所属
未来社会創造機構 ナノライフシステム研究所 マイクロ・ナノメカトロニクス研究部門 特任講師
大学院医学系研究科 特任講師
大学院医学系研究科 特任講師
職名
特任講師
外部リンク
イノウエ アイコ
井上 愛子
INOUE Aiko
学歴
学歴 2
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名古屋大学 大学院医学系研究科 総合医学専攻博士課程
- 2017年3月
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国名： 日本国
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浜松医科大学 大学院医学系研究科看護学専攻修士課程
- 2003年3月
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国名： 日本国
委員歴
委員歴 4
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豊山町地域包括支援センター運営協議会委員
2121年8月
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豊山町健康づくり審議会委員
2022年7月
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豊山町地域包括支援センター 豊山町地域包括ケアシステム推進協議会
2022年7月
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団体区分：自治体
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豊山町総合計画審議会委員
2018年11月
受賞
受賞 2
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第4回日本サルコペニア・フレイル学会大会最優秀演題賞
2017年10月 第4回日本サルコペニア・フレイル学会大会
井上愛子、成憲武、朴麗梅、五藤大貴、小笠原真雄、葛谷雅文
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受賞区分：国内学会・会議・シンポジウム等の賞 受賞国：日本国
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2006年11月 日本自律神経学会 食事摂取と体位が健常者の核心温ならびに血圧に及ぼす影響―炭水化物摂取と仰臥位・長坐位における検討―
長谷川愛子、伊藤 剛、 石津みゑ子、 花輪壽彦
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受賞区分：国内学会・会議・シンポジウム等の賞 受賞国：日本国
論文
論文 62
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Cathepsin S activity controls chronic stress-induced muscle atrophy and dysfunction in mice
Wan, Y; Piao, LM; Xu, SN; Meng, XK; Huang, Z; Inoue, A; Wang, HL; Yue, XL; Jin, XY; Nan, YS; Shi, GP; Murohara, T; Umegaki, H; Kuzuya, M; Cheng, XW
CELLULAR AND MOLECULAR LIFE SCIENCES 80 巻 ( 9 ) 頁： 254 2023年9月
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記述言語：英語 出版者・発行元：Cellular and Molecular Life Sciences
Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS+/+) and CTSS-knockout (CTSS−/−) mice were randomly assigned to non-stress and variable-stress groups. CTSS+/+ stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS+/+ mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In C2C12 cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity.
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Ozaki, Y; Ohashi, K; Otaka, N; Kawanishi, H; Takikawa, T; Fang, LX; Takahara, K; Tatsumi, M; Ishihama, S; Takefuji, M; Kato, K; Shimizu, Y; Bando, YK; Inoue, A; Kuzuya, M; Miura, S; Murohara, T; Ouchi, N
NATURE COMMUNICATIONS 14 巻 ( 1 ) 頁： 4675 2023年8月
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記述言語：英語 出版者・発行元：Nature Communications
To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.
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Wan, Y; Piao, LM; Xu, SN; Inoue, A; Meng, XK; Lei, YN; Huang, Z; Wang, HL; Yue, XL; Shi, GP; Kuzuya, M; Cheng, XW
FASEB JOURNAL 37 巻 ( 8 ) 頁： e23086 2023年8月
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記述言語：英語 出版者・発行元：FASEB Journal
Cathepsin S (CTSS) is a widely expressed cysteinyl protease that has garnered attention because of its enzymatic and non-enzymatic functions under inflammatory and metabolic pathological conditions. Here, we examined whether CTSS participates in stress-related skeletal muscle mass loss and dysfunction, focusing on protein metabolic imbalance. Eight-week-old male wildtype (CTSS+/+) and CTSS-knockout (CTSS−/−) mice were randomly assigned to non-stress and variable-stress groups for 2 weeks, and then processed for morphological and biochemical studies. Compared with non-stressed mice, stressed CTSS+/+ mice showed significant losses of muscle mass, muscle function, and muscle fiber area. In this setting, the stress-induced harmful changes in the levels of oxidative stress-related (gp91phox and p22phox,), inflammation-related (SDF-1, CXCR4, IL-1β, TNF-α, MCP-1, ICAM-1, and VCAM-1), mitochondrial biogenesis-related (PPAR-γ and PGC-1α) genes and/or proteins and protein metabolism-related (p-PI3K, p-Akt, p-FoxO3α, MuRF-1, and MAFbx1) proteins; and these alterations were rectified by CTSS deletion. Metabolomic analysis revealed that stressed CTSS−/− mice exhibited a significant improvement in the levels of glutamine metabolism pathway products. Thus, these findings indicated that CTSS can control chronic stress-related skeletal muscle atrophy and dysfunction by modulating protein metabolic imbalance, and thus CTSS was suggested to be a promising new therapeutic target for chronic stress-related muscular diseases.
