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写真a

ナカムラ クニユキ
中村 晋之
NAKAMURA KUNIYUKI
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九州大学病院 腎・高血圧・脳血管内科 助教
医学部 医学科(併任)
職名
助教
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<研究> 脳血管障害に対する修復機構の解明に関して、特に脳血管ペリサイトおよび細胞外マトリックスに着目して基礎的研究を行っている。 <教育> 医学科学生の基礎配属、概説講義、シミュレーション実習、ベッドサイド実習、クリニカルクラークシップでの実習指導を行っている。大学院生に対する研究指導を行っている。 <臨床> 九州大学病院における脳血管障害急性期の対応(脳卒中ホットライン)および脳血管障害患者の外来/入院診療にあたっている。
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学位

  • 博士(医学)

経歴

  • 福岡歯科大学 2013.4~2015.3   

研究テーマ・研究キーワード

  • 研究テーマ: 脳血管ペリサイトおよび細胞外マトリックスによる、脳血管障害に対する修復機構の解明

    研究キーワード: ペリサイト, 細胞外マトリックス, 血液脳関門, 脳梗塞

    研究期間: 2018年4月

受賞

  • Young Investigator Award

    2018年6月   第50回日本結合組織学会学術大会   細胞外マトリックス蛋白Perlecanは脳梗塞後のペリサイトの遊走を促進し、血液脳関門の修復に関与する.

  • Fellows Award for Research Excellence (FARE) 2018

    2017年11月   National Institutes of Health  

  • Young bursary

    2007年5月   The 23rd International Symposium on Cerebral Blood Flow, Metabolism and Function  

論文

  • Low-dose sodium-glucose cotransporter 2 inhibitor ameliorates ischemic brain injury in mice through pericyte protection without glucose-lowering effects. 査読 国際誌

    Masamitsu Takashima, Kuniyuki Nakamura, Takuya Kiyohara, Yoshinobu Wakisaka, Masaoki Hidaka, Hayato Takaki, Kei Yamanaka, Tomoya Shibahara, Masanori Wakisaka, Tetsuro Ago, Takanari Kitazono

    Communications biology   5 ( 1 )   653 - 653   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have attracted attention for their cardiorenal-protective properties beyond their glucose-lowering effect. However, their benefits in ischemic stroke remain controversial. Here we show the effects of luseogliflozin, a selective SGLT2 inhibitor, in acute ischemic stroke, using a permanent middle cerebral artery occlusion (pMCAO) model in non-diabetic mice. Pretreatment with low-dose luseogliflozin, which does not affect blood glucose levels, significantly attenuated infarct volume, blood-brain barrier disruption, and motor dysfunction after pMCAO. SGLT2 was expressed predominantly in brain pericytes and was upregulated in peri- and intra-infarct areas. Notably, luseogliflozin pretreatment reduced pericyte loss in ischemic areas. In cultured pericytes, luseogliflozin activated AMP-activated protein kinase α and increased mitochondrial transcription factor A expression and number of mitochondria, conferring resistance to oxygen-glucose deprivation. Collectively, pre-stroke inhibition of SGLT2 induces ischemic tolerance in brain pericytes independent of the glucose-lowering effect, contributing to the attenuation of ischemic brain injury.

    DOI: 10.1038/s42003-022-03605-4

  • Reciprocal Interaction Between Pericytes and Macrophage in Poststroke Tissue Repair and Functional Recovery. 査読 国際誌

    Tomoya Shibahara, Tetsuro Ago, Masaki Tachibana, Kuniyuki Nakamura, Kei Yamanaka, Junya Kuroda, Yoshinobu Wakisaka, Takanari Kitazono

    Stroke   51 ( 10 )   3095 - 3106   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND PURPOSE: Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery. METHODS: We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFRβ (platelet-derived growth factor receptor β) heterozygous knockout (Pdgfrb+/-) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types. RESULTS: Localization of PDGFRβ-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated in Pdgfrb+/- mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower in Pdgfrb+/- mice. Cultured pericytes expressed Ccl2 and Csf1, both of which were significantly increased by PDGF-BB and suppressed by a PDGFRβ inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated in Pdgfrb+/- mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors, Msr1 and Lrp1. Macrophages processing myelin debris produced trophic factors, enhancing PDGFRβ signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated in Pdgfrb+/- mice, parallel with the extent of tissue repair. CONCLUSIONS: A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.

    DOI: 10.1161/STROKEAHA.120.029827.

  • Pericyte-Mediated Tissue Repair through PDGFRβ Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke. 査読 国際誌

    Shibahara T, Ago T, Nakamura K, Tachibana M, Yoshikawa Y, Komori M, Yamanaka K, Wakisaka Y, Kitazono T.

    eNeuro   7 ( 2 )   2020年3月

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    記述言語:英語  

    DOI: 10.1523/ENEURO.0474-19.2020.

  • Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier. 査読 国際誌

    Nakamura K, Ikeuchi T, Nara K, Rhodes CS, Zhang P, Chiba Y, Kazuno S, Miura Y, Ago T, Arikawa-Hirasawa E, Mukouyama YS, Yamada Y.

    J Cell Biol.   218 ( 10 )   3506 - 3525   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Ischemic stroke causes blood-brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2 - / - -TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2 - / - -TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke.

    DOI: 10.1083/jcb.201807178.

  • Possible involvement of basic FGF in the upregulation of PDGFRβ in pericytes after ischemic stroke. 査読 国際誌

    Nakamura K*, Arimura K*, Nishimura A, Tachibana M, Yoshikawa Y, Makihara N, Wakisaka Y, Kuroda J, Kamouchi M, Ooboshi H, Kitazono T, Ago T. * equally contributed

    Brain Res.   1630   98 - 108   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Central nervous system (CNS) pericytes have been recognized as an indispensable component of the neurovascular unit. The expression of platelet-derived growth factor receptor β (PDGFRβ) is markedly increased in CNS pericytes after brain ischemia. It has been elucidated that PDGFRβ, expressed in pericytes and pericyte-derived fibroblast-like cells, plays important roles in the maintenance of the blood-brain barrier (BBB) and in the repair process in infarct areas. The aim of this study was to uncover how the PDGFRβ expression is regulated in pericytes after brain ischemia. We found that basic fibroblast growth factor (bFGF), but neither hypoxia at 1% O2 nor acidification at pH 6.5, significantly upregulated the PDGFRβ expression in human cultured CNS pericytes. SU5402, an inhibitor of FGF receptor (FGFR), and inhibitors of its downstream effectors Akt and Erk abolished the bFGF-induced upregulation of PDGFRβ. On the other hand, acidification significantly upregulated the expression of bFGF, while hypoxia upregulated the expression of FGFR1 in the pericytes. The expression of bFGF and FGFR1 was markedly induced in the ischemic hemisphere after ischemic insult in a middle cerebral artery occlusion stroke model. Immunofluorescent double labeling demonstrated that the expression of bFGF and FGFR1 was co-localized with PDGFRβ-positive cells in peri-infarct areas. Moreover, treatment with bFGF enhanced cell growth and the PDGF-BB-induced migratory activity of cultured pericytes, which were significantly suppressed by SU5402 or Sunitinib, an inhibitor of PDGFR. These data suggested that increased bFGF upregulates the expression of PDGFRβ and may enhance PDGFRβ-mediated pericyte functions after brain ischemia.

    DOI: 10.1016/j.brainres.2015.11.003

  • Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke. 査読 国際誌

    Makihara N, Arimura K, Ago T, Tachibana M, Nishimura A, Nakamura K, Matsuo R, Wakisaka Y, Kuroda J, Sugimori H, Kamouchi M, Kitazono T.

    Exp Neurol.   264   127 - 34   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Fibrosis is concomitant with repair processes following injuries in the central nervous system (CNS). Pericytes are considered as an origin of fibrosis-forming cells in the CNS. Here, we examined whether platelet-derived growth factor receptor β (PDGFRβ), a well-known indispensable molecule for migration, proliferation, and survival of pericytes, was involved in the production of extracellular matrix proteins, fibronectin and collagen type I, which is crucial for fibrosis after ischemic stroke. Immunohistochemistry demonstrated induction of PDGFRβ expression in vascular cells of peri-infarct areas at 3-7days in a mouse stroke model. The PDGFRβ-expressing cells extended from peri-infarct areas toward the ischemic core after day 7 while expressing fibronectin and collagen type I in the infarct areas. In contrast, desmin and α-smooth muscle actin, markers of pericytes, were only expressed in vascular cells. In PDGFRβ heterozygous knockout mice, the expression of fibronectin and collagen type I was attenuated at both mRNA and protein levels with an enlargement of the infarct volume after ischemic stroke compared with that in wild-type littermates. In cultured brain pericytes, the expression of PDGF-B, PDGFRβ, fibronectin, and collagen type I, but not desmin, was significantly increased by serum depletion (SD). The SD-induced upregulation of fibronectin and collagen type I was suppressed by SU11652, an inhibitor of PDGFRβ, while PDGF-B further increased the SD-induced upregulation. In conclusion, the expression level of PDGFRβ may be a crucial determinant of fibrosis after ischemic stroke. Moreover, PDGFRβ signaling participates in the production of fibronectin and collagen type I after ischemic stroke.

    DOI: 10.1016/j.expneurol.2014.12.007

  • Extracellular acidification activates cAMP responsive element binding protein via Na+/H+ exchanger isoform 1-mediated Ca2+ oscillation in central nervous system pericytes. 査読 国際誌

    Nakamura K, Kamouchi M, Arimura K, Nishimura A, Kuroda J, Ishitsuka K, Tokami H, Sugimori H, Ago T, Kitazono T.

    Arterioscler Thromb Vasc Biol.   32 ( 11 )   2670 - 7   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: We have previously shown that Na(+)/H(+) exchanger isoform 1 (NHE1) plays an important role in Ca(2+) signaling and cell proliferation in human central nervous system (CNS) pericytes. The aims of the present study were to elucidate how NHE1-induced Ca(2+) signaling during acidosis is transformed into cellular responses in CNS pericytes. METHODS AND RESULTS: Human CNS pericytes were cultured, and the activation of cAMP responsive element-binding protein (CREB) was evaluated by Western blotting analysis, immunofluorescence, and luciferase assays. In human CNS pericytes, low extracellular Na(+) or low pH generated Ca(2+) oscillation and subsequently phosphorylated Ca(2+)/calmodulin-dependent kinase II (CaMKII) and CREB in a time-dependent manner. Focal cerebral ischemia was applied using photothrombotic distal middle cerebral artery occlusion in mice, and the phosphorylation of CREB and the production of interleukin-6 were observed in pericytes migrating into the peri-infarct penumbra during the early phase after ischemic insult. CONCLUSIONS: Our results indicate that extracellular acidosis induces Ca(2+) oscillation via NHE1, leading to Ca(2+)/CaMKII-dependent CREB activation in human CNS pericytes. Acidosis may upregulate a variety of proteins, such as interleukin-6, through the NHE1-Ca2+/CaMKII-CREB pathway in brain pericytes and may thus modulate brain ischemic insult.

