Osaka Ohtani University

Allergic rhinitis (AR) is a type I allergic disease characterized by sneezing, watery rhinorrhea, and nasal obstruction. An epidemiological survey found that approximately 50% of Japanese individuals have AR.Histamine is a major chemical mediator that induces AR symptoms through its binding to histamine H1 receptor(H1R). We demonstrated that antihistamines have a blocking effect on histamine signaling of H1R, and the suppressive effect on histamine-induced up-regulation of transcriptional activation, and the suppressive effect on basal transcription of H1R in the absence of histamine which may be part of the inverse agonist action of antihistamine. Sublingual immunotherapy (SLIT) with a standardized Japanese cedar (JC) pollen significantly improved nasal symptoms and AR-related sleep disturbance in patients with JC pollinosis. Dual SLIT with JC pollen and house dust mites (HDM) suppressed both JC pollen-induced seasonal and HDM-induced perennial nasal symptoms in bisensitized patients with AR. Dual SLIT was more effective in suppressing nasal obstruction at the peak JC pollen period than mono SLIT with JC pollen. Posterior nasal neurectomy (PNN) improved nasal symptoms and medication scores in patients with severe perennial AR. Herein, we describe recent advances in the management of AR. J. Med. Invest. 72 : 14-20, February, 2025.

T cells recirculate through tissues and lymphatic organs to scan for their cognate antigen. Radiation therapy provides site-specific cytotoxicity to kill cancer cells but also has the potential to eliminate the tumor-specific T cells in field. To dynamically study the effect of radiation on CD8 T cell recirculation, we used the Kaede mouse model to photoconvert tumor-infiltrating cells and monitor their movement out of the field of radiation. We demonstrate that radiation results in loss of CD8 T cell recirculation from the tumor to the lymph node and to distant sites. Using scRNASeq, we see decreased proliferating CD8 T cells in the tumor following radiation therapy resulting in a proportional enrichment in exhausted phenotypes. By contrast, 5 days following radiation increased recirculation of T cells from the tumor to the tumor draining lymph node corresponds with increased immunosurveillance of the treated tumor. These data demonstrate that tumor radiation therapy transiently impairs systemic T cell recirculation from the treatment site to the draining lymph node and distant untreated tumors. This may inform timing therapies to improve systemic T cell-mediated tumor immunity.

Enteral nutrients (ENs) affect the plasma drug concentration of orally co-administered drugs, particularly those of antiepileptic drugs, such as phenytoin and carbamazepine. However, few studies have reported the interactions of levetiracetam (LEV), an upcoming antiepileptic drug, with ENs. In this study we aimed to investigate the pharmacokinetics of LEV in 55 rats after oral co-administration of LEV with liquid or semisolid ENs. Compared with the control group, co-administration with Terumeal ® Soft significantly decreased the plasma LEV concentration at 0.5, 1, and 2 h and area under the plasma concentration-time curve from 0 to 3 h (AUC0→3h) (P < 0.01). However, the AUC0→3h of LEV remained unchanged following the administration of Terumeal ® Soft 2 h after the initial LEV administration. Moreover, co-administration with semisolid Racol® NF delayed the absorption of LEV without decreasing the AUC0→3h, whereas liquid Racol ® NF did not alter LEV pharmacokinetics. Thus, co-administration of LEV with Terumeal® Soft reduced the absorption of LEV from the gastrointestinal tract, which was prevented by administering Terumeal ® Soft 2 h after LEV administration. Semisolid Racol ® NF altered LEV pharmacokinetics without decreasing its gastrointestinal absorption. Our findings suggested that careful monitoring of the plasma LEV levels is necessary when co-administering LEV with Terumeal ® Soft, semisolid Racol ® NF, or any other semisolid ENs, to prevent the inadvertent effects of the interaction between LEV and ENs.

Danazol (DNZ) is a synthetic androgen derivative used for the treatment of intractable hematological disorders. In this study, we investigated the effects of DNZ on CYP3A activity in hepatic and small intestinal microsomes and the pharmacokinetics of midazolam (MDZ), a typical substrate for CYP3A, in rats. MDZ 4-hydroxylation activities in hepatic and small intestinal microsomes significantly decreased 24 h after DNZ (100 mg/kg, i.p.) treatment. Time-dependent inactivation of MDZ 4-hydroxylation activities was noted when microsomes were pre-incubated with DNZ in the presence of a NADPH-generating system. The Western blot analysis indicated that the decrease observed in enzyme activity was not due to changes in the protein expression of CYP3A. In contrast to the intravenous administration, serum MDZ concentrations in DNZ-treated rats were markedly higher than those in control rats when administered orally. DNZ treatment increased MDZ oral bioavailability by approximately 2.5-folds. We herein demonstrated that DNZ increased the bioavailability of orally administered MDZ through irreversible inactivation of hepatic and intestinal CYP3A in rats.

Type 2 diabetes mellitus (T2DM) incidence is increasing worldwide. The fatty acid composition of phospholipids—a major component of biological membranes—has received research attention owing to their involvement in T2DM onset and progression. We hypothesized that changes in the fatty acid composition of phospholipids in the liver, the central organ of energy metabolism, alleviate their aberrant metabolism. We focused on lysophospholipid acyltransferase 10 (LPLAT10/LPCAT4/LPEAT2), an enzyme that changes the fatty acid composition of phospholipids, and examined the effect of LPLAT10 on glucose metabolism. To overexpress LPLAT10 in mouse liver, we generated an LPLAT10-expressing adenovirus (Ad) vector (Ad-LPLAT10) using an improved Ad vector. Hepatic LPLAT10 mRNA and protein expression in Ad-LPLAT10-treated mice was much higher than that in mice treated with control Ad vector. Induction of glucose-stimulated insulin secretion (GSIS) suppressed postprandial hyperglycemia in Ad-LPLAT10-treated mice compared with that in control Ad-vector-treated mice. Hepatic and serum levels of phosphatidylcholine, containing polyunsaturated fatty acid, were elevated in Ad-LPLAT10-treated mice. Elevated phosphatidylcholine levels increased GSIS in mouse insulinoma cells. Our study suggests that LPLAT10 is a promising new therapeutic target for T2DM.