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CTSS Modulates Stress-Related Carotid Artery Thrombosis in a Mouse FeCl<sub>3</sub> Model
Xu, SN; Piao, LM; Wan, Y; Huang, Z; Meng, XK; Inoue, A; Wang, HL; Yue, XL; Jin, XL; Shi, GP; Kuzuya, M; Cheng, XW
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 43 巻 ( 7 ) 頁： E238 - E253 2023年7月
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記述言語：英語 出版者・発行元：Arteriosclerosis, Thrombosis, and Vascular Biology
Background: Exposure to chronic psychological stress is a risk factor for metabolic cardiovascular disease. Given the important role of lysosomal CTSS (cathepsin S) in human pathobiology, we examined the role of CTSS in stress-related thrombosis, focusing on inflammation, oxidative stress, and apoptosis. Methods: Six-week-old wild-type mice (CTSS+/+) and CTSS-deficient mice (CTSS-/-) randomly assigned to nonstress and 2-week immobilization stress groups underwent iron chloride3 (FeCl3)-induced carotid thrombosis surgery for morphological and biochemical studies. Results: On day 14 poststress/surgery, stress had increased the lengths and weights of thrombi in the CTSS+/+mice, plus harmful changes in the levels of PAI-1 (plasminogen activation inhibitor-1), ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 13 motifs), and vWF (von Willebrand factor) and arterial tissue CTSS expression. Compared to the nonstressed CTSS+/+mice, the stressed CTSS-/-mice had decreased levels of PAI-1, vWF, TNF (tumor necrosis factor)-α, interleukin-1β, toll-like receptor-4, cleaved-caspase 3, cytochrome c, p16INK4A, gp91phox, p22phox, ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemoattractant protein-1), MyD88 (myeloid differentiation primary response 88), and MMP (matrix metalloproteinase)-2/-9 and increased levels of ADAMTS13, SOD (superoxide dismutase)-1/-2, eNOS (endothelial NO synthase), p-Akt (phospho-protein kinase B), Bcl-2 (B-cell lymphoma-2), p-GSK3α/β (phospho-glycogen synthase kinases alpha and beta), and p-Erk1/2 (phospho-extracellular signal-regulated kinase 1 and 2) mRNAs and/or proteins. CTSS deletion also reduced the arterial thrombus area and endothelial loss. A pharmacological inhibition of CTSS exerted a vasculoprotective action. In vitro, CTSS silencing and overexpression, respectively, reduced and increased the stressed serum and oxidative stress-induced apoptosis of human umbilical vein endothelial cells, and they altered apoptosis-related proteins. Conclusions: CTSS inhibition appeared to improve the stress-related thrombosis in mice that underwent FeCl3-induction surgery, possibly by reducing vascular inflammation, oxidative stress, and apoptosis. CTSS could thus become a candidate therapeutic target for chronic psychological stress-related thrombotic events in metabolic cardiovascular disease.
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Wang, HL; Inoue, A; Lei, YN; Wu, HX; Hong, L; Cheng, XW
CELLULAR SIGNALLING 103 巻 頁： 110531 2023年3月
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記述言語：英語 出版者・発行元：Cellular Signalling
Cathepsins can be found in the extracellular space, cytoplasm, and nucleus. It was initially suspected that the primary physiological function of the cathepsins was to break down intracellular protein, and that they also had a role in pathological processes including inflammation and apoptosis. However, the many actions of cathepsins outside the cell and their complicated biological impacts have garnered much interest. Cathepsins play significant roles in a number of illnesses by regulating parenchymal cell proliferation, cell migration, viral invasion, inflammation, and immunological responses through extracellular matrix remodeling, signaling disruption, leukocyte recruitment, and cell adhesion. In this review, we outline the physiological roles of cathepsins in the extracellular space, the crucial pathological functions performed by cathepsins in illnesses, and the recent breakthroughs in the detection and therapy of specific inhibitors and fluorescent probes in associated dysfunction.