    DOI: 10.1161/ATVBAHA.112.254946

  • PDGF receptor β signaling in pericytes following ischemic brain injury. 査読 国際誌

    Arimura K, Ago T, Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J, Sugimori H, Ooboshi H, Sasaki T, Kitazono T.

    Curr Neurovasc Res.   9 ( 1 )   1 - 9   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Platelet derived growth factor (PDGF)-B plays a neuroprotective role in brain damages, including ischemic stroke. It has been suggested recently that PDGF receptor β (PDGFRβ) expressed in brain pericytes as well as in neurons and astrocytes may mediate the neuroprotective role of PDGF-B. The aims of this study were to elucidate the roles of PDGFRβ signaling in brain pericytes after ischemic stroke. In a rat middle cerebral artery occlusion (MCAO) model, PDGFRβ expression was induced specifically in the pericytes in peri-infarct areas and its level was gradually increased. PDGF-B induced marked phosphorylation of Akt in cultured brain pericytes. Consistently, PDGF-B was upregulated in endothelial cells in per-infarct areas and Akt was strongly phosphorylated in the PDGFRβ-expressing pericytes in periinfarct areas after MCAO. In the cultured pericytes, PDGF-B induced cell growth and anti-apoptotic responses through Akt. Furthermore, PDGF-B significantly increased the expression of nerve growth factor (NGF) and neurotrophin-3 (NT-3) through Akt in the pericytes. Thus, the PDGFRβ-Akt signaling in brain pericytes may play various important roles leading to neuroprotection after ischemic stroke.

  • Role of NHE1 in calcium signaling and cell proliferation in human CNS pericytes. 査読 国際誌

    Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Matsuo R, Hagiwara N, Ishikawa E, Ooboshi H, Ibayashi S, Iida M.

    Am J Physiol Heart Circ Physiol.   294 ( 4 )   H1700-7   2008年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The central nervous system (CNS) pericytes play an important role in brain microcirculation. Na(+)/H(+) exchanger isoform 1 (NHE1) has been suggested to regulate the proliferation of nonvascular cells through the regulation of intracellular pH, Na(+), and cell volume; however, the relationship between NHE1 and intracellular Ca(2+), an essential signal of cell growth, is still not known. The aim of the present study was to elucidate the role of NHE1 in Ca(2+) signaling and the proliferation of human CNS pericytes. The intracellular Ca(2+) concentration was measured by fura 2 in cultured human CNS pericytes. The cells showed spontaneous Ca(2+) oscillation under quasi-physiological ionic conditions. A decrease in extracellular pH or Na(+) evoked a transient Ca(2+) rise followed by Ca(2+) oscillation, whereas an increase in pH or Na(+) did not induce the Ca(2+) responses. The Ca(2+) oscillation was inhibited by an inhibitor of NHE in a dose-dependent manner and by knockdown of NHE1 by using RNA interference. The Ca(2+) oscillation was completely abolished by thapsigargin. The proliferation of pericytes was attenuated by inhibition of NHE1. These results demonstrate that NHE1 regulates Ca(2+) signaling via the modulation of Ca(2+) release from the endoplasmic reticulum, thus contributing to the regulation of proliferation in CNS pericytes.

    DOI: 10.1152/ajpheart.01203.2007

  • Association between decreases in serum uric acid levels and unfavorable outcomes after ischemic stroke: A multicenter hospital-based observational study. 査読 国際誌

    Kuniyuki Nakamura, Kana Ueki, Ryu Matsuo, Takuya Kiyohara, Fumi Irie, Yoshinobu Wakisaka, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono

    PloS one   18 ( 6 )   e0287721   2023年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The association between clinical outcomes in ischemic stroke patients and decreases in serum uric acid levels, which often occur during the acute phase, remains unknown. Herein, we aimed to investigate the association using a large-scale, multicenter stroke registry. METHODS: We analyzed 4,621 acute ischemic stroke patients enrolled in the Fukuoka Stroke Registry between June 2007 and September 2019 whose uric acid levels were measured at least twice during hospitalization (including on admission). The study outcomes were poor functional outcome (modified Rankin Scale score ≥3) and functional dependence (modified Rankin Scale score 3-5) at 3 months after stroke onset. Changes in uric acid levels after admission were evaluated using a decrease rate that was classified into 4 sex-specific grades ranging from G1 (no change/increase after admission) to G4 (most decreased). Multivariable logistic regression analyses were used to assess the associations between decreases in uric acid levels and the outcomes. RESULTS: The frequencies of the poor functional outcome and functional dependence were lowest in G1 and highest in G4. The odds ratios (95% confidence intervals) of G4 were significantly higher for poor functional outcome (2.66 [2.05-3.44]) and functional dependence (2.61 [2.00-3.42]) when compared with G1 after adjusting for confounding factors. We observed no heterogeneity in results for subgroups categorized according to age, sex, stroke subtype, neurological severity, chronic kidney disease, or uric acid level on admission. CONCLUSIONS: Decreases in serum uric acid levels were independently associated with unfavorable outcomes after acute ischemic stroke.

    DOI: 10.1371/journal.pone.0287721

  • Sex Differences in Long-Term Functional Decline after Ischemic Stroke: A Longitudinal Observational Study from the Fukuoka Stroke Registry 査読 国際誌

    Fumi Irie, Ryu Matsuo, Kuniyuki Nakamura, Yoshinobu Wakisaka, Tetsuro Ago, Takanari Kitazono, Masahiro Kamouchi; Fukuoka Stroke Registry Investigators

    Cerebrovasc Dis .   1 - 8   2023年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Data on sex differences in poststroke functional status for a period longer than 1 year based on large cohorts are sparse. This study aimed to determine whether there are sex differences in long-term functional decline after ischemic stroke. METHODS: We tracked functional status for 5 years among 3-month survivors of acute ischemic stroke and compared outcomes between women and men using a large-scale hospital-based stroke registry in Fukuoka, Japan. Functional status was assessed using the modified Rankin Scale (mRS). Functional dependency was defined as an mRS score of 3, 4, or 5. Logistic regression analysis was used to estimate odds ratios (ORs) and 95&#37; confidence intervals of outcomes after adjusting for possible confounders. RESULTS: A total of 8,446 patients (71.9 ± 12.5 years, 3,377 (40.0&#37;) female patients) were enrolled in this study. Female sex was associated with a higher risk of functional dependency at 5 years poststroke even when adjusting for age, 3-month mRS score, and other confounding factors (multivariable-adjusted OR vs. men, 1.56 [95&#37; confidence interval, 1.26-1.93]). This significant association of female sex with higher dependency at 5 years was also found among patients who were independent at 3 months poststroke. Subgroup analysis showed that increased risk of functional dependency in female patients was more marked in patients aged ≥75 years than in those aged <75 years (p for heterogeneity = 0.02). Conversely, female sex was associated with a lower risk of death. No sex difference was observed in stroke recurrence during 5 years poststroke. DISCUSSION/CONCLUSION: This longitudinal observational study suggests that female sex was independently associated with an increased risk of functional decline in the chronic phase of stroke, especially in older patients. There was no sex difference in 5-year stroke recurrence, and thus, other factors might be involved in more significant deterioration of functional status in female survivors of ischemic stroke. Further studies are needed to elucidate underlying causes of sex differences in long-term functional decline after stroke.

    DOI: 10.1159/000526940

  • PDGFRβ-positive cell-mediated post-stroke remodeling of fibronectin and laminin α2 for tissue repair and functional recovery 査読

    Tomoya Shibahara, Kuniyuki Nakamura, Yoshinobu Wakisaka, Masahiro Shijo, Kei Yamanaka, Masamitsu Takashima, Hayato Takaki, Masaoki Hidaka, Takanari Kitazono, Tetsuro Ago

    Journal of Cerebral Blood Flow &amp; Metabolism   43 ( 4 )   518 - 530   2022年12月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    Post-stroke intra-infarct repair promotes peri-infarct neural reorganization leading to functional recovery. Herein, we examined the remodeling of extracellular matrix proteins (ECM) that constitute the intact basal membrane after permanent middle cerebral artery occlusion (pMCAO) in mice. Among ECM, collagen type IV remained localized on small vessel walls surrounding CD31-positive endothelial cells within infarct areas. Fibronectin was gradually deposited from peri-infarct areas to the ischemic core, in parallel with the accumulation of PDGFRβ-positive cells. Cultured PDGFRβ-positive pericytes produced fibronectin, which was enhanced by the treatment with PDGF-BB. Intra-infarct deposition of fibronectin was significantly attenuated in pericyte-deficient Pdgfrb+/−mice. Phagocytic activity of macrophages against myelin debris was significantly enhanced on fibronectin-coated dishes. In contrast, laminin α2, produced by GFAP- and aquaporin 4-positive astrocytes, accumulated strongly in the boundary of peri-infarct areas. Pericyte-conditioned medium increased the expression of laminin α2 in cultured astrocytes, partly through TGFβ1. Laminin α2 increased the differentiation of oligodendrocyte precursor cells into oligodendrocytes and the expression of myelin-associated proteins. Peri-infarct deposition of laminin α2 was significantly reduced in Pdgfrb+/−mice, with attenuated oligodendrogenesis in peri-infarct areas. Collectively, intra-infarct PDGFRβ-positive cells may orchestrate post-stroke remodeling of key ECM that create optimal environments promoting clearance of myelin debris and peri-infarct oligodendrogenesis.

    DOI: 10.1177/0271678x221145092

  • Deletion of Nox4 enhances remyelination following cuprizone-induced demyelination by increasing phagocytic capacity of microglia and macrophages in mice. 査読 国際誌

    Kei Yamanaka, Kuniyuki Nakamura, Tomoya Shibahara, Masamitsu Takashima, Hayato Takaki, Masaoki Hidaka, Motohiro Komori, Yoji Yoshikawa, Yoshinobu Wakisaka, Tetsuro Ago, Takanari Kitazono

    Glia   2022年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    NOX4 is a major reactive oxygen species-producing enzyme that modulates cell stress responses. We here examined the effect of Nox4 deletion on demyelination-remyelination, the most common pathological change in the brain. We used a model of cuprizone (CPZ)-associated demyelination-remyelination in wild-type and Nox4-deficient (Nox4-/- ) mice. While the CPZ-induced demyelination in the corpus callosum after 4 weeks of CPZ intoxication was slightly less pronounced in Nox4-/- mice than that in wild-type mice, remyelination following CPZ withdrawal was significantly enhanced in Nox4-/- mice with an increased accumulation of IBA1-positive microglia/macrophages in the demyelinating corpus callosum. Consistently, locomotor function, as assessed by the beam walking test, was significantly better during the remyelination phase in Nox4-/- mice. Nox4 deletion did not affect autonomous growth of primary-culture oligodendrocyte precursor cells. Although Nox4 expression was higher in cultured macrophages than in microglia, Nox4-/- microglia and macrophages both showed enhanced phagocytic capacity of myelin debris and produced increased amounts of trophic factors upon phagocytosis. The expression of trophic factors was higher, in parallel with the accumulation of IBA1-positive cells, in the corpus callosum in Nox4-/- mice than that in wild-type mice. Nox4 deletion suppressed phagocytosis-induced increase in mitochondrial membrane potential, enhancing phagocytic capacity of macrophages. Treatment with culture medium of Nox4-/- macrophages engulfing myelin debris, but not that of Nox4-/- astrocytes, enhanced cell growth and expression of myelin-associated proteins in cultured oligodendrocyte precursor cells. Collectively, Nox4 deletion promoted remyelination after CPZ-induced demyelination by enhancing microglia/macrophage-mediated clearance of myelin debris and the production of trophic factors leading to oligodendrogenesis.

