start-ver=1.4 cd-journal=joma no-vol=329 cd-vols= no-issue=1 article-no= start-page=L183 end-page=L196 dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=20250701 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Activated factor X inhibition ameliorates NF-ƒÈB-IL-6-mediated perivascular inflammation and pulmonary hypertension en-subtitle= kn-subtitle= en-abstract= kn-abstract=Activated factor X (FXa) induces inflammatory response and cell proliferation in various cell types via activation of proteinase-activated receptor-1 (PAR1) and/or PAR2. We thus aimed to investigate the impact of FXa on the development of pulmonary arterial hypertension (PAH) and the mechanisms involved. The effects of edoxaban, a selective FXa inhibitor, on hemodynamic, right ventricular (RV) hypertrophy, and vascular remodeling were evaluated in a monocrotaline (MCT)-exposed pulmonary hypertension (PH) rat model. At 21 days after a single subcutaneous injection of MCT of 60 mg/kg, right ventricular systolic pressure (RVSP) and total pulmonary vascular resistance index (TPRI) were elevated concomitant with the increased plasma FXa and lung interleukin-6 (IL-6) mRNA. Daily administration of edoxaban (10 mg/kg/day, by gavage) starting from the day of MCT injection for 21 days ameliorated RVSP, TPRI, RV hypertrophy, pulmonary vascular remodeling, and macrophage accumulation. Edoxaban reduced nuclear factor-kappa B (NF-ƒÈB) activity and IL-6 mRNA level in the lungs of MCT-exposed rats. mRNA levels of FXa, PAR1, and PAR2 in cultured pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with PAH were higher than those seen in normal PASMCs. FXa stimulation increased cell proliferation and mRNA level of IL-6 in normal PASMCs, both of which were blunted by edoxaban and PAR1 antagonist. Moreover, FXa stimulation activated extracellularly regulated kinases 1/2 in a PAR1-dependent manner. Inhibition of FXa ameliorates NF-ƒÈB-IL-6-mediated perivascular inflammation, pulmonary vascular remodeling, and the development of PH in MCT-exposed rats, suggesting that FXa may be a potential target for the treatment of PAH.
NEW & NOTEWORTHY This study demonstrated that chronic treatment with activated factor X (FXa) inhibitor ameliorated NF-ƒÈB-IL-6-mediated perivascular inflammation in a rat model with pulmonary arterial hypertension, which is associated with elevated FXa activity. FXa may act on pulmonary arterial smooth muscle cells, inducing cell proliferation and inflammatory response via upregulated PAR1, thereby contributing to pulmonary vascular remodeling. Understanding the patient-specific pathophysiology is a prerequisite for applying FXa-targeted therapy to the treatment of pulmonary arterial hypertension. en-copyright= kn-copyright= en-aut-name=ImakiireSatomi en-aut-sei=Imakiire en-aut-mei=Satomi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=KimuroKeiji en-aut-sei=Kimuro en-aut-mei=Keiji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YoshidaKeimei en-aut-sei=Yoshida en-aut-mei=Keimei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MasakiKohei en-aut-sei=Masaki en-aut-mei=Kohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IzumiRyo en-aut-sei=Izumi en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ImabayashiMisaki en-aut-sei=Imabayashi en-aut-mei=Misaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WatanabeTakanori en-aut-sei=Watanabe en-aut-mei=Takanori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=IshikawaTomohito en-aut-sei=Ishikawa en-aut-mei=Tomohito kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=HosokawaKazuya en-aut-sei=Hosokawa en-aut-mei=Kazuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=MatsushimaShouji en-aut-sei=Matsushima en-aut-mei=Shouji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HashimotoToru en-aut-sei=Hashimoto en-aut-mei=Toru kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=ShinoharaKeisuke en-aut-sei=Shinohara en-aut-mei=Keisuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=KatsukiShunsuke en-aut-sei=Katsuki en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=MatobaTetsuya en-aut-sei=Matoba en-aut-mei=Tetsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=NakamuraKazufumi en-aut-sei=Nakamura en-aut-mei=Kazufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=HiranoKatsuya en-aut-sei=Hirano en-aut-mei=Katsuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=TsutsuiHiroyuki en-aut-sei=Tsutsui en-aut-mei=Hiroyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=AbeKohtaro en-aut-sei=Abe en-aut-mei=Kohtaro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= affil-num=1 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=2 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=3 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=4 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=5 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=6 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=7 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=8 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=9 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=10 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=11 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=12 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=13 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=14 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=15 en-affil=Department of Cardiovascular Medicine, Okayama University kn-affil= affil-num=16 en-affil=Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University kn-affil= affil-num=17 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= affil-num=18 en-affil=Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University kn-affil= en-keyword=factor Xa kn-keyword=factor Xa en-keyword=IL-6 kn-keyword=IL-6 en-keyword=proteinase-activated receptor kn-keyword=proteinase-activated receptor en-keyword=pulmonary arterial hypertension