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Inoue Aiko, Piao Limei, Yue Xueling, Huang Zhe, Hu Lina, Wu Hongxian, Meng Xiangkun, Xu Wenhu, Yu Chenglin, Sasaki Takeshi, Itakura Kohji, Umegaki Hiroyuki, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 2022年9月
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記述言語：日本語 出版者・発行元：Journal of Cachexia, Sarcopenia and Muscle
Background: Young bone marrow transplantation (YBMT) has been shown to stimulate vascular regeneration in pathological conditions, including ageing. Here, we investigated the benefits and mechanisms of the preventive effects of YBMT on loss of muscle mass and function in a senescence-associated mouse prone 10 (SAMP10) model, with a special focus on the role of growth differentiation factor 11 (GDF-11). Methods: Nine-week-old male SAMP10 mice were randomly assigned to a non-YBMT group (n = 6) and a YBMT group (n = 7) that received the bone marrow of 8-week-old C57BL/6 mice. Results: Compared to the non-YBMT mice, the YBMT mice showed the following significant increases (all P < 0.05 in 6–7 mice): endurance capacity (>61.3%); grip strength (>37.9%), percentage of slow myosin heavy chain fibres (>14.9–15.9%). The YBMT also increased the amounts of proteins or mRNAs for insulin receptor substrate 1, p-Akt, p-extracellular signal-regulated protein kinase1/2, p-mammalian target of rapamycin, Bcl-2, peroxisom proliferator-activated receptor-γ coactivator (PGC-1α), plus cytochrome c oxidase IV and the numbers of proliferating cells (n = 5–7, P < 0.05) and CD34+/integrin-α7+ muscle stem cells (n = 5–6, P < 0.05). The YMBT significantly decreased the levels of gp91phox, caspase-9 proteins and apoptotic cells (n = 5–7, P < 0.05) in both muscles; these beneficial changes were diminished by the blocking of GDF-11 (n = 5–6, P < 0.05). An administration of mouse recombinant GDF-11 improved the YBMT-mediated muscle benefits (n = 5–6, P < 0.05). Cell therapy with young bone marrow from green fluorescent protein (GFP) transgenic mice exhibited GFP+ myofibres in aged muscle tissues. Conclusions: These findings suggest that YBMT can prevent muscle wasting and dysfunction by mitigating apoptosis and proliferation via a modulation of GDF-11 signalling and mitochondrial dysfunction in SAMP10 mice.
DOI： 10.1002/jcsm.13058
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Yue Xueling, Piao Limei, Wang Hailong, Huang Zhe, Meng Xiangkun, Sasaki Takeshi, Inoue Aiko, Nakamura Kae, Wan Ying, Xu Shengnan, Shi Guo-Ping, Kim Weon, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
HYPERTENSION 79 巻 ( 8 ) 頁： 1713 - 1723 2022年8月
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記述言語：日本語 出版者・発行元：Hypertension
Background: Chronic psychological stress is a risk factor for kidney disease, including kidney dysfunction and hypertension. Lysosomal CatK (cathepsin K) participates in various human pathobiologies. We investigated the role of CatK in kidney remodeling and hypertension in response to 5/6 nephrectomy injury in mice with or without chronic stress. Methods: Male 7-week-old WT (wild type; CatK+/+) and CatK-deficient (CatK-/-) mice that were or were not subjected to chronic stress underwent 5/6 nephrectomy. At 8 weeks post-stress/surgery, the stress was observed to have accelerated injury-induced glomerulosclerosis, proteinuria, and blood pressure elevation. Results: Compared with the nonstressed mice, the stressed mice showed increased levels of TLR (Toll-like receptor)-2/4, p22phox, gp91phox, CatK, MMP (matrix metalloproteinase)-2/9, collagen type I and III genes, PPAR-γ (peroxisome proliferator-activated receptor-gamma), NLRP-3 (NOD-like receptor thermal protein domain associated protein 3), p21, p16, and cleaved caspase-8 proteins, podocyte foot process effacement, macrophage accumulation, apoptosis, and decreased levels of Bcl-2 (B cell lymphoma 2) and Sirt1, as well as decreased glomerular desmin expression in the kidneys. These harmful changes were retarded by the genetic or pharmacological inhibition of CatK. Consistently, CatK inhibition ameliorated 5/6 nephrectomy-related kidney injury and dysfunction. In mesangial cells, CatK silencing or overexpression, respectively, reduced or increased the PPAR-γ and cleaved caspase-8 protein levels, providing evidence and a mechanistic explanation of CatK's involvement in PPAR-γ/caspase-8-mediated cell apoptosis in response to superoxide and stressed serum. Conclusions: These results demonstrate that CatK plays an essential role in kidney remodeling and hypertension in response to 5/6 nephrectomy or stress, possibly via a reduction of glomerular inflammation, apoptosis, and fibrosis, suggesting a novel therapeutic strategy for controlling kidney injury in mice under chronic psychological stress conditions.
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Piao Limei, Huang Zhe, Inoue Aiko, Kuzuya Masafumi, Cheng Xian Wu
STEM CELL RESEARCH & THERAPY 13 巻 ( 1 ) 頁： 226 2022年6月
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記述言語：日本語 出版者・発行元：Stem Cell Research and Therapy
Background: Skeletal muscle mass and function losses in aging individuals are associated with quality of life deterioration and disability. Mesenchymal stromal cells exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in aging-related degenerative disease. Methods and results: We investigated the efficacy of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) on sarcopenia-related skeletal muscle atrophy and dysfunction in senescence-accelerated mouse prone 10 (SAMP10) mice. We randomly assigned 24-week-old male SAMP10 mice to a UC-MSC treatment group and control group. At 12 weeks post-injection, the UC-MSC treatment had ameliorated sarcopenia-related muscle changes in performance, morphological structures, and mitochondria biogenesis, and it enhanced the amounts of proteins or mRNAs for myosin heavy chain, phospho-AMP-activated protein kinase, phospho-mammalian target of rapamycin, phospho-extracellular signal-regulated kinase1/2, peroxisome proliferator-activated receptor-γ coactivator, GLUT-4, COX-IV, and hepatocyte growth factor in both gastrocnemius and soleus muscles, and it reduced the levels of proteins or mRNAs for cathepsin K, cleaved caspase-3/-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and gp91phox mRNAs. The UC-MSC treatment retarded mitochondria damage, cell apoptosis, and macrophage infiltrations, and it enhanced desmin/laminin expression and proliferating and CD34+/Integrin α7+ cells in both types of skeletal muscle of the SAMP10 mice. In vitro, we observed increased levels of HGF, PAX-7, and MoyD mRNAs at the 4th passage of UC-MSCs. Conclusions: Our results suggest that UC-MSCs can improve sarcopenia-related skeletal muscle atrophy and dysfunction via anti-apoptosis, anti-inflammatory, and mitochondrial biogenesis mechanisms that might be mediated by an AMPK-PGC1-α axis, indicating that UC-MSCs may provide a promising treatment for sarcopenia/muscle diseases.