    DOI: 10.1002/glia.24292

  • The presence of sodium glucose co-transporter 2 in mesangial cells and pericytes and its roles in mesangial lesions and in capillaries under diabetic and ischemic conditions. 査読 国際誌

    Masanori Wakisaka, Kuniyuki Nakamura, Takanari Kitazono

    Diabetes research and clinical practice   192   110096 - 110096   2022年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    SGLT2 is expressed in mesangial cells and pericytes, and is upregulated byhigh glucose and ischemia. Upregulated SGLT2 in both cells might directly worsen ischemia in kidney interstitial legion, heart and brain. The overexpression of SGLT2 in these cells could induce various organ failures via damages or loss of capillaries and dysfunctions of mesangial cells, which are attenuated by SGLT2 inhibitors.

    DOI: 10.1016/j.diabres.2022.110096

  • Neurosarcoidosis Presenting with Prominent Periventricular White-Matter Lesions during Steroid Treatment for Autoimmune Hepatitis 査読

    Tomoya Shibahara, Fumitaka Yoshino, Mikiaki Matsuoka, Masaki Tachibana, Kuniyuki Nakamura, Tetsuro Ago, Junya Kuroda, Hiroshi Nakane

    Case Reports in Neurology   334 - 340   2022年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1159/000526223

  • Causes of ischemic stroke in young adults versus non-young adults: A multicenter hospital-based observational study. 査読 国際誌

    Yuichiro Ohya, Ryu Matsuo, Noriko Sato, Fumi Irie, Kuniyuki Nakamura, Yoshinobu Wakisaka, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono

    PloS one   17 ( 7 )   e0268481   2022年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Very few comparative studies have focused on the differences in the causes of ischemic stroke between young adults and non-young adults. This study was performed to determine what causes of ischemic stroke are more important in young adults than in non-young adults using a large-scale multicenter hospital-based stroke registry in Fukuoka, Japan. METHODS AND RESULTS: We investigated data on 15,860 consecutive patients aged ≥18 years with acute ischemic stroke (mean age: 73.5 ± 12.4 years, 58.2&#37; men) who were hospitalized between 2007 and 2019. In total, 779 patients were categorized as young adults (≤50 years of age). Although vascular risk factors, including hypertension, diabetes mellitus, and dyslipidemia, were less frequent in young adults than in non-young adults, the prevalence of diabetes mellitus and dyslipidemia in young adults aged >40 years were comparable to those of non-young adults. Lifestyle-related risk factors such as smoking, drinking, and obesity were more frequent in young adults than in non-young adults. As young adults became older, the proportions of cardioembolism and stroke of other determined etiologies decreased, but those of large-artery atherosclerosis and small-vessel occlusion increased. Some embolic sources (high-risk sources: arterial myxoma, dilated cardiomyopathy, and intracardiac thrombus; medium-risk sources: atrial septal defect, nonbacterial thrombotic endocarditis, patent foramen ovale, and left ventricular hypokinesis) and uncommon causes (vascular diseases: reversible cerebral vasoconstriction syndrome, moyamoya disease, other vascular causes, arterial dissection, and cerebral venous thrombosis; hematologic diseases: antiphospholipid syndrome and protein S deficiency) were more prevalent in young adults than in non-young adults, and these trends decreased with age. CONCLUSIONS: Certain embolic sources and uncommon causes may be etiologically important causes of ischemic stroke in young adults. However, the contribution of conventional vascular risk factors and lifestyle-related risk factors is not negligible with advancing age, even in young adults.

    DOI: 10.1371/journal.pone.0268481

  • Progressive Small-Vessel Strokes Following Antiretroviral Therapy in a Patient with Acquired Immunodeficiency Syndrome. 査読 国際誌

    Tomoya Shibahara, Kuniyuki Nakamura, Daisuke Abe, Naoki Tagawa, Yoshinobu Wakisaka, Takanari Kitazono, Tetsuro Ago

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   31 ( 5 )   106409 - 106409   2022年5月

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    記述言語:英語  

    We report a case of a 59-year-old man with human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS) who developed multiple small-vessel strokes during the immune reconstitution phase. The patient had been diagnosed with HIV/AIDS with a low CD4 count and high viral load and started combinational antiretroviral therapy (cART) with raltegravir, emtricitabine, and tenofovir alafenamide fumarate seven months before the admission. He was admitted to our hospital with complaints of mild dysarthria and left-sided hemiparesis, but lacking consciousness/cognitive disturbances. Diffusion-weighted images (DWI) revealed multiple areas of hyperintensity in the anterior circulation system of the brain. Because we identified decreased activity of protein S through extensive examinations, we treated him initially with intravenous infusion of heparin sodium and aspirin; however, DWI detected multiple progressive small-vessel strokes after that. We considered that the immune reconstitution accounted for the small-vessel vasculopathy/vasculitis, leading to ischemic stroke. Therefore, we initiated oral administration of prednisolone, which successfully prevented stroke recurrence. This report describes a case of multiple small-vessel strokes following cART for AIDS during the immune reconstitution phase, effectively treated with steroids, which may often go undiagnosed due to their relatively mild symptoms.

    DOI: 10.1016/j.jstrokecerebrovasdis.2022.106409

  • Sex Differences in the Risk of 30-Day Death After Acute Ischemic Stroke. 査読 国際誌

    Fumi Irie, Ryu Matsuo, Kuniyuki Nakamura, Yoshinobu Wakisaka, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono

    Neurology. Clinical practice   11 ( 6 )   e809-e816   2021年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To examine sex differences in early stroke deaths according to cause of death. METHODS: We investigated 30-day deaths in patients with acute ischemic stroke enrolled in a multicenter stroke registry between 2007 and 2019 in Fukuoka, Japan. We estimated the multivariable-adjusted hazard ratios (HRs) and 95&#37; confidence intervals (CIs) of cause-specific deaths for women vs men using Cox proportional hazards models and competing risk models. The risk of acute infections during hospitalization and the associated case fatality rates were also compared between the sexes. RESULTS: Among 17,956 patients with acute ischemic stroke (women: 41.3&#37;), the crude 30-day death rate after stroke was higher in women than men. However, adjusting for age and stroke severity resulted in a lower risk of death among women (HR [95&#37; CI]: 0.76 [0.62-0.92]). Analyses using competing risk models revealed that women were less likely to die of acute infections (subdistribution HR [95&#37; CI]: 0.33 [0.20-0.54]). Further analyses showed that women were associated with a lower risk of acute infections during hospitalization (OR [95&#37; CI]: 0.62 [0.52-0.74]) and a lower risk of death due to these infections (subdistribution HR [95&#37; CI]: 052 [0.33-0.83]). CONCLUSIONS: When adjusting for confounders, the female sex was associated with a lower risk of 30-day death after stroke, which could be explained by a female survival advantage in poststroke infections. Sex-specific strategies are needed to reduce early stroke deaths. CLASSIFICATION OF EVIDENCE: This is a Class I prognostic study because it is a prospective population-based cohort with objective outcomes. Female sex appears to be protective against early stroke deaths and post stroke infections.

    DOI: 10.1212/CPJ.0000000000001087

  • Day-by-Day Blood Pressure Variability in the Subacute Stage of Ischemic Stroke and Long-Term Recurrence. 査読 国際誌

    Kenji Fukuda, Ryu Matsuo, Masahiro Kamouchi, Fumi Kiyuna, Noriko Sato, Kuniyuki Nakamura, Jun Hata, Yoshinobu Wakisaka, Tetsuro Ago, Tsutomu Imaizumi, Hisashi Kai, Takanari Kitazono, FSR Investigators

    Stroke   53 ( 1 )   70 - 78   2021年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND PURPOSE: This study aimed to determine whether variability of day-by-day blood pressure (BP) during the subacute stage of acute ischemic stroke is predictive of long-term stroke recurrence. METHODS: We analyzed 7665 patients (mean±SD age: 72.9±13.1 years; women: 42.4&#37;) hospitalized for first-ever ischemic stroke in 7 stroke centers in Fukuoka, Japan, from June 2007 to November 2018. BP was measured daily during the subacute stage (4-10 days after onset). Its mean and coefficient of variation (CV) values were calculated and divided into 4 groups according to the quartiles of these BP parameters. Patients were prospectively followed up for recurrent stroke or all-cause death. The cumulative event rate was calculated with the Kaplan-Meier method. We estimated the hazard ratios and 95&#37; confidence intervals of the events of interest after adjusting for potential confounders and mean BP values using Cox proportional hazards models. The Fine-Gray model was also used to account for the competing risk of death. RESULTS: With a mean (±SD) follow-up duration of 3.9±3.2 years, the rates of recurrent stroke and all-cause death were 3.9 and 9.9 per 100 patient-years, respectively. The cumulative event rates of recurrent stroke and all-cause death increased with increasing CVs of systolic BP and diastolic BP. The systolic BP CV was significantly associated with an increased risk of recurrent stroke after adjusting for multiple confounders and mean BP (hazard ratio [95&#37; CI] for fourth quartile versus first quartile, 1.26 [1.05-1.50]); the risk of recurrent stroke also increased with an increasing systolic BP CV for nonfatal strokes (1.26 [1.05-1.51]) and when death was regarded as a competing risk (1.21 [1.02-1.45]). Similar associations were observed for the diastolic BP CV. CONCLUSIONS: Day-by-day variability of BP during the subacute stage of acute ischemic stroke was associated with an increased long-term risk of recurrent stroke.

    DOI: 10.1161/STROKEAHA.120.033751.

  • Roles of Sodium-Glucose Cotransporter 2 of Mesangial Cells in Diabetic Kidney Disease. 査読 国際誌

    Masanori Wakisaka, Kuniyuki Nakamura, Toshiaki Nakano, Takanari Kitazono

    Journal of the Endocrine Society   5 ( 8 )   bvab083   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We have been studying the presence of sodium-glucose cotransporter 2 (SGLT2) in mesangial cells and pericytes since 1992. Recent large placebo-controlled studies of SGLT2 inhibitors in patients with type 2 diabetes mellitus have reported desirable effects of the inhibitors on the diabetic kidney and the diabetic heart. Most studies have indicated that these effects of SGLT2 inhibitors could be mediated by the tubuloglomerular feedback system. However, a recent study about urine sodium excretion in the presence of an SGLT2 inhibitor did not show any increases in urine sodium excretion. A very small dose of an SGLT2 inhibitor did not inhibit SGLT2 at the S1 segment of proximal tubules. Moreover, SGLT2 inhibition protects against progression in chronic kidney disease with and without type 2 diabetes. In these circumstances, the tubuloglomerular feedback hypothesis involves several theoretical concerns that must be clarified. The presence of SGLT2 in mesangial cells seems to be very important for diabetic nephropathy. We now propose a novel mechanism by which the desirable effects of SGLT2 inhibitors on diabetic nephropathy are derived from the direct effect on SGLT2 expressed in mesangial cells.