kn-keyword=pulmonary arterial hypertension en-keyword=pulmonary hypertension kn-keyword=pulmonary hypertension END start-ver=1.4 cd-journal=joma no-vol=326 cd-vols= no-issue=6 article-no= start-page=F1054 end-page=F1065 dt-received= dt-revised= dt-accepted= dt-pub-year=2024 dt-pub=20240530 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Preventive effects of vasohibin-2-targeting peptide vaccine for diabetic nephropathy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Diabetic nephropathy remains the leading cause of end-stage kidney disease in many countries, and additional therapeutic targets are needed to prevent its development and progression. Some angiogenic factors are involved in the pathogenesis of diabetic nephropathy. Vasohibin-2 (VASH2) is a novel proangiogenic factor, and our previous study showed that glomerular damage is inhibited in diabetic Vash2 homozygous knockout mice. Therefore, we established a VASH2-targeting peptide vaccine as a tool for anti-VASH2 therapy in diabetic nephropathy. In this study, the preventive effects of the VASH2-targeting peptide vaccine against glomerular injury were examined in a streptozotocin (STZ)-induced diabetic mouse model. The mice were subcutaneously injected with the vaccine at two doses 2 wk apart and then intraperitoneally injected with 50 mg/kg STZ for 5 consecutive days. Glomerular injury was evaluated 20 wk after the first vaccination. Treatment with the VASH2-targeting peptide vaccine successfully induced circulating anti-VASH2 antibody without inflammation in major organs. Although the vaccination did not affect blood glucose levels, it significantly prevented hyperglycemia-induced increases in urinary albumin excretion and glomerular volume. The vaccination did not affect increased VASH2 expression but significantly inhibited renal angiopoietin-2 (Angpt2) expression in the diabetic mice. Furthermore, it significantly prevented glomerular macrophage infiltration. The preventive effects of vaccination on glomerular injury were also confirmed in db/db mice. Taken together, the results of this study suggest that the VASH2-targeting peptide vaccine may prevent diabetic glomerular injury in mice by inhibiting Angpt2-mediated microinflammation. en-copyright= kn-copyright= en-aut-name=NakashimaYuri en-aut-sei=Nakashima en-aut-mei=Yuri kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanabeKatsuyuki en-aut-sei=Tanabe en-aut-mei=Katsuyuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MifuneTomoyo en-aut-sei=Mifune en-aut-mei=Tomoyo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NakadoiTakato en-aut-sei=Nakadoi en-aut-mei=Takato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HayashiHiroki en-aut-sei=Hayashi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NakagamiHironori en-aut-sei=Nakagami en-aut-mei=Hironori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SatoYasufumi en-aut-sei=Sato en-aut-mei=Yasufumi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=WadaJun en-aut-sei=Wada en-aut-mei=Jun kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=2 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=3 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=4 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= affil-num=5 en-affil=Department of Health Development and Medicine, Osaka University Graduate School of Medicine kn-affil= affil-num=6 en-affil=Department of Health Development and Medicine, Osaka University Graduate School of Medicine kn-affil= affil-num=7 en-affil=New Industry Creation Hatchery Center, Tohoku University kn-affil= affil-num=8 en-affil=Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences kn-affil= en-keyword=albuminuria kn-keyword=albuminuria en-keyword=diabetic nephropathy kn-keyword=diabetic nephropathy en-keyword=macrophages kn-keyword=macrophages en-keyword=peptide vaccine kn-keyword=peptide vaccine en-keyword=vasohibin-2 kn-keyword=vasohibin-2 END start-ver=1.4 cd-journal=joma no-vol=127 cd-vols= no-issue=5 article-no= start-page=1398 end-page=1406 dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220509 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tactile angle discriminability improvement: contributions of working memory training and continuous attended sensory input en-subtitle= kn-subtitle= en-abstract= kn-abstract=Perceptual learning is commonly assumed to enhance perception through continuous attended sensory input. However, learning is generalizable to performance in untrained stimuli and tasks. Although previous studies have observed a possible generalization effect across tasks as a result of working memory (WM) training, comparisons of the contributions of WM training and continuous attended sensory input to perceptual learning generalization are still rare. Therefore, we compared which factors contributed most to perceptual generalization and investigated which skills acquired during WM training led to tactile generalization across tasks. Here, a Braille-like dot pattern matching n-back WM task was used as the WM training task, with four workload levels (0, 1, 2, and 3-back levels). A tactile angle discrimination (TAD) task was used as a pre- and posttest to assess improvements in tactile perception. Between tests, four subject groups were randomly assigned to four different workload n-back tasks to consecutively complete three sessions of training. The results showed that tactile n-back WM training could enhance TAD performance, with the 3-back training group having the highest TAD threshold improvement rate. Furthermore, the rate of WM capacity improvement on the 3-back level across training sessions was correlated with the rate of TAD threshold improvement. These findings suggest that continuous attended sensory input and enhanced WM capacity can lead to improvements in TAD ability, and that greater improvements in WM capacity can predict greater improvements in TAD performance.
NEW & NOTEWORTHY Perceptual learning is not always specific to the trained task and stimuli. We demonstrate that both continuous attended sensory input and improved WM capacity can be used to enhance tactile angle discrimination (TAD) ability. Moreover, WM capacity improvement is important in generalizing the training effect to the TAD ability. These findings contribute to understanding the mechanism of perceptual learning generalization across tasks. en-copyright= kn-copyright= en-aut-name=WangWu en-aut-sei=Wang en-aut-mei=Wu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YangJiajia en-aut-sei=Yang en-aut-mei=Jiajia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YuYinghua en-aut-sei=Yu en-aut-mei=Yinghua kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=LiHuazhi en-aut-sei=Li en-aut-mei=Huazhi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=LiuYulong en-aut-sei=Liu en-aut-mei=Yulong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=YuYiyang en-aut-sei=Yu en-aut-mei=Yiyang kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=YuJiabin en-aut-sei=Yu en-aut-mei=Jiabin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=TangXiaoyu en-aut-sei=Tang en-aut-mei=Xiaoyu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=YangJingjing en-aut-sei=Yang en-aut-mei=Jingjing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=TakahashiSatoshi en-aut-sei=Takahashi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=EjimaYoshimichi en-aut-sei=Ejima en-aut-mei=Yoshimichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=WuJinglong en-aut-sei=Wu en-aut-mei=Jinglong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=School of Psychological and Cognitive Sciences, Peking University kn-affil= affil-num=2 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=College of Information Engineering, China Jiliang University kn-affil= affil-num=8 en-affil=School of Psychology, Liaoning Collaborative Innovation Center of Children and Adolescents Healthy Personality Assessment and Cultivation, Liaoning Normal University kn-affil= affil-num=9 en-affil=School of Computer Science and Technology, Changchun University of Science and Technology kn-affil= affil-num=10 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=11 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=12 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=continuous attended sensory input kn-keyword=continuous attended sensory input en-keyword=perceptual learning kn-keyword=perceptual learning en-keyword=tactile angle discriminability kn-keyword=tactile angle discriminability en-keyword=tactile generalization kn-keyword=tactile generalization en-keyword=working memory training kn-keyword=working memory training END start-ver=1.4 cd-journal=joma no-vol=122 cd-vols= no-issue=5 article-no= start-page=1918 end-page=1927 dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20191025 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Tactile angle discriminability improvement: roles of training time intervals and different types of training tasks en-subtitle= kn-subtitle= en-abstract= kn-abstract=Perceptual learning, which is not limited to sensory modalities such as vision and touch, emerges within a training session and between training sessions and is accompanied by the remodeling of neural connections in the cortex. However, limited knowledge exists regarding perceptual learning between training sessions. Although tactile studies have paid attention to between-session learning effects, there have been few studies asking fundamental questions regarding whether the time interval between training sessions affects tactile perceptual learning and generalization across tactile tasks. We investigated the effects of different training time intervals on the consecutive performance of a tactile angle discrimination (AD) task and a tactile orientation discrimination (OD) task training on tactile angle discriminability. The results indicated that in the short-interval training group, AD task performance significantly improved in the early stage of learning and nearly plateaued in the later stage, whereas in the long-interval training group, significant improvement was delayed and then also nearly plateaued in the later stage; additionally, improved OD task performance resulted in improved AD task performance. These findings suggest that training time interval affects the early stage of learning but not the later stage and that generalization occurs between different types of tactile tasks. en-copyright= kn-copyright= en-aut-name=WangWu en-aut-sei=Wang en-aut-mei=Wu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=YangJiajia en-aut-sei=Yang en-aut-mei=Jiajia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=WuQiong en-aut-sei=Wu en-aut-mei=Qiong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YuJiabin en-aut-sei=Yu en-aut-mei=Jiabin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=TakahashiSatoshi en-aut-sei=Takahashi en-aut-mei=Satoshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=EjimaYoshimichi en-aut-sei=Ejima en-aut-mei=Yoshimichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=WuJinglong en-aut-sei=Wu en-aut-mei=Jinglong kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama kn-affil= affil-num=3 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil= Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=between-session learning kn-keyword=between-session learning en-keyword=generalization kn-keyword=generalization en-keyword=tactile angle discriminability kn-keyword=tactile angle discriminability en-keyword=training time interval kn-keyword=training time interval END