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Cathepsin K activity controls cachexia-induced muscle atrophy via the modulation of IRS1 ubiquitination
Meng Xiangkun, Huang Zhe, Inoue Aiko, Wang Hailong, Wan Ying, Yue Xueling, Xu Shengnan, Jin Xueying, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 13 巻 ( 2 ) 頁： 1197 - 1209 2022年4月
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Short- and long-term effects of different exercise programs on the gait performance of older adults with subjective cognitive decline: A randomized controlled trial
Fujita Kosuke, Umegaki Hiroyuki, Makino Taeko, Uemura Kazuki, Hayashi Takahiro, Inoue Aiko, Uno Chiharu, Kitada Tomoharu, Huang Chi Hsien, Shimada Hiroyuki, Kuzuya Masafumi
EXPERIMENTAL GERONTOLOGY 156 巻 2021年12月
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Proliferin-1 Ameliorates Cardiotoxin-Related Skeletal Muscle Repair in Mice
Goto Hiroki, Inoue Aiko, Piao Limei, Hu Lina, Huang Zhe, Meng Xiangkun, Suzuki Yusuke, Umegaki Hiroyuki, Kuzuya Masafumi, Cheng Xian Wu
STEM CELLS INTERNATIONAL 2021 巻 2021年11月
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Sequestration of RBM10 in Nuclear Bodies: Targeting Sequences and Biological Significance
Wang Ling-Yu, Xiao Sheng-Jun, Kunimoto Hiroyuki, Tokunaga Kazuaki, Kojima Hirotada, Kimura Masatsugu, Yamamoto Takahiro, Yamamoto Naoki, Zhao Hong, Nishio Koji, Tani Tokio, Nakajima Koichi, Sunami Kishiko, Inoue Akira
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 22 巻 ( 19 ) 2021年10月
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記述言語：日本語 出版者・発行元：International Journal of Molecular Sciences
RBM10 is an RNA-binding protein that regulates alternative splicing (AS). It localizes to the extra-nucleolar nucleoplasm and S1-1 nuclear bodies (NBs) in the nucleus. We investigated the biological significance of this localization in relation to its molecular function. Our analyses, employing deletion mutants, revealed that RBM10 possesses two S1-1 NB-targeting sequences (NBTSs), one in the KEKE motif region and another in the C2H2 Zn finger (ZnF). These NBTSs act synergistically to localize RBM10 to S1-1 NBs. The C2H2 ZnF not only acts as an NBTS, but is also essential for AS regulation by RBM10. Moreover, RBM10 does not participate in S1-1 NB formation, and without alterations of RBM10 protein levels, its NB-localization changes, increasing as cellular transcriptional activity declines, and vice versa. These results indicate that RBM10 is a transient component of S1-1 NBs and is sequestered in NBs via its NBTSs when cellular transcription decreases. We propose that the C2H2 ZnF exerts its NB-targeting activity when RBM10 is unbound by pre-mRNAs, and that NB-localization of RBM10 is a mechanism to control its AS activity in the nucleus.