    DOI: 10.1210/jendso/bvab083

  • β-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke 査読 国際誌

    Takuya Kiyohara, Ryu Matsuo, Jun Hata, Kuniyuki Nakamura, Yoshinobu Wakisaka, Masahiro Kamouchi, Takanari Kitazono, Tetsuro Ago, FSR Investigators

    Stroke   52 ( 8 )   2621 - 2628   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background and Purpose: Little is known about how β-cell dysfunction affects clinical outcome after ischemic stroke. We examined whether β-cell function is associated with clinical outcome after acute ischemic stroke and if so, whether insulin resistance influences this association in a prospective study of patients with acute stroke. Methods: A total of 3590 nondiabetic patients with acute ischemic stroke (mean age, 71 years) were followed up for 3 months. β-Cell function was assessed using the homeostasis model assessment for β-cell function (HOMA-β). Study outcomes were poor functional outcome (modified Rankin Scale score, 3–6) and stroke recurrence at 3 months after stroke onset and neurological deterioration (≥2-point increase in the National Institutes of Health Stroke Scale score) at discharge. Logistic regression analysis was used to evaluate the association between quintile levels of serum HOMA-β and clinical outcomes. Results: The age- and sex-adjusted odds ratios for poor functional outcome and neurological deterioration increased significantly with decreasing HOMA-β levels (P for trend, <0.001 and 0.001, respectively). These associations became more prominent after adjustment for HOMA-insulin resistance and were substantially unchanged even after further adjustment for other confounders, namely, body mass index, dyslipidemia, hypertension, estimated glomerular filtration rate, stroke subtype, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy (odds ratio [95&#37; CI] for the first versus fifth quintile of HOMA-β, 3.30 [2.15–5.08] for poor functional outcome and 10.69 [4.99–22.90] for neurological deterioration). Such associations were not observed for stroke recurrence. In stratified analysis for the combination of HOMA-β and HOMA-insulin resistance levels, lower HOMA-β and higher HOMA-insulin resistance levels were independently associated with increased risks of poor functional outcome and neurological deterioration. Conclusions: Our findings suggest that β-cell dysfunction is significantly associated with poor short-term clinical outcome independently of insulin resistance in nondiabetic patients with acute ischemic stroke.

    DOI: 10.1161/STROKEAHA.120.031392.

  • Pre-Stroke Cholinesterase Inhibitor Treatment Is Beneficially Associated with Functional Outcome in Patients with Acute Ischemic Stroke and Pre-Stroke Dementia: The Fukuoka Stroke Registry 査読 国際誌

    Yoshinobu Wakisaka, Ryu Matsuo, Kuniyuki Nakamura, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono, Fukuoka Stroke Registry Investigators

    Cerebrovasc Dis.   50 ( 4 )   390 - 396   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    INTRODUCTION: Pre-stroke dementia is significantly associated with poor stroke outcome. Cholinesterase inhibitors (ChEIs) might reduce the risk of stroke in patients with dementia. However, the association between pre-stroke ChEI treatment and stroke outcome remains unresolved. Therefore, we aimed to determine this association in patients with acute ischemic stroke and pre-stroke dementia. METHODS: We enrolled 805 patients with pre-stroke dementia among 13,167 with ischemic stroke within 7 days of onset who were registered in the Fukuoka Stroke Registry between June 2007 and May 2019 and were independent in basic activities of daily living (ADLs) before admission. Primary and secondary study outcomes were poor functional outcome (modified Rankin Scale [mRS] score: 3-6) at 3 months after stroke onset and neurological deterioration (≥2-point increase in the NIH Stroke Scale [NIHSS] during hospitalization), respectively. Logistic regression analysis was used to evaluate associations between pre-stroke ChEI treatment and study outcomes. To improve covariate imbalance, we further conducted a propensity score (PS)-matched cohort study. RESULTS: Among the participants, 212 (26.3&#37;) had pre-stroke ChEI treatment. Treatment was negatively associated with poor functional outcome (odds ratio: 0.68 [95&#37; confidence interval: 0.46-0.99]) and neurological deterioration (0.52 [0.31-0.88]) after adjusting for potential confounding factors. In the PS-matched cohort study, the same trends were observed between pre-stroke ChEI treatment and poor functional outcome (0.61 [0.40-0.92]) and between the treatment and neurological deterioration (0.47 [0.25-0.86]). CONCLUSIONS: Our findings suggest that pre-stroke ChEI treatment is associated with reduced risks for poor functional outcome and neurological deterioration after acute ischemic stroke in patients with pre-stroke dementia who are independent in basic ADLs before the onset of stroke.

    DOI: 10.1159/000514368.

  • Anticoagulation and Risk of Stroke Recurrence in Patients with Embolic Stroke of Undetermined Source Having No Potential Source of Embolism 査読 国際誌

    Noriko Sato, Ryu Matsuo, Fumi Kiyuna, Kuniyuki Nakamura, Jun Hata, Yoshinobu Wakisaka, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono, collab on behalf of the Fukuoka Stroke Registry Investigators

    Cerebrovasc Dis.   49 ( 6 )   601 - 608   2020年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: This study aimed to determine whether use of oral anticoagulants (OACs) was associated with a reduced risk of recurrent stroke compared with use of antiplatelets (APs) in patients with embolic stroke of undetermined source (ESUS) having no potential source of embolism. METHODS: Of 8,790 patients with acute ischemic stroke registered at 7 centers in the Fukuoka Stroke Registry from June 2007 to May 2017, we included 681 patients (mean age 69.7 [SD 14.1] years, 48.3&#37; men) who experienced ESUS without a potential source of embolism and received OAC alone or AP alone. We estimated hazard ratios (HRs) and 95&#37; confidential intervals (CIs) of recurrent ischemic stroke or any stroke after discharge using a Cox proportional hazards model and Fine and Gray model. RESULTS: During a mean follow-up of 3.4 (SD 1.7) years, event rates of recurrent ischemic stroke were 4.4 per 100 person-years in 489 patients treated with AP and 2.0 per 100 person-years in 192 patients treated with OAC. OAC use was associated with a reduced risk of recurrent ischemic stroke, even after adjusting for potential confounding factors (multivariable-adjusted HR [95&#37; CI], 0.42 [0.23-0.80]) and when additionally considering death as a competing risk (0.45 [0.24-0.85]). The reduced risk of recurrent ischemic stroke was still observed in patients treated with OAC (0.32 [0.15-0.67]) in reference to propensity score-matched patients treated with AP. These associations were maintained for all types of stroke, including ischemic and hemorrhagic stroke. CONCLUSIONS: This nonrandomized observational study suggests that anticoagulation therapy might be associated with a reduced risk of recurrent stroke compared with antiplatelet therapy in patients with ESUS in whom no potential source of embolism was identified. Further study should be performed in consideration of a potential source of embolism even in patients with ESUS.

    DOI: 10.1159/000510773.

  • Epstein-Barr Virus-Associated Encephalopathy Presenting with Nonconvulsive Status Epilepticus in an Immunosuppressive State. 査読 国際誌

    Yuichiro Ohya, Kuniyuki Nakamura, Yoshinobu Wakisaka, Hiroaki Sato, Kayo Wakisaka, Masaya Kumamoto, Yohei Muraya, Junya Kuroda, Hiroshi Nakane, Goichi Yoshimoto, Takanari Kitazono, Tetsuro Ago

    Case Rep Neurol.   2020年8月

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    記述言語:英語  

    DOI: 10.1159/000507976.

  • Response to Letter regarding case report, "Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes due to m.3243A > G mutation in a 76-year-old woman". 査読 国際誌

    Tetsuro Ago, Kana Ueki, Yoshinobu Wakisaka, Kuniyuki Nakamura, Takanari Kitazono

    Journal of the neurological sciences   414   116925 - 116925   2020年7月

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    記述言語:英語  

    DOI: 10.1016/j.jns.2020.116925

  • An Embolic Stroke in a Patient With PROC p.Lys193del. 査読 国際誌

    Kana Ueki, Kuniyuki Nakamura, Yoshinobu Wakisaka, Shinichi Wada, Yoji Yoshikawa, Shinya Matsumoto, Taeko Hotta, Dongchong Kang, Takanari Kitazon, Tetsuro Ago

    J Stroke Cerebrovasc Dis.   29 ( 5 )   104597 - 104597   2020年5月

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    記述言語:英語  

    We report a 58-year-old woman who suddenly developed brain infarction with weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in the posterior circulation system of the brain. Despite extensive examinations, we could not identify any embolic sources except hypoplasia of the right vertebral artery. We found decreased activity of protein C against its antigen level (activity: 59&#37; versus antigen: 122&#37;) with enhanced activity of coagulation factor VIII (178&#37;) and von Willebrand factor (285&#37;). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del). We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of an embolic stroke in this patient.

    DOI: 10.1016/j.jstrokecerebrovasdis.2019.104597.

  • Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes due to m.3243A > G mutation in a 76-year-old woman. 査読 国際誌

    Kana Ueki, Yoshinobu Wakisaka, Kuniyuki Nakamura, Yuji Shono, Shinichi Wada, Yoji Yoshikawa, Yuta Matsukuma, Takeshi Uchiumi, Dongchong Kang, Takanari Kitazono, Tetsuro Ago

    J Neurol Sci.   2020年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: DOI: 10.1016/j.jns.2020.116791

  • Smoking Status and Functional Outcomes After Acute Ischemic Stroke. 査読 国際誌

    Matsuo R, Ago T, Kiyuna F, Sato N, Nakamura K, Kuroda J, Wakisaka Y, Kitazono T; Fukuoka Stroke Registry Investigators.

    Stroke   51 ( 3 )   846 - 852   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background and Purpose- Smoking is an established risk factor for stroke; however, it is uncertain whether prestroke smoking status affects clinical outcomes of acute ischemic stroke. This study aimed to elucidate the association between smoking status and functional outcomes after acute ischemic stroke. Methods- Using a multicenter hospital-based stroke registry in Japan, we investigated 10 825 patients with acute ischemic stroke hospitalized between July 2007 and December 2017 who had been independent before stroke onset. Smoking status was categorized into those who had never smoked (nonsmokers), former smokers, and current smokers. Clinical outcomes included poor functional outcome (modified Rankin Scale score ≥2) and functional dependence (modified Rankin Scale score 2-5) at 3 months. We adjusted for potential confounding factors using a logistic regression analysis. Results- The mean age of patients was 70.2±12.2 years, and 37.0&#37; were women. There were 4396 (42.7&#37;) nonsmokers, 3328 (32.4&#37;) former smokers, and 2561 (24.9&#37;) current smokers. The odds ratio (95&#37; CI) for poor functional outcome after adjusting for confounders increased in current smokers (1.29 [1.11-1.49] versus nonsmokers) but not in former smokers (1.05 [0.92-1.21] versus nonsmokers). However, among the former smokers, the odds ratio of poor functional outcome was higher in those who quit smoking within 2 years of stroke onset (1.75 [1.15-2.66] versus nonsmokers). The risk of poor functional outcome tended to increase as the number of daily cigarettes increased in current smokers (P for trend=0.002). All these associations were maintained for functional dependence. Conclusions- Current and recent smoking is associated with an increased risk of unfavorable functional outcomes at 3 months after acute ischemic stroke. Registration- URL: http://www.fukuoka-stroke.net/english/index.html. Unique identifier: 000000800.

