Development of tactile allodynia and thermal hyperalgesia by intrathecally administered platelet-activating factor in mice

Platelet-activating factor (PAF) is a potent inflammatory lipid mediator in peripheral tissues. However, its role in mediation of nociception in central nervous system is unknown. In the present study, whether PAF plays some role in pain transduction in the spinal cord was studied in mice. Intrathecal injection of PAF induced tactile pain, tactile allodynia at as low as 10 fg ~ 1 pg with a peak response at 100 fg, while lyso-PAF was without effect in the range of doses. Tactile allodynia induced by PAF was blocked by a PAF receptor antagonists, TCV-309, WEB 2086 and BN 50739. The expression of PAF receptor mRNA by RT-PCR was observed in DRG and spinal cord in mice. ATP P2X receptor antagonists, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP), NMDA receptor antagonist, MK 801 and nitric oxide synthetase inhibitor, 7-nitroindazole blocked the PAF-induced tactile allodynia. PAF-induced tactile allodynia and thermal hyperalgesia disappeared in neonatally capsaicin-treated adult mice, while tactile allodynia but not thermal hyperalgesia induced by intrathecally injected α,β-methylene ATP, a P2X receptor agonist, was capsaicin-insensitive. The present study demonstrated that PAF is a potent inducer of tactile allodynia and thermal hyperalgesia at the level of the spinal cord. PAF-evoked tactile allodynia is suggested to be mediated by ATP and the following NMDA and NO cascade through capsaicin-sensitive fiber, different from exogenously injected α,β-methylene ATP which is insensitive to capsaicin treatment

A Genetic Variant in the IL-17 Promoter Is Functionally Associated with Acute Graft-Versus-Host Disease after Unrelated Bone Marrow Transplantation

Interleukin IL-17 is a proinflammatory cytokine that has been implicated in the pathogenesis of various autoimmune diseases. The single nucleotide polymorphism (SNP), rs2275913, in the promoter region of the IL-17 gene is associated with susceptibility to ulcerative colitis. When we examined the impact of rs2275913 in a cohort consisting of 438 pairs of patients and their unrelated donors transplanted through the Japan Marrow Donor Program, the donor IL-17 197A allele was found to be associated with a higher risk of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.00 to 2.13; P = 0.05). Next, we investigated the functional relevance of the rs2275913 SNP. In vitro stimulated T cells from healthy individuals possessing the 197A allele produced significantly more IL-17 than those without the 197A allele. In a gene reporter assay, the 197A allele construct induced higher luciferase activity than the 197G allele, and the difference was higher in the presence of T cell receptor activation and was abrogated by cyclosporine treatment. Moreover, the 197A allele displayed a higher affinity for the nuclear factor activated T cells (NFAT), a critical transcription factor involved in IL-17 regulation. These findings substantiate the functional relevance of the rs2275913 polymorphism and indicate that the higher IL-17 secretion by individuals with the 197A allele likely accounts for their increased risk for acute GVHD and certain autoimmune diseases

A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis

In clinical studies, the next-generation anti-tumor necrosis factor-alpha (TNF-α) single domain antibody ozoralizumab showed high clinical efficacy shortly after the subcutaneous injection. To elucidate the mechanism underlying the rapid onset of the effects of ozoralizumab, we compared the biodistribution kinetics of ozoralizumab and adalimumab after subcutaneous injection in an animal model of arthritis. Alexa Fluor 680-labeled ozoralizumab and adalimumab were administered by subcutaneous injection once (2 mg/kg) at five weeks after induction of collagen-induced arthritis (CIA) in an animal arthritis model. The time-course of changes in the fluorescence intensities of the two compounds in the paws and serum were evaluated. The paws of the CIA mice were harvested at four and eight hours after the injection for fluorescence microscopy. Biofluorescence imaging revealed better distribution of ozoralizumab to the joint tissues than of adalimumab, as early as at four hours after the injection. Fluorescence microscopy revealed a greater fluorescence intensity of ozoralizumab in the joint tissues than that of adalimumab at eight hours after the injection. Ozoralizumab showed a significantly higher absorption rate constant as compared with adalimumab. These results indicate that ozoralizumab enters the systemic circulation more rapidly and is distributed to the target tissues earlier and at higher levels than conventional IgG antibodies. Our investigation provides new insight into the mechanism underlying the rapid onset of the effects of ozoralizumab in clinical practice.Oyama S., Ebina K., Etani Y., et al. A novel anti-TNF-α drug ozoralizumab rapidly distributes to inflamed joint tissues in a mouse model of collagen induced arthritis. Scientific Reports 12, 18102 (2022); https://doi.org/10.1038/s41598-022-23152-6

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Genetic Variants of Human Granzyme B Predict Transplant Outcomes after HLA Matched Unrelated Bone Marrow Transplantation for Myeloid Malignancies

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41–0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27–0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47–0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35–1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT

Research Activities in the Department of Nursing

Research activity at the Department of Nursing is overviewed from the point of research topics, the theme of the projects admitted for grant from the Ministry of Education and Science of Japan, and expected research topics, trying to clarify the needs and challenges of the Department from multilateral aspects in future research activities. The Department of Nursing, Aino University is currently divided into the five areas and further into 12 fields. On the other hand, according to the Scientific Research Grant Program (2015 fiscal year), the research topics in nursing science is subdivided into the five areas; a) basic nursing, b) clinical nursing, c) lifelong developmental nursing, d) elderly nursing, and e) community health nursing