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Statins Mitigate Stress-Related Vascular Aging and Atherosclerosis in apoE-Deficient Mice Fed High Fat-Diet: The Role of Glucagon-Like Peptide-1/Adiponectin Axis
Lei Yanna, Cui Qingsong, Yang Guang, Piao Limei, Inoue Aiko, Wu Hongxian, Li Xiang, Kuzuya Masafumi, Cheng Xian Wu
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY 9 巻 2021年7月
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Effect of Various Exercises on Intrinsic Capacity in Older Adults With Subjective Cognitive Concerns
Huang Chi Hsien, Umegaki Hiroyuki, Makino Taeko, Uemura Kazuki, Hayashi Takahiro, Kitada Tomoharu, Inoue Aiko, Shimada Hiroyuki, Kuzuya Masafumi
JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION 22 巻 ( 4 ) 頁： 780 - + 2021年4月
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Mental Health Status of the Older Adults in Japan During the COVID-19 Pandemic
Fujita Kosuke, Inoue Aiko, Kuzuya Masafumi, Uno Chiharu, Huang Chi Hsien, Umegaki Hiroyuki, Onishi Joji
JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION 22 巻 ( 1 ) 頁： 220 - 221 2021年1月
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Effect of various exercises on frailty among older adults with subjective cognitive concerns: a randomised controlled trial
Huang Chi Hsien, Umegaki Hiroyuki, Makino Taeko, Uemura Kazuki, Hayashi Takahiro, Kitada Tomoharu, Inoue Aiko, Shimada Hiroyuki, Kuzuya Masafumi
AGE AND AGEING 49 巻 ( 6 ) 頁： 1011 - 1019 2020年11月
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Increased dipeptidyl peptidase-4 accelerates chronic stress-related thrombosis in a mouse carotid artery model
Jin Xianglan, Jin Chunzi, Nakamura Kae, Jin Tiefeng, Xin Minglong, Wan Ying, Yue Xueling, Jin Shengyu, Wang Hailong, Inoue Aiko, Nan Yongshan, Lin Zhenhua, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF HYPERTENSION 38 巻 ( 8 ) 頁： 1504 - 1513 2020年8月
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Deficiency of cysteinyl cathepsin K suppresses the development of experimental intimal hyperplasia in response to chronic stress
Meng Xiangkun, Piao Limei, Wang Hailong, Inoue Aiko, Huang Zhe, Jiang Haiying, Nakamura Kae, Sasaki Takeshi, Li Xiang, Xu Wenhu, Yu Chenglin, Hu Lina, Wu Hongxian, Murohara Toyoaki, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF HYPERTENSION 38 巻 ( 8 ) 頁： 1514 - 1524 2020年8月
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Combined Impact of Physical Frailty and Social Isolation on Rate of Falls in Older Adults
Hayashi T., Umegaki Hiroyuki, Makino T., Huang C. H., Inoue A., Shimada H., Kuzuya M.
JOURNAL OF NUTRITION HEALTH & AGING 24 巻 ( 3 ) 頁： 312 - 318 2020年3月
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PLF-1 (Proliferin-1) Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia
Hu Lina, Huang Zhe, Ishii Hideki, Wu Hongxian, Suzuki Susumu, Inoue Aiko, Kim Weon, Jiang Haiying, Li Xiang, Zhu Enbo, Piao Limei, Zhao Guangxian, Lei Yanna, Okumura Kenji, Shi Guo-Ping, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF THE AMERICAN HEART ASSOCIATION 8 巻 ( 24 ) 2019年12月
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Cathepsin S-Mediated Negative Regulation of Wnt5a/SC35 Activation Contributes to Ischemia-Induced Neovascularization in Aged Mice
Xu Wenhu, Yu Chenglin, Piao Limei, Inoue Aiko, Wang Hailong, Meng Xiangkun, Li Xiang, Cui Lan, Umegaki Hiroyuki, Shi Guo-Ping, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
CIRCULATION JOURNAL 83 巻 ( 12 ) 頁： 2537 - + 2019年12月
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Cathepsin S Deficiency Mitigated Chronic Stress-Related Neointimal Hyperplasia in Mice
Wang Hailong, Meng Xiangkun, Piao Limei, Inoue Aiko, Xu Wenhu, Yu Chenglin, Nakamura Kae, Hu Lina, Sasaki Takeshi, Wu Hongxian, Unno Kazumasa, Umegaki Hiroyuki, Murohara Toyoaki, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF THE AMERICAN HEART ASSOCIATION 8 巻 ( 14 ) 2019年7月
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Cathepsin S Deficiency Impaired Noevascularization in Response to Ischemia via the Activation of Wnt5-SC35 Signaling Pathway in Advanced Age
Xu Wenhu, Yu Chenglin, Piao Limei, Inoue Aiko, Kuzuya Masafumi, Cheng Xian Wu
CIRCULATION 138 巻 2018年11月
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ACDF-1Modulates Smooth Muscle Cell Proliferation and Development of Experimental Intimal Hyperplasia
