Hochuekkito (HET), Juzentaihoto (JTT), and Ninjin’yoeito (NYT) have been used as Hozai, a group of traditional Japanese herbal medicines, to treat physically and mentally weak cancer patients. Their compositions are quite different, and Japanese pharmaceutical companies have been using different types or quantities of herbs for formulations with the same name. Here, we compared the immunological differences between HET, JTT, and NYT with respect to the induced T cell subsets and cytokines. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers and treated with 0 (control), 25, 50, 100, 200, or 400 μg/mL HET, JTT, or NYT (manufactured by Tsumura [TJ], Kracie [KR], and Kotaro [KO]). PBMC proliferation, CD4+ T cell, CD8+ T cell, and regulatory T cell (Treg) proportions and interleukin (IL) concentrations (IL-6, IL-10, IL-17A, interferon-γ, tumor necrosis factor-α, and transforming growth factor (TGF)-β) secreted by PBMCs were measured using Cell Counting Kit-8 or flow cytometry bead analysis. PBMC proliferation and CD4+ T cell percentages were similar in the HET, JTT, NYT, and control groups; however, the percentage of CD8+ T cells tended to increase after treatments. Tregs were suppressed by HET, JTT, and NYT, and TJ-JTT significantly decreased Treg numbers (compared with control). The concentrations of all cytokines except TGF-β were increased in a concentration-dependent manner ( p < 0.05 ); particularly, KR-HET induced IL-6 secretion (compared with the control, TJ-HET, and KO-HET; 37-, 7-, and 17-fold, respectively; p < 0.05 ). The TGF-β concentration was decreased in a concentration-dependent manner by HET, JTT, and NYT (compared with the control). These results suggest that, compared with TJ-HET and KO-HET, KR-HET should be administered with caution. Although HET, JTT, and NYT belong to the same Hozai group and have the same names among companies, their differing effects on immune activity must be considered and they must be administered with caution.

Oral mucositis (OM) is a common side effect in patients with cancer receiving chemotherapy and radiotherapy; however, no salivary mediator is known to be associated with OM. We aimed to determine candidate salivary inflammatory mediators potentially associated with OM in patients with cancer. To this end, we compared the relationships between OM grade, oral mucosal dryness, and inflammatory mediators (Interleukin (IL)-1β, IL-6, IL-10, IL-12p70, tumor necrosis factor (TNF), prostaglandin E2, and vascular endothelial growth factor) in patients with cancer and in healthy volunteers (HV). We collected saliva samples from 18 patients with cancer according to the following schedule: 1) within 14 days of treatment initiation, 2) within 3 days of OM occurrence, 3) when OM was improved or got worsened, and 4) within 7 days after chemotherapy completion. The oral care support team determined the OM grade at each sample collection point based on CTCAE version 5.0. Salivary inflammatory mediator concentrations were detected using cytometric bead array or enzyme-linked immunoassay. We compared oral mucosal dryness in pre- and post-index patients with cancer to that in HV (n = 33) using an oral moisture-checking device. Fourteen of eighteen patients experienced OM (four, grade 3 OM; four, grade 2 OM; six, grade 1 OM). IL-6, IL-10, and TNF salivary concentrations were significantly increased in the post-index group compared to those in the pre-index group (p = 0.0002, p = 0.0364, and p = 0.0160, respectively). Additionally, salivary IL-6, IL-10, and TNF levels were significantly higher in the post-index group than in the HV group (p < 0.0001, p < 0.05, and p < 0.05, respectively). Significant positive correlations were observed between OM grade and salivary IL-6, IL-10, and TNF levels (p = 0.0004, r = 0.4939; p = 0.0171, r = 0.3394; and p = 0007, r = 0.4662, respectively). Oral mucosal dryness was significantly higher in the HV than in the pre- and post-index groups (p < 0.001). Our findings suggest that salivary IL-6, IL-10, and TNF levels may be used as biomarkers for OM occurrence and grade in patients with cancer. Furthermore, monitoring oral mucosal dryness and managing oral hygiene before cancer treatment is essential.

ObjectivesManaging perioperative anxiety improves postoperative recovery significantly by reducing postoperative pain. However, little is known about association between preoperative anxiety and postoperative pain in oral surgical procedures. In the present study, we examined the effect between preoperative anxiety and postoperative pain in mandibular third molar extraction and the anxiolytic effect of Yokukansan (YKS) during the perioperative period.Materials and methodsWe conducted a prospective cohort study from September 2021 to May 2022. For patients with a complaint of insomnia on the day before surgery, 2.5 g per package of YKS was administered before sleep on the day before surgery. Twelve patients were administered YKS, and 23 patients were not (non‐YKS).ResultsPerioperative anxiety was assessed by the Hospital Anxiety and Depression Scale (HADS) and amylase in saliva, and perioperative pain was assessed by the Numerical Rating Scale (NRS) and the total number of times pain medication. There were no significant differences in HADS and amylase in saliva between the YKS and non‐YKS. The median postoperative NRS was 5 for YKS and 7 for non‐YKS. The maximum use of pain medication was 16 in YKS and 24 in non‐YKS. Although no significant difference was observed in the anxiolytic effects and the improvement of postoperative pain during the perioperative period of mandibular third molar extraction between patients who took YKS and those who did not, NRS and the maximum use of pain medication were less in the YKS patients.ConclusionsTherefore, YKS may be useful for managing postoperative pain through the preoperative anxiolytic effect in oral surgical procedures.

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EphrinB2 is expressed in osteoclasts and functions as a coupling factor between osteoblasts and osteoclasts. In this study, EphrinB2 was systemically administered to ovariectomized (OVX) mice to verify its effects on bone loss and the mechanisms. EphrinB2 administration significantly suppressed OVX-induced bone loss, and EphrinB2 increased the number of osteoblasts and decreased the number of osteoclasts on the surface of trabecular bone. EphrinB2 inhibited the osteoclast differentiation of mouse bone marrow cells, mouse bone marrow-derived macrophages, and RAW264.7 to a similar extent in vitro. Since the inhibitory effect of osteoclast differentiation was not accompanied by suppression of gene expression of osteoclast markers such as ACP5, CTSK, and DC-STAMP, it was considered that cell-cell fusion for the maturation of multinucleated osteoclasts was suppressed. On the other hand, EphrinB2 promoted osteoblast differentiation of bone marrow cells, but not osteoprogenitor cells such as calvarial cells and bone marrow-derived stromal cells. This means that EphrinB2 indirectly promotes osteoblast differentiation by acting on cells other than osteoprogenitor cells contained in the bone marrow. EphrinB2 increased the expression of BMP2 in osteoclast progenitor cells, RAW264.7, suggesting the possibility that BMP2 is involved in the action of EphrinB2 to promote osteoblast differentiation. Taken together, these results indicate that EphrinB2 can be used as a novel osteoporosis therapeutic agent having a dual effect.