvascular endothelial cells (HMVECs) were cultured for 6 days in a CVM chamber with or without human dermal fibroblasts (HDFs) cocultured on the reverse surface of the CVM. The endothelial barrier function was evaluated by measurement of transendothelial electrical resistance (TEER) and macromolecular permeation. RESULTS: The TEER value of a monolayer of HMVECs cultured on the CVM was 15-20 Ωï½¥cm2 during the culture period while it reached over 60 Ωï½¥cm2 by coculturing with HDFs. The TEER value was decreased from 5.7 to 3.4 Ωï½¥cm2 by 100 µM histamine in the monolayer model and from 50 to 32 Ωï½¥cm2 by 1 nM histamine in the coculture model, respectively. Interestingly, the permeability coefficient of the compound with a molecular weight of not 376 and 40,000 but 4000 was selectively increased in the histamine-treated coculture model. DISCUSSION: HMVECs cocultured with HDFs via a CVM formed the tight endothelial barrier and showed high responsivity to histamine. The model might be useful for exploring molecules that modulate microvascular permeability and pass through the microvascular endothelial barrier.

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

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 1ß-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.

Multifunctional Actions of Ninjinyoeito, a Japanese Kampo Medicine: Accumulated Scientific Evidence Based on Experiments With Cells and Animal Models, and Clinical Studies.

Herbal medicines are currently employed for the treatment of several types of diseases, and also employed for the improvement of Quality of Life (QOL) of patients over the world, in particular, in Asian countries. In Japan, a Japanese herbal medicine namely kampo medicine has been prescribed for the improvement of QOL of patients. Ninjinyoeito (NYT), composed of 12 herbal plants, is one of kampo medicines and used for helping recovery of diseases and improving several symptoms that suffer patients such as anemia, anorexia and fatigue. Recent scientific research approaches to kampo medicines with cells and animal models enable to prove that NYT has multiple functions for improvement of symptoms. Also, clinical studies using NYT support such actions to be widely used for the improvement of symptoms that reduce the QOL of patients.