Hu Lina, Ishii Hideki, Wu Hongxian, Suzuki Susumu, Inoue Aiko, Shi Guo-Ping, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
CIRCULATION 138 巻 2018年11月
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Adiponectin/AdipoR1 Signal Inactivation Contributes to Impaired Angiogenesis in Mice of Advanced Age
Piao Limei, Yu Chenglin, Xu Wenhu, Inoue Aiko, Shibata Rei, Ouchi Noriyuki, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
CIRCULATION 138 巻 2018年11月
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Apoptotic Cell-Derived Growth Factor-1 Modulates Noevascularization in Response to Ischemia via the activation of PI3K/Akt/p38MAPK-Depended and -Independent mTOR Signaling Cascades
Yu Chenglin, Piao Limei, Xu Wenhu, Inoue Aiko, Kuzuya Masafumi, Cheng Xian Wu
CIRCULATION 138 巻 2018年11月
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Cathepsin S Controls Injury-Related Neointimal Formation in Mice Under Chronic Stress via the Modulation of Inflammation and Immune Action
Wang Hailong, Li Limei, Meng Xiangkun, Inoue Aiko, Shi Guo-Ping, Kuzuya Masafumi, Cheng Xian Wu
CIRCULATION 138 巻 2018年11月
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Adiponectin/AdiopR1 signal inactivation contributes to impaired angiogenesis in mice of advanced age
Piao Limei, Yu Chenglin, Xu Wenhu, Inoue Aiko, Shibata Rei, Li Xiang, Nan Yongshan, Zhao Guangxian, Wang Hailong, Meng Xiangkun, Lei Yanna, Goto Hiroki, Ouchi Noriyuki, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
INTERNATIONAL JOURNAL OF CARDIOLOGY 267 巻 頁： 150-155 2018年9月
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Response to letter "DPP-4 inhibition as a therapeutic strategy to ameliorate diabetic metabolic memory"
Cheng Xian Wu, Lei Yanna, Piao Limei, Inoue Aiko, Yang Guang, Zhu Enbo, Kuzuya Masafumi
INTERNATIONAL JOURNAL OF CARDIOLOGY 256 巻 頁： 17-17 2018年4月
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Cathepsin K activity controls cardiotoxin-induced skeletal muscle repair in mice
Ogasawara Shinyu, Cheng Xian Wu, Inoue Aiko, Hu Lina, Piao Limei, Yu Chenglin, Goto Hiroki, Xu Wenhu, Zhao Guangxian, Lei Yanna, Yang Guang, Kimura Kaoru, Umegaki Hiroyuki, Shi Guo-Ping, Kuzuya Masafumi
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 9 巻 ( 1 ) 頁： 160 - 175 2018年2月
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井上 愛子, 成 憲武, 五籐 大貴, 葛谷 雅文
日本老年医学会雑誌 55 巻 ( 1 ) 頁： 13 - 24 2018年
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記述言語：日本語 出版者・発行元：一般社団法人 日本老年医学会
<p>サルコペニア（sarcopenia）は，加齢に伴うさまざまな要因により，骨格筋蛋タンパクの合成と分解のアンバランス，筋肉修復能低下などが生じることより発症すると考えているが，その詳細に関して多くは不明である．サルコペニアをはじめとした骨格筋萎縮と機能低下の臨床的重要性が認知されつつあるとともに，骨格筋疾患に関する研究も新たな転換期を迎えている．加齢に伴う骨格筋の形態ならびに機能的変化に基づいたオリジナリティーの高い基礎研究が続々と発表され，従来では考えもし得なかった目覚しい発展を遂げている状況である．加齢による骨格筋疾患（サルコペニア）には骨格筋障害を伴っていることがしばしば多く，治療には骨格筋障害へのアプローチが必要である．サルコペニアの発症機序は多因子である．サルコペニア発症・進展プロセスにおいて骨格筋リモデリングと再生不全は重要であり，蛋白質分解システムの異常，そしてタンパク質合成と分解のアンバランスや骨格筋幹細胞の機能不全など様々な要因が関わっている．本稿では，プロテアーゼ·細胞外マトリックス代謝異常，骨格筋タンパク質合成と分解のアンバランス，骨格筋幹細胞老化・機能不全，炎症亢進，骨格筋細胞増殖とアポトーシスアンバランスならびにミトコンドリア機能不全の多方面から前3者に焦点を当てて，本研究グループの研究成果を交えてサルコペニアの新たな分子機構に関する最近の知見について概説する．</p>
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Chronic Psychological Stress Accelerates Vascular Senescence and Impairs Ischemia-Induced Neovascularization: The Role of Dipeptidyl Peptidase-4/Glucagon-Like Peptide-1-Adiponectin Axis
Piao Limei, Zhao Guangxian, Zhu Enbo, Inoue Aiko, Shibata Rei, Lei Yanna, Hu Lina, Yu Chenglin, Yang Guang, Wu Hongxian, Xu Wenhu, Okumura Kenji, Ouchi Noriyuki, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF THE AMERICAN HEART ASSOCIATION 6 巻 ( 10 ) 2017年10月
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Increased dipeptidyl peptidase-4 accelerates diet-related vascular aging and atherosclerosis in ApoE-deficient mice under chronic stress
Lei Yanna, Yang Guang, Hu Lina, Piao Limei, Inoue Aiko, Jiang Haiying, Sasaki Takeshi, Zhao Guangxian, Yisireyili Maimaiti, Yu Chenglin, Xu Wenhu, Takeshita Kyosuke, Okumura Kenji, Kuzuya Masafumi, Cheng Xian Wu
INTERNATIONAL JOURNAL OF CARDIOLOGY 243 巻 頁： 413-420 2017年9月
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Exenatide mitigated diet-induced vascular aging and atherosclerotic plaque growth in ApoE-deficient mice under chronic stress
Yang Guang, Lei Yanna, Inoue Aiko, Piao Limei, Hu Lina, Jiang Haiying, Sasaki Takeshi, Wu Hongxian, Xu Wenhu, Yu Chenglin, Zhao Guangxian, Ogasawara Shinyu, Okumura Kenji, Kuzuya Masafumi, Cheng Xian-Wu