    DOI: 10.1161/STROKEAHA.119.027230.

  • Early initiation of a factor Xa inhibitor can attenuate tissue repair and neurorestoration after middle cerebral artery occlusion. 査読 国際誌

    Komori M, Ago T, Wakisaka Y, Nakamura K, Tachibana M, Yoshikawa Y, Shibahara T, Yamanaka K, Kuroda J, Kitazono T.

    Brain Res.   1718   201 - 211   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO) in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood-brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized.

    DOI: 10.1016/j.brainres.2019.05.020

  • Pannexin-3 Deficiency Delays Skin Wound Healing in Mice due to Defects in Channel Functionality. 査読 国際誌

    Zhang P, Ishikawa M, Rhodes C, Doyle A, Ikeuchi T, Nakamura K, Chiba Y, He B, Yamada Y

    J Invest Dermatol.   139 ( 4 )   909 - 918   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pannexin-3 (Panx3) is a gap junction protein that is required for regulating cell cycle exit and the differentiation of osteoblasts and chondrocytes during skeletal development. However, the role of Panx3 in skin tissue regeneration remains unclear. After dorsal skin punch biopsies, Panx3-knockout mice exhibited a significant delay in wound healing with insufficient re-epithelialization, decreased inflammatory reaction, and reduced collagen remodeling. Panx3 expression coincided with inflammatory reactions both in vivo and in vitro. By applying exogenous tumor necrosis factor-α to mimic inflammation in vitro, Panx3 expression was induced in HaCaT cells. In addition, Panx3 depletion reduced epithelial-mesenchymal transition during skin wound healing. A protein essential for signaling in epithelial-mesenchymal transition, transforming growth factor-β interacted with Panx3 by modulating intracellular adenosine triphosphate levels and thereby enhanced HaCaT cell migration ability with Panx3 overexpression. In conclusion, Panx3 plays a key role in the skin wound healing process by controlling keratinocytes and keratinocyte-mesenchyme cross-talk via hemichannel and endoplasmic reticulum Ca channel functions, which differs from another gap junction, connexin 43 (Cx43), during skin wound healing. 2+

    DOI: 10.1016/j.jid.2018.08.033.

  • Early Reperfusion After Brain Ischemia Has Beneficial Effects Beyond Rescuing Neurons. 査読 国際誌

    Tachibana M, Ago T, Wakisaka Y, Kuroda J, Shijo M, Yoshikawa Y, Komori M, Nishimura A, Makihara N, Nakamura K, Kitazono T.

    Stroke.   48 ( 8 )   2222 - 2230   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND PURPOSE: Recent studies show that successful endovascular thrombectomy 6 to 12 hours after stroke onset enhances functional outcomes 3 months later. In this study, we investigated the effects of reperfusion after ischemia on repair processes in the ischemic areas, as well as on functional recovery, using mouse stroke models. METHODS: We examined time-dependent histological changes and functional recovery after transient middle cerebral artery occlusion of different durations, including permanent middle cerebral artery occlusion, using the CB-17 (CB-17/lcr-+/+Jcl) mouse strain, which has poor pial collateral blood flow. RESULTS: Large microtubule-associated protein 2-negative areas of neuronal death were produced in mice subjected to ≥60 minutes of ischemia followed by reperfusion on day 1, while restricted microtubule-associated protein 2-negative regions were observed in mice subjected to a 45-minute period of ischemia. A substantial reduction in microtubule-associated protein 2-negative areas was observed on day 7 in mice given early reperfusion and was associated with better functional recovery. Klüver-Barrera staining demonstrated that white matter injury on day 1 was significantly lesser in mice with reperfusion. Immunohistochemistry and electron microscopy revealed that a greater number of endothelial cells were present in the infarct areas in mice with earlier reperfusion and were associated with a more rapid recruitment of platelet-derived growth factor receptor β-positive pericytes and subsequent intrainfarct fibrosis. Early reperfusion also resulted in a greater accumulation of glial fibrillary acidic protein-positive astrocytes in peri-infarct areas. Peri-infarct astrogliosis was attenuated in platelet-derived growth factor receptor β heterozygous knockout mice. CONCLUSIONS: Early reperfusion after ischemia enhances the survival of endothelial cells and pericytes within ischemic areas even after the infarct is established, resulting in efficient intrainfarct fibrosis and peri-infarct astrogliosis. These effects might be associated with efficient peri-infarct reorganization and functional recovery.

    DOI: 10.1161/STROKEAHA.117.016689

  • Detrimental role of pericyte Nox4 in the acute phase of brain ischemia. 査読 国際誌

    Nishimura A, Ago T, Kuroda J, Arimura K, Tachibana M, Nakamura K, Wakisaka Y, Sadoshima J, Iihara K, Kitazono T.

    J Cereb Blood Flow Metab.   36 ( 6 )   1143 - 54   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pericytes are mural cells abundantly present in cerebral microvessels and play important roles, including the formation and maintenance of the blood-brain barrier. Nox4 is a major source of reactive oxygen species in cardiovascular cells and modulate cellular functions, particularly under pathological conditions. In the present study, we found that the expression of Nox4 was markedly induced in microvascular cells, including pericytes, in peri-infarct areas after middle cerebral artery occlusion stroke models in mice. The upregulation of Nox4 was greater in a permanent middle cerebral artery occlusion model compared with an ischemia/reperfusion transient middle cerebral artery occlusion model. We performed permanent middle cerebral artery occlusion on mice with Nox4 overexpression in pericytes (Tg-Nox4). Infarct volume was significantly greater with enhanced reactive oxygen species production and blood-brain barrier breakdown in peri-infarct areas in Tg-Nox4, compared with littermate controls. In cultured brain pericytes, Nox4 was significantly upregulated by hypoxia and was promptly downregulated by reoxygenation. Phosphorylation of NFκB and production of matrix metalloproteinase 9 were significantly increased in both cultured pericytes overexpressing Nox4 and in peri-infarct areas in Tg-Nox4. Collectively, Nox4 is upregulated in pericytes in peri-infarct areas after acute brain ischemia and may enhance blood-brain barrier breakdown through activation of NFκB and matrix metalloproteinase 9, thereby causing enlargement of infarct volume.

    DOI: 10.1177/0271678X15606456

  • A CADASIL-Like Case with a Novel Noncysteine Mutation of the NOTCH3 Gene and Granular Deposits in the Renal Arterioles. 査読 国際誌

    Kuniyuki Nakamura, Tetsuro Ago, Akihiro Tsuchimoto, Nozomi Noda, Asako Nakamura, Toshiharu Ninomiya, Takeshi Uchiumi, Kazuhiko Tsuruya, Masahiro Kamouchi, Hiroaki Ooboshi, Takanari Kitazono

    Case reports in neurological medicine   2015   431461 - 431461   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    We herein report the finding of a 62-year-old male, who developed dysarthria and dysphagia, with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy- (CADASIL-) like cerebral lesions. He also suffered from slowly progressive renal failure with the findings of granular deposits similar to electron-dense granular osmiophilic material in the renal arterioles. We found a novel heterozygous missense mutation of the NOTCH3 gene, c.4039G>C in exon 24, resulting in a p.Gly1347Arg substitution in its extracellular domain. The noncysteine substitution may underlie the pathogenesis of white matter lesions in the brain and of the chronic renal failure in the present case.

    DOI: 10.1155/2015/431461

  • Nox4 is a major source of superoxide production in human brain pericytes. 査読 国際誌

    Kuroda J, Ago T, Nishimura A, Nakamura K, Matsuo R, Wakisaka Y, Kamouchi M, Kitazono T.

    J Vasc Res.   51 ( 6 )   429 - 38   2015年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Pericytes are multifunctional cells surrounding capillaries and postcapillary venules. In brain microvasculature, pericytes play a pivotal role under physiological and pathological conditions by producing reactive oxygen species (ROS). The aims of this study were to elucidate the source of ROS and its regulation in human brain pericytes. METHODS: The expression of Nox enzymes in the cells was evaluated using RT-PCR and western blot. Superoxide production was determined by superoxide dismutase-inhibitable chemiluminescence. Silencing of Nox4 was performed using RNAi, and cell proliferation was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. RESULTS: Nox4 was predominant among the Nox family in human brain pericytes. Membrane fractions of cells produced superoxide in the presence of NAD(P)H. Superoxide production was almost abolished with diphenileneiodonium, a Nox inhibitor; however, inhibitors of other possible superoxide-producing enzymes had no effect on NAD(P)H-dependent superoxide production. Pericytes expressed angiotensin II (Ang II) receptors, and Ang II upregulated Nox4 expression. Hypoxic conditions also increased the Nox4 expression. Silencing of Nox4 significantly reduced ROS production and attenuated cell proliferation. CONCLUSION: Our study showed that Nox4 is a major superoxide-producing enzyme and that its expression is regulated by Ang II and hypoxic stress in human brain pericytes. In addition, Nox4 may promote cell growth.

    DOI: 10.1159/000369930

  • Neurotrophin production in brain pericytes during hypoxia: a role of pericytes for neuroprotection. 査読 国際誌

    Ishitsuka K, Ago T, Arimura K, Nakamura K, Tokami H, Makihara N, Kuroda J, Kamouchi M, Kitazono T.

    Microvasc Res.   83 ( 3 )   352 - 9   2012年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neurotrophins are crucial regulators of neuronal survival and death. Evidence suggests that cells comprising the neurovascular unit (NVU) cooperatively mediate neuronal development, survival and regeneration. The aim of this study was to test whether cerebrovascular cells, endothelial cells and pericytes, produce neurotrophins and play neuroprotective roles during hypoxic insults. We examined the expression of neurotrophins and their receptors in cultured human cerebral microvascular endothelial cells and pericytes, astrocytes and the rat neuronal cell line PC12. Differentiated PC12 cells expressed TrkA, the NGF receptor, which was significantly upregulated by hypoxia at 1&#37; O(2) and regulated neuronal survival. Both pericytes and astrocytes expressed three neurotrophins, i.e. NGF, BDNF and NT-3, while TrkB and TrkC, specific receptors for BDNF and NT-3, were expressed in astrocytes, but not pericytes. In response to hypoxia, among the neurotrophins expressed in pericytes and astrocytes only NT-3 expression was significantly upregulated in pericytes. Treatment of astrocytes with NT-3 significantly activated Erk1/2 and increased the expression of NGF both at mRNA and protein levels. The MEK1 inhibitor U0126 or siRNA-mediated knockdown of TrkC abolished the NT-3-induced upregulation of NGF in astrocytes. Taken together, cerebral microvascular pericytes and astrocytes are potent producers of neurotrophins in the NVU. In response to hypoxia, pericytes increase NT-3 production, which induces astrocytes to increase NGF production through the TrkC-Erk1/2 pathway. The interplay between pericytes and astrocytes through neurotrophins in the NVU may play an important role in neuronal survival under hypoxic conditions.

    DOI: 10.1016/j.mvr.2012.02.009

  • Change in Intracellular pH causes the toxic Ca2+ entry via NCX1 in neuron- and glia-derived cells. 査読 国際誌

    Shono Y, Kamouchi M, Kitazono T, Kuroda J, Nakamura K, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.

    Cell Mol Neurobiol.   30 ( 3 )   453 - 60   2010年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Brain hypoxia or ischemia causes acidosis and the intracellular accumulation of Ca(2+) in neuron. The aims of the present study were to elucidate the interaction between intracellular pH and Ca(2+) during transient acidosis and its effects on the viability of neuronal and glial cells. Intracellular Ca(2+) and pH were measured using the fluorescence of fura-2 and 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester in neuroblastoma (IMR-32), glioblastoma (T98G), and astrocytoma (CCF-STTG1) cell lines. The administration of 5 mM propionate caused intracellular acidification in IMR-32 and T98G cells but not in CCF-STTG1 cells. After the removal of propionate, the intracellular pH recovered to the resting level. The intracellular Ca(2+) transiently increased upon the removal of propionate in IMR-32 and T98G cells but not in CCF-STTG1 cells. The transient Ca(2+) increase caused by the withdrawal of intracellular acidification was abolished by the removal of external Ca(2+), diminished by a reduction of external Na(+), and inhibited by benzamil. Transient acidosis caused cell death, whereas the cells were more viable in the absence of external Ca(2+). Benzamil alleviated cell death caused by transient acidosis in IMR-32 and T98G cells but not in CCF-STTG1 cells. These results suggest that recovery from intracellular acidosis causes a transient increase in cytosolic Ca(2+) due to reversal of Ca(2+) transport via Na(+)/Ca(2+) exchanger coactivated with Na(+)/H(+) exchanger, which can cause cell death.

    DOI: 10.1007/s10571-009-9470-7

  • Midkine gene transfer protects against focal brain ischemia and augments neurogenesis. 査読 国際誌

    Ishikawa E, Ooboshi H, Kumai Y, Takada J, Nakamura K, Ago T, Sugimori H, Kamouchi M, Kitazono T, Ibayashi S, Iida M.

    J Neurol Sci.   285 ( 1-2 )   78 - 84   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND AND PURPOSE: Midkine is a heparin-binding growth factor having various biological activities including chemotaxis of inflammatory cells, angiogenesis and migration of neuronal cells. These biological activities are expected to have a great impact on the pathology of brain infarction in subacute phase. Therefore, we investigated the effect of post-ischemic gene transfer of midkine in the phase. METHODS: Brain ischemia was produced by the photothrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats. We measured cerebral blood flow by laser Doppler flowmetry. At 90 min after induction of brain ischemia, adenovirus vectors encoding mouse midkine (AdMK) or enhanced green fluorescence protein (AdGFP) were injected into the lateral ventricle. At 7 days after brain ischemia, the infarct volume, angiogenesis, inflammation and neuronal regeneration were evaluated. RESULTS: There were no differences in cerebral blood flow changes between AdMK and AdGFP groups. However, infarct volume of AdMK group was significantly smaller than AdGFP group by 33&#37;. The vascular density, the numbers of leukocytes in blood vessels, infiltrated macrophages and proliferated neuronal precursor cells were not significantly different between both groups. Contrastingly the numbers of migrating neuronal precursor cells toward the brain infarction were significantly increased in AdMK group than AdGFP group. CONCLUSIONS: Neuroprotective effect of midkine gene transfer persisted until the subacute phase of brain infarction. Midkine may contribute to neuronal regeneration. These results suggest the usefulness of midkine gene transfer for treatment of brain infarction.

    DOI: 10.1016/j.jns.2009.05.026

  • Hemorrhagic shock and obstructive uropathy due to a large rectus sheath hematoma in a patient on anticoagulant therapy. 査読

    Jiro Toyonaga, Kazuhiko Tsuruya, Kohsuke Masutani, Hiroto Maeda, Kuniyuki Nakamura, Masatomo Taniguchi, Hideki Hirakata, Mitsuo Iida

    Internal medicine (Tokyo, Japan)   48 ( 24 )   2119 - 22   2009年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A 54-year-old woman was transferred to our hospital with disseminated intravascular coagulation, and was treated with heparin. On hospitalization day 13, she developed lower abdominal pain and mass followed by circulatory shock. She became oliguric and laboratory tests showed serum creatinine of 3.5 mg/dL and hemoglobin of 7.4 g/dL. Computed tomography showed hematoma in the left rectus sheath, compressing the urinary bladder exteriorly, which resulted in worsening of bilateral hydronephrosis. Conservative treatment resulted in resolution of the rectus sheath hematoma and improvement of renal function. Rectus sheath hematoma can be treated conservatively without surgical intervention even in complicated cases.

  • Amiloride inhibits hydrogen peroxide-induced Ca2+ responses in human CNS pericytes. 査読 国際誌

    Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Shono Y, Hagiwara N, Ago T, Ooboshi H, Ibayashi S, Iida M.

    Microvasc Res.   77 ( 3 )   327 - 34   2009年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The aims of the present study were to investigate the mechanisms of Ca(2+) signaling caused by hydrogen peroxide in CNS pericytes. In cultured human brain microvascular pericytes, cytosolic Ca(2+) concentration was measured by means of fura-2 fluorescence. Reverse transcription and polymerase chain reaction was performed to examine the expression of mRNA. Knockdown of Na(+)/H(+) exchanger (NHE) was done by transfecting the cells with specific double-strand siRNAs for NHE. Externally applied hydrogen peroxide dose-dependently (100 microM-10 mM) increased cytosolic Ca(2+) in human CNS pericytes. Cytosolic Ca(2+) remained high after wash-out of hydrogen peroxide. However, the addition of dithiothreitol rapidly reversed cytosolic Ca(2+) to the resting level. The hydrogen peroxide-induced Ca(2+) increase was not inhibited by nicardipine, Gd(3+), La(3+), or omission of external Ca(2+). Neither thapsigargin nor carbonyl cyanide 4-trifluoromethoxyphenylhydrazone attenuated the hydrogen peroxide-induced Ca(2+) rise. Amiloride and its derivatives, benzamil and hexamethylene amiloride reversed the hydrogen peroxide-induced Ca(2+) increase. Human CNS pericytes expressed acid sensing ion channel (ASIC) 1a, Na(+)/Ca(2+) exchanger (NCX) 1, Na(+)/H(+) exchanger (NHE) 1, and NHE7. However, the removal of external Na(+), treatment with KB-R 7943 and mibefradil, or knockdown of NHE1 and NHE7 did not affect the hydrogen peroxide-induced Ca(2+) increase. Hydrogen peroxide releases Ca(2+) from intracellular Ca(2+) pool via an amiloride-sensitive protein, which is controlled by oxidation of thiol group in human CNS pericytes.

    DOI: 10.1016/j.mvr.2008.12.001

  • Combined and staged endovascular recanalization of cervical and intracranial arteries in hyperacute ischemic stroke. 査読

    Kazunori Toyoda, Ken Uda, Akiko Shirakawa, Kotaro Yasumori, Kuniyuki Nakamura, Tooru Inoue, Yasushi Okada

    Internal medicine (Tokyo, Japan)   46 ( 23 )   1935 - 6   2007年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

  • Hydrogen peroxide-induced Ca2+ responses in CNS pericytes. 査読 国際誌

    Kamouchi M, Kitazono T, Ago T, Wakisaka M, Kuroda J, Nakamura K, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.

    Neurosci Lett.   416 ( 1 )   12 - 6   2007年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: The aims of the present study were to elucidate the interaction of reactive oxygen species (ROS) and Ca(2+) response in central nervous system (CNS) pericytes. METHODS: The intracellular Ca(2+) concentration was measured using fluorescent Ca(2+) indicator, fura-2, in cultured CNS pericytes. RESULTS: Hydrogen peroxide evoked a dose-dependent increase in cytosolic Ca(2+), which was completely inhibited by catalase. Removal of external Ca(2+) or addition of nicardipine (1 microM) during application of hydrogen peroxide did not affect Ca(2+) response. Incubation of the cells in Ca(2+) free solution did not abolish but slightly reduced Ca(2+) response by hydrogen peroxide. Ca(2+) response to hydrogen peroxide was not altered by the depletion of intracellular Ca(2+) by thapsigargin (1 microM). Pretreatment of the cells with tyrosine kinase inhibitor genistein (100 microM) or tyrphostin A47 (30 microM) significantly reduced Ca(2+) increase by hydrogen peroxide. CONCLUSIONS: These results indicate that hydrogen peroxide evokes Ca(2+) increase predominantly by release from intracellular Ca(2+) store, which may be regulated by tyrosine kinases.

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書籍等出版物

  • 脳梗塞急性期と慢性期の抗血小板療法.最新主要文献でみる脳神経外科学レビュー2023-24

    中村 晋之(担当:共著)

    総合医学社  2022年10月 

     詳細を見る

    担当ページ:82-8   記述言語:日本語  

  • 細胞外マトリックス.最新臨床脳卒中学(第2版)(下)

    中村 晋之

    日本臨牀社  2022年2月 

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    記述言語:日本語  

  • 脳梗塞急性期と慢性期の抗血小板療法.最新主要文献でみる脳神経外科学レビュー2019

    中村晋之

    総合医学社  2019年8月 

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    担当ページ:77-83   記述言語:日本語   著書種別:学術書

  • 内皮細胞・周皮細胞の立場から.  最新臨床脳卒中学(上)

    中村晋之,吾郷哲朗

    2014年6月 

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    記述言語:日本語  

  • 慢性期再発予防のコツ. レジデントのための脳卒中診療のコツ,阿部康二(編)

    中村晋之,北園孝成

    2014年6月 

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    記述言語:日本語  

  • データバンクにおける脳梗塞病型別頻度と久山町における時代的推移.脳卒中データバンク2009, 小林祥泰(編)

    中村晋之,井林雪郎,金大成

    2009年6月 

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    記述言語:日本語  

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講演・口頭発表等

  • 脳梗塞後のneurovascular unit修復過程におけるペリサイト保護戦略. 招待

    中村晋之、清原卓也、脇坂義信、吾郷哲朗、北園孝成.

    第64回脳循環代謝学会学術集会  2023年11月 

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    開催年月日: 2023年11月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:福岡   国名:日本国  

  • ペリサイトを標的とした脳梗塞治療戦略 招待

    中村晋之、吾郷哲朗、高島正光、芝原友也、清原卓也、脇坂義信、北園孝成

    第48回日本脳卒中学会学術集会  2023年3月 

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    開催年月日: 2023年3月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:横浜   国名:日本国  

  • Perlecan Regulates Pericyte Dynamics in the Repair Process of the Blood-Brain Barrier against Ischemic Stroke 国際会議

    Nakamura K, Ikeuchi T, Zhang P, Rhodes C, Chiba Y, Ago T, Mukouyama YS, Yamada Y

    International Stroke Conference 2018  2018年1月 

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    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Los Angeles   国名:アメリカ合衆国  

  • Macrophage infiltration is required for pericyte recruitment in poststroke tissue repair. 国際会議

    Hidaka M, Nakamura K, Yoshino F, Takashima M, Kiyohara T, Wakisaka Y, Kitazono T, Ago T

    Neuroscience 2023  2023年11月 

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    開催年月日: 2023年11月

    記述言語:英語  

    開催地:Washington DC   国名:アメリカ合衆国  

  • 抗凝固療法新時代における課題と戦略. 招待

    中村 晋之

    第64回脳循環代謝学会学術集会  2023年11月 

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    開催年月日: 2023年11月

    記述言語:日本語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

    開催地:福岡   国名:日本国  

  • Nox4 plays crucial role in angiogenic responses and in recruitment of pericytes and macrophages in poststroke tissue repair. 国際会議

    Nakamura K, Hidaka M, Yoshino F, Takashima M, Kiyohara T, Wakisaka Y, Kitazono T, Ago T.

    Neuroscience 2023  2023年11月 

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    開催年月日: 2023年11月

    記述言語:英語  

    開催地:Washington DC   国名:アメリカ合衆国  

  • 脳卒中二次予防における病態とエビデンスを考慮した危険因子の管理. 招待

    中村 晋之

    地域医師のための生涯研修セミナー  2023年7月 

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    開催年月日: 2023年7月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:九州医療センター   国名:日本国  

  • 脳梗塞における糖代謝異常の病態と管理 招待

    中村晋之、吾郷哲朗、清原卓也、松尾龍、脇坂義信、鴨打正浩、北園孝成.

    第48回日本脳卒中学会学術集会  2023年3月 

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    開催年月日: 2023年3月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:横浜   国名:日本国  

  • Decrease in serum uric acid levels are associated with unfavorable outcomes after ischemic stroke. 国際会議

    Nakamura K, Ueki K, Matsuo R, Kiyohara T, Irie F, Wakisaka Y, Ago T, Kamouchi M, Kitazono T.

    The 10th Korea-Japan Joint Stroke Conference  2022年9月 

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    開催年月日: 2022年9月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Osaka (Web)   国名:日本国  

  • 脳卒中における血圧と心不全の管理. 招待

    @中村 晋之

    第5回日本神経学会特別教育研修会:脳卒中コース  2022年7月 

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    開催年月日: 2022年7月 - 2023年5月

    記述言語:日本語   会議種別:公開講演,セミナー,チュートリアル,講習,講義等  

    開催地:長崎   国名:日本国  

  • グリア瘢痕におけるlaminin α2再構築が脳梗塞後の再髄鞘化を促進し、機能回復に関与する

    中村晋之、芝原友也、脇坂義信、吾郷哲朗、北園孝成

    第53回日本結合組織学会学術大会  2021年6月 

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    開催年月日: 2021年6月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:順天堂大学(Web)   国名:日本国  

  • 血清尿酸値低値は脳梗塞後の短期機能転帰不良に関連する:Fukuoka Stroke Registry

    中村晋之、松尾龍、植木香奈、脇坂義信、吾郷哲朗、鴨打正浩、北園孝成

    第46回日本脳卒中学会学術集会  2021年3月 

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    開催年月日: 2021年3月

    記述言語:日本語   会議種別:口頭発表(一般)  

    開催地:福岡   国名:日本国  

  • 脳梗塞後のペリサイト-アストロサイト-細胞外マトリックス連関を介した組織修復および機能回復 招待

    中村晋之、吾郷哲朗、芝原友也、脇坂義信、北園孝成

    第46回日本脳卒中学会学術集会  2021年3月 

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    開催年月日: 2021年3月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:福岡   国名:日本国  

  • 脳卒中研究のススメ 基礎 招待

    中村晋之

    第46回日本脳卒中学会学術集会  2021年3月 

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    開催年月日: 2021年3月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:福岡   国名:日本国  

  • 脳梗塞後のNVU修復過程における細胞外マトリックスタンパク質の重要性

    中村晋之, Yoh-suke Mukouyama, 平澤恵理, 脇坂義信, 吾郷哲朗, 北園孝成, Yoshihiko Yamada

    日本脳循環代謝学会学術集会  2019年11月 

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    開催年月日: 2019年11月

    記述言語:日本語   会議種別:シンポジウム・ワークショップ パネル(公募)  

    開催地:仙台   国名:日本国  

  • Role of NHE1 in calcium oscillation and cell proliferation in human CNS pericytes. 国際会議

    Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Matsuo R, Hagiwara N, Ooboshi H, Ibayashi S, Iida M.

    The 23rd International Symposium on Cerebral Blood Flow, Metabolism and Function  2007年5月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Osaka   国名:日本国  

  • Expression of NHE1 and cell proliferation in human CNS pericytes. 国際会議

    Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Matsuo R, Hagiwara N, Ishikawa E, Ooboshi H, Ibayashi S, Iida M.

    The 2nd Meeting of Asian Stroke Forum  2007年9月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Kyoto   国名:日本国  

  • Brain-derived neurotrophic factor and its related factors after ischemic stroke - Research for Biomarkers in Ischemic Stroke (REBIOS) – 国際会議

    Nakamura K, Ago T, Kamouchi M, Nakamura A, Tokami H, Ishitsuka K, Makihara N, Isomura T, Watabe W, Awano H, Suzuki K, Kiyohara Y, Kitazono T.

    European Stroke Conference 2011  2011年5月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Hamburg   国名:ドイツ連邦共和国  

  • The expression of pericyte PDGFRβ is regulated by basic FGF after ischemic stroke. 国際会議

    Ago T, Nakamura K, Arimura K, Nishimura A, Makihara N, Wakisaka Y, Kuroda J, Kamouchi M, Kitazono T.

    Neuroscience 2013  2013年11月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:San Diego   国名:アメリカ合衆国  

  • Temporal profile of basic fibroblast growth factor and its clinical implications in ischemic stroke - Research for Biomarkers in Ischemic Stroke (REBIOS)- 国際会議

    Nakamura K, Ago T, Matsuo R, Kuroda J, Wakisaka Y, Isomura T, Awano H, Suzuki K, Kamouchi M, Kiyohara Y, Ooboshi H, Kitazono T.

    Neuroscience 2013  2013年11月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:San Diego   国名:アメリカ合衆国  

  • Basic fibroblast growth factor after ischemic stroke in diabetic patients - Research for Biomarkers in Ischemic Stroke (REBIOS) - 国際会議

    Nakamura K, Ago T, Arimura K, Makihara N, Nishimura A, Matsuo R, Wakisaka Y, Kuroda J, Isomura T, Awano H, Suzuki K, Okada Y, Kamouchi M, Kiyohara Y, Ooboshi H, Kitazono T.

    International Stroke Conference 2014  2014年2月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:San Diego   国名:アメリカ合衆国  

  • Deficiency of Perlecan, a basement membrane heparan sulfate proteoglycan, leads to the blood-brain barrier deterioration in a mouse ischemic stroke model. 国際会議

    Nakamura K, Zhang P, Ikeuchi T, Rhodes C, Mahboubi D, Chiba Y, Ago T, Mukouyama YS, Yamada Y.

    Neuroscience 2016  2016年11月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:San Diego   国名:アメリカ合衆国  

  • Perlecan Is Required for the Maintenance of the Blood-Brain Barrier through the Interaction with Pericytes in a Mouse Ischemic Stroke Model. 国際会議

    Nakamura K, Ikeuchi T, Zhang P, Rhodes C, Chiba Y, Ago T, Mukouyama YS, Yamada Y.

    International Stroke Conference 2017  2017年2月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Houston   国名:アメリカ合衆国  

  • Perlecan is essential for the maintenance and repair of the blood-brain barrier against ischemic stroke through interacting with and activating pericytes. 国際会議

    Nakamura K, Ikeuchi T, Zhang P, Rhodes C, Chiba Y, Ago T, Mukouyama YS, Yamada Y.

    Neuroscience 2017  2017年11月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:英語   会議種別:口頭発表(一般)  

    開催地:Washington DC   国名:アメリカ合衆国  

  • 細胞外マトリックス蛋白Perlecanは脳梗塞後のペリサイトの遊走を促進し、血液脳関門の修復に関与する

    中村晋之、吾郷哲朗、平澤恵理、向山洋介、山田吉彦

    第50回日本結合組織学会学術大会  2018年6月 

     詳細を見る

    開催年月日: 2018年6月

    記述言語:日本語  

    開催地:福岡   国名:日本国  

▼全件表示

MISC

  • Pericyte-Mediated Molecular Mechanisms Underlying Tissue Repair and Functional Recovery after Ischemic Stroke.

    Kuniyuki Nakamura, Tetsuro Ago

    J Atheroscler Thromb.   2023年9月

     詳細を見る

    記述言語:英語   掲載種別:記事・総説・解説・論説等(学術雑誌)  

  • 脳血管ペリサイトの生理的役割と脳虚血応答

    中村晋之, 吾郷哲朗

    脳循環代謝(日本脳循環代謝学会機関誌)   2014年6月

     詳細を見る

    記述言語:日本語  

    Neurovascular unit は神経細胞,脳血管内皮細胞,ペリサイト(血管周皮細胞),アストロサイト(星状膠細胞)などを構成単位とする概念である.これらの細胞は互いに密接かつ複雑に関わっており,血液脳関門や微小循環の調節など多彩な脳機能の維持を担っている.なかでもペリサイトは内皮細胞を被覆して血管を物理的に安定化させるのみならず,内皮細胞と相互に作用し,微小血管の成熟,安定化,血液脳関門の維持などに重要な役割を果たしている.脳虚血時にペリサイトは虚血周囲へ誘導され,サイトカインや神経栄養因子の分泌を行って周囲の細胞に作用し,神経細胞の保護,破綻したBBB の再構築,さらには血管・神経再生を促進している可能性がある.ペリサイトはNVU の保護や修復過程において中心的な役割を果たしている可能性が考えられ,脳虚血や認知症など種々の中枢神経疾患に対する新たな治療標的として期待される.

    DOI: 10.16977/cbfm.25.2_109

  • Roles of Sodium-Glucose Cotransporter 2 of Mesangial Cells in Diabetic Kidney Disease. 査読

    Masanori Wakisaka, Kuniyuki Nakamura, Toshiaki Nakano, Takanari Kitazono

    Journal of the Endocrine Society   2021年8月

     詳細を見る

    記述言語:英語  

    We have been studying the presence of sodium-glucose cotransporter 2 (SGLT2) in mesangial cells and pericytes since 1992. Recent large placebo-controlled studies of SGLT2 inhibitors in patients with type 2 diabetes mellitus have reported desirable effects of the inhibitors on the diabetic kidney and the diabetic heart. Most studies have indicated that these effects of SGLT2 inhibitors could be mediated by the tubuloglomerular feedback system. However, a recent study about urine sodium excretion in the presence of an SGLT2 inhibitor did not show any increases in urine sodium excretion. A very small dose of an SGLT2 inhibitor did not inhibit SGLT2 at the S1 segment of proximal tubules. Moreover, SGLT2 inhibition protects against progression in chronic kidney disease with and without type 2 diabetes. In these circumstances, the tubuloglomerular feedback hypothesis involves several theoretical concerns that must be clarified. The presence of SGLT2 in mesangial cells seems to be very important for diabetic nephropathy. We now propose a novel mechanism by which the desirable effects of SGLT2 inhibitors on diabetic nephropathy are derived from the direct effect on SGLT2 expressed in mesangial cells.

    DOI: 10.1210/jendso/bvab083

  • Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes due to m.3243A > G mutation in a 76-year-old woman. 査読

    Kana Ueki, Yoshinobu Wakisaka, Kuniyuki Nakamura, Yuji Shono, Shinichi Wada, Yoji Yoshikawa, Yuta Matsukuma, Takeshi Uchiumi, Dongchong Kang, Takanari Kitazono, Tetsuro Ago

    J Neurol Sci.   2020年5月

     詳細を見る

    記述言語:英語  

    DOI: 10.1016/j.jns.2020.116791

  • 【新しい『高尿酸血症・痛風の治療ガイドライン』を読み解く】合併症の管理はどう変わったのか 脳血管障害 血清尿酸値と脳卒中

    中村晋之, 吾郷哲朗, 北園孝成

    2019年12月

     詳細を見る

    記述言語:日本語  

  • 時間で追う脳虚血の病態と治療:(2)亜急性期 脳梗塞後のNVU修復過程における細胞外マトリックスタンパク質の重要性

    中村 晋之, Mukouyama Yoh-suke, 平澤 恵理, 脇坂 義信, 吾郷 哲朗, 北園 孝成, Yamada Yoshihiko

    脳循環代謝   2019年11月

     詳細を見る

    記述言語:日本語  

  • 脳卒中は遺伝するか

    中村 晋之, 北園 孝成

    2018年7月

     詳細を見る

    記述言語:日本語  

  • 脳保護戦略の新展開

    中村晋之, 吾郷哲朗, 北園孝成

    2015年1月

     詳細を見る

    記述言語:日本語  

  • アストロサイトは MEGF10 および MERTK 経路を介してシナプス除去に関与する

    中村晋之, 黒田淳哉

    2014年2月

     詳細を見る

    記述言語:日本語  

  • Notch3非典型的変異によりCADASIL様の臨床症候を呈した一例

    山田 奈津子, 中村 晋之, 吾郷 哲朗, 中村 麻子, 二宮 利治, 鶴屋 和彦, 鴨打 正浩, 北園 孝成, 康 東天

    臨床神経学   2011年8月

     詳細を見る

    記述言語:日本語  

    Notch3非典型的変異によりCADASIL様の臨床症候を呈した一例

  • 脳卒中危険因子と血液脳関門障害

    中村晋之, 北園孝成

    2010年9月

     詳細を見る

    記述言語:日本語  

  • Potential augmentation of neurogenesis by post-ischemic gene transfer of midkine

    Eiichi Ishikawa, Hiroaki Ooboshi, Yasuhiro Kumai, Junichi Takada, Kuniyuki Nakamura, Junya Kuroda, Hiroshi Sugimori, Masahiro Kamouchi, Takanari Kitazono, Setsurou Ibayashi, Mitsuo Iida

    STROKE   2008年2月

     詳細を見る

    記述言語:英語  

  • 脳血管障害の発症抑制作用

    中村晋之, 井林雪郎

    2007年9月

     詳細を見る

    記述言語:日本語  

  • くも膜下出血の疫学とリスクファクター

    中村晋之, 井林雪郎

    2007年6月

     詳細を見る

    記述言語:日本語  

▼全件表示

所属学協会

  • 日本内科学会

  • 日本脳卒中学会

  • 日本老年医学会

  • 日本神経学会

  • 日本脳循環代謝学会

  • The American Heart Association and American Stroke Association

  • The Society for Neuroscience

  • The International Society of Cerebral Blood Flow and Metabolism

  • 日本結合組織学会

  • 日本認知症学会

  • 日本頭痛学会

▼全件表示

委員歴

  • 日本脳循環代謝学会   代議員   国内

    2013年11月 - 現在   

学術貢献活動

  • 学術論文等の審査

    役割:査読

    2023年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:16

  • 学術論文等の審査

    役割:査読

    2022年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:9

  • 学術論文等の審査

    役割:査読

    2021年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:4

  • 学術論文等の審査

    役割:査読

    2020年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:5

  • 学術論文等の審査

    役割:査読

    2019年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:4

  • 学術論文等の審査

    役割:査読

    2018年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:2

  • 学術論文等の審査

    役割:査読

    2016年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:2

  • 学術論文等の審査

    役割:査読

    2015年

     詳細を見る

    種別:査読等 

    外国語雑誌 査読論文数:1

▼全件表示

共同研究・競争的資金等の研究課題

  • 脳梗塞機能回復治療への挑戦 - ペリサイトをいかに再動員させるか?

    研究課題/領域番号:24K02556  2024年 - 2027年

    日本学術振興会  科学研究費助成事業  基盤研究(B)

      詳細を見る

    担当区分:研究分担者  資金種別:科研費

  • SGLT2を標的とした脳梗塞後のペリサイト機能維持機構の探索

    研究課題/領域番号:22K09236  2022年 - 2024年

    日本学術振興会  科学研究費助成事業  基盤研究(C)

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 血清尿酸値が急性期脳梗塞発症後の転帰に及ぼす影響に関する検討

    2021年

    公益財団法人 痛風・尿酸財団 研究助成

      詳細を見る

    担当区分:研究代表者  資金種別:受託研究

  • 脳虚血病態におけるペリサイトの細胞死にフェロトーシスは関与するか?

    研究課題/領域番号:20K09373  2020年 - 2022年

    日本学術振興会  科学研究費助成事業  基盤研究(C)

      詳細を見る

    担当区分:研究分担者  資金種別:科研費

  • 脳梗塞におけるペリサイトを介した組織修復および機能回復機構の解明

    2020年 - 2021年

    持田記念医学薬学振興財団 研究助成金

      詳細を見る

    担当区分:研究代表者  資金種別:受託研究

  • 細胞外マトリックスperlecanによる脳血管障害の新規修復治療法の開発

    研究課題/領域番号:19K09511  2019年 - 2021年

    日本学術振興会  科学研究費助成事業  基盤研究(C)

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 脳血管障害後の組織修復に細胞外マトリックスperlecanが与える影響に関する研究

    2018年

    先進医薬研究振興財団 循環医学分野 若手研究者助成

      詳細を見る

    担当区分:研究代表者  資金種別:受託研究

  • Neurovascular unit の発生と修復におけるPerlecan の意義

    2015年

    上原記念生命科学財団 リサーチフェローシップ

      詳細を見る

    担当区分:研究代表者  資金種別:受託研究

  • 脳虚血に対する細胞移植治療におけるペリサイトの果たす役割

    研究課題/領域番号:26861169  2014年

    科学研究費助成事業  若手研究(B)

      詳細を見る

    担当区分:研究代表者  資金種別:科研費

  • 脳虚血に対する細胞移植治療における脳血管ペリサイトの果たす役割

    2014年

    貝原守一医学振興財団 研究助成金

      詳細を見る

    担当区分:研究代表者  資金種別:受託研究

  • 脳血管周皮細胞の細胞内カルシウム応答が脳虚血に及ぼす影響に関する研究

    2009年

    先進医薬研究振興財団 循環医学分野 萌芽研究助成

      詳細を見る

    担当区分:研究代表者  資金種別:受託研究

▼全件表示

教育活動概要

  • 医学科学生の基礎配属、概説講義、シミュレーション実習、ベッドサイド実習、クリニカルクラークシップでの実習指導を行っている。大学院生に対する研究指導を行っている。

担当授業科目

  • 5年生ベッドサイド実習

    2024年4月 - 2025年3月   通年

  • 6年生クリニカルクラークシップ

    2024年4月 - 2025年3月   通年

  • 3年生概説講義「神経」

    2023年10月 - 2024年3月   後期

  • 6年生クリニカルクラークシップ

    2023年4月 - 2024年3月   通年

  • 5年生ベッドサイド実習

    2023年4月 - 2024年3月   通年

  • 4年生臨床医学基本実習

    2023年4月 - 2023年9月   前期

  • 3年生概説講義「神経」

    2022年10月 - 2023年3月   後期

  • 6年生クリニカルクラークシップ

    2022年4月 - 2023年3月   通年

  • 5年生ベッドサイド実習

    2022年4月 - 2023年3月   通年

  • 4年生臨床医学基本実習

    2022年4月 - 2022年9月   前期

  • 4年生臨床医学基本実習「神経系の診察」

    2021年10月 - 2022年3月   後期

  • 3年生概説講義「神経」

    2021年10月 - 2022年3月   後期

  • 5年生ベッドサイド実習

    2021年4月 - 2021年9月   前期

  • 6年生クリニカルクラークシップ

    2021年4月 - 2021年9月   前期

  • 3年生概説講義「神経」

    2020年10月 - 2021年3月   後期

  • 5年生ベッドサイド実習

    2020年4月 - 2020年9月   前期

  • 6年生クリニカルクラークシップ

    2020年4月 - 2020年9月   前期

  • 3年生概説講義「神経」

    2019年10月 - 2020年3月   後期

  • 5年生ベッドサイド実習

    2019年4月 - 2019年9月   前期

  • 6年生クリニカルクラークシップ

    2019年4月 - 2019年9月   前期

  • 3年生概説講義「神経」

    2018年10月 - 2019年3月   後期

  • 6年生クリニカルクラークシップ

    2018年4月 - 2018年9月   前期

  • 5年生ベッドサイド実習

    2018年4月 - 2018年9月   前期

▼全件表示

海外渡航歴

  • 2015年4月 - 2018年3月

    滞在国名1:アメリカ合衆国   滞在機関名1:National Institutes of Health/National Institute of Dental and Craniofacial Research/Molecular Biology Section

学内運営に関わる各種委員・役職等

  • 2023年4月 - 2024年3月   その他 消化管内科/腎・高血圧・脳血管内科 医局長

  • 2019年4月 - 2022年3月   その他 ARO専門委員会

専門診療領域

  • 生物系/医歯薬学/内科系臨床医学/脳卒中学

臨床医資格

  • 専門医

    日本内科学会

  • 専門医

    日本脳卒中学会

  • 専門医

    日本老年医学会

医師免許取得年

  • 2003年

特筆しておきたい臨床活動

  • 脳卒中ホットラインに対応し脳卒中センターにおける急性期脳血管障害の診療に携わっている。