ATHEROSCLEROSIS 264 巻 頁： 1-10 2017年9月
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Dipeptidyl Peptidase-4 Regulates Hematopoietic Stem Cell Activation in Response to Chronic Stress
Zhu Enbo, Hu Lina, Wu Hongxian, Piao Limei, Zhao Guangxian, Inoue Aiko, Kim Weon, Yu Chenglin, Xu Wenhu, Bando Yasuko K., Li Xiang, Lei Yanna, Hao Chang-Ning, Takeshita Kyosuke, Kim Woo-Shik, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi, Cheng Xian Wu
JOURNAL OF THE AMERICAN HEART ASSOCIATION 6 巻 ( 7 ) 2017年7月
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Exercise restores muscle stem cell mobilization, regenerative capacity and muscle metabolic alterations via adiponectin/AdipoR1 activation in SAMP10 mice 査読有り
Aiko Inoue, Xian Wu Cheng, Zhe Huang, Lina Hu, Ryosuke Kikuchi, Haiying Jiang, Limei Piao,Takeshi Sasaki, Kohji Itakura, Hongxian Wu, Guangxian Zhao, Yanna Lei, Guang Yang, Enbo Zhu, Xiang Li, Kohji Sato, Teruhiko Koike, Masafumi Kuzuya.
Journal of Cachexia, Sarcopenia and Muscle 8 巻 ( 3 ) 頁： 370-385 2017年6月
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Exercise restores muscle stem cell mobilization, regenerative capacity and muscle metabolic alterations via adiponectin/AdipoR1 activation in SAMP10 mice
Inoue Aiko, Cheng Xian Wu, Huang Zhe, Hu Lina, Kikuchi Ryosuke, Jiang Haiying, Piao Limei, Sasaki Takeshi, Itakura Kohji, Wu Hongxian, Zhao Guangxian, Lei Yanna, Yang Guang, Zhu Enbo, Li Xiang, Sato Kohji, Koike Teruhiko, Kuzuya Masafumi
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE 8 巻 ( 3 ) 頁： 370 - 385 2017年6月
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The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice
Zhao Guangxian, Cheng Xian W., Piao Limei, Hu Lina, Lei Yanna, Yang Guang, Inoue Aiko, Ogasawara Shinyu, Wu Hongxian, Hao Chang-Ning, Okumura Kenji, Kuzuya Masafumi
AGING AND DISEASE 8 巻 ( 3 ) 頁： 287-300 2017年6月
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Wu Hongxian, Cheng Xian Wu, Hu Lina, Takeshita Kyosuke, Hu Chen, Du Qiuna, Li Xiang, Zhu Enbo, Huang Zhe, Yisireyili Maimaiti, Zhao Guangxian, Piao Limei, Inoue Aiko, Jiang Haiying, Lei Yanna, Zhang Xiaohong, Liu Shaowen, Dai Qiuyan, Kuzuya Masafumi, Shi Guo-Ping, Murohara Toyoaki
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 36 巻 ( 8 ) 頁： 1549 - 1557 2016年8月
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記述言語：日本語 出版者・発行元：Arteriosclerosis, Thrombosis, and Vascular Biology
Objective - Cathepsin S (CatS) participates in atherogenesis through several putative mechanisms. The ability of cathepsins to modify histone tail is likely to contribute to stem cell development. Histone deacetylase 6 (HDAC6) is required in modulating the proliferation and migration of various types of cancer cells. Here, we investigated the cross talk between CatS and HADC6 in injury-related vascular repair in mice. Approach and Results - Ligation injury to the carotid artery in mice increased the CatS expression, and CatS-deficient mice showed reduced neointimal formation in injured arteries. CatS deficiency decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and toll-like receptor 2 expression in ligated arteries. The genetic or pharmacological inhibition of CatS also alleviated the increased phosphorylation of p38 mitogen-activated protein kinase, Akt, and HDAC6 induced by platelet-derived growth factor BB in cultured vascular smooth muscle cells (VSMCs), and p38 mitogen-activated protein kinase inhibition and Akt inhibition decreased the phospho-HDAC6 levels. Moreover, CatS inhibition caused decrease in the levels of the HDAC6 activity in VSMCs in response to platelet-derived growth factor BB. The HDAC6 inhibitor tubastatin A downregulated platelet-derived growth factor-induced VSMC proliferation and migration, whereas HDAC6 overexpression exerted the opposite effect. Tubastatin A also decreased the intimal VSMC proliferation and neointimal hyperplasia in response to injury. Toll-like receptor 2 silencing decreased the phosphorylation levels of p38 mitogen-activated protein kinase, Akt, and HDAC6 and VSMC migration and proliferation. Conclusions - This is the first report detailing cross-interaction between toll-like receptor 2-mediated CatS and HDAC6 during injury-related vascular repair. These data suggest that CatS/HDAC6 could be a potential therapeutic target for the control of vascular diseases that are involved in neointimal lesion formation.
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Cathepsin S activity controls ischemia-induced neovascularization in mice
Li Xiang, Cheng Xian Wu, Hu Lina, Wu Hongxian, Guo-Ping, Hao Chang-Ning, Jiang Haiying, Zhu Enbo, Huang Zhe, Inoue Aiko, Sasaki Takeshi, Du Qiuna, Takeshita Kyosuke, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi
INTERNATIONAL JOURNAL OF CARDIOLOGY 183 巻 頁： 198 - 208 2015年3月
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記述言語：日本語 出版者・発行元：International Journal of Cardiology
Abstract Background Evidence from human and animal studies has demonstrated elevated levels of the cysteine protease cathepsin S (CatS) in hypoxic atherosclerotic lesions. We hypothesized that silencing of CatS gene would suppress ischemia-induced angiogenic action. Methods and results Left femoral artery ligation-induced ischemia in mice showed the increased expression and activity of CatS in the ischemic muscle. The CatS-deficiency (CatS-/-) mice showed impaired functional recovery following hindlimb ischemia and reduced levels of peroxisome proliferator-activated receptor-γ (PPAR-γ), phospho-Akt (p-Akt), p-endothelial nitric oxide synthase, p-extracellular signal-regulated kinase1/2 (Erk1/2), p-p38 mitogen-activated protein kinase, and vascular endothelial growth factor (VEGF) proteins, as well as reduced levels of matrix metalloproteinase-9 and macrophage infiltration in the ischemic muscles. In vitro, CatS silencing reduced the levels of these targeted essential molecules for angiogenesis and vasculogenesis. Together, the results indicated that the effects of CatS knockdown led to defective endothelial cell invasion, proliferation, and tube formation. This notion was reinforced by the finding that CatS inhibition led to a decreased PPAR-γ level and VEGF/Erk1/2 signaling activation in response to ischemia. CatS-/- resulted in decreased circulating EPC-like CD31+/c-Kit+ cells, accompanied by the reduction of the cellular levels of PPAR-γ, p-Akt, and VEGF induced by ischemic stress. Transplantation of bone-marrow-derived mononuclear cells from CatS+/+ mice restored neovascularization in CatS-/- mice. Conclusions CatS activity controls ischemia-induced neovascularization partially via the modulation of PPAR-γ and VEGF/Akt signaling activation.
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Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia
Jiang Haiying, Cheng Xian Wu, Shi Guo-Ping, Hu Lina, Inoue Aiko, Yamamura Yumiko, Wu Hongxian, Takeshita Kyosuke, Li Xiang, Huang Zhe, Song Haizhen, Asai Masashi, Hao Chang-Ning, Unno Kazumasa, Koike Teruhiro, Oshida Yoshiharu, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi
NATURE COMMUNICATIONS 5 巻 頁： 3838 2014年6月
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記述言語：日本語 出版者・発行元：Nature Communications
Cysteine proteases play important roles in pathobiology. Here we reveal that cathepsin K (CatK) has a role in ischaemia-induced neovascularization. Femoral artery ligation-induced ischaemia in mice increases CatK expression and activity, and CatK-deficient mice show impaired functional recovery following hindlimb ischaemia. CatK deficiency reduces the levels of cleaved Notch1 (c-Notch1), Hes1 Hey1, Hey2, vascular endothelial growth factor, Flt-1 and phospho-Akt proteins of the ischaemic muscles. In endothelial cells, silencing of CatK mimicked, whereas CatK overexpression enhanced, the levels of c-Notch1 and the expression of Notch downstream signalling molecules, suggesting CatK contributes to Notch1 processing and activates downstream signalling. Moreover, CatK knockdown leads to defective endothelial cell invasion, proliferation and tube formation, and CatK deficiency is associated with decreased circulating endothelial progenitor cells-like CD31 + /c-Kit + cells in mice following hindlimb ischaemia. Transplantation of bone marrow-derived mononuclear cells from CatK +/+ mice restores the impairment of neovascularization in CatK -/- mice. We conclude that CatK may be a potential therapeutic target for ischaemic disease. © 2014 Macmillan Publishers Limited.
DOI： 10.1038/ncomms4838
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Kimura Kaoru, Cheng Xian Wu, Inoue Aiko, Hu Lina, Koike Teruhiko, Kuzuya Masafumi
NUTRITION RESEARCH 34 巻 ( 4 ) 頁： 368 - 374 2014年4月
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記述言語：日本語 出版者・発行元：Nutrition Research
β-Hydroxy- β-methylbutyrate (HMB) prevents deleterious muscle responses under pathological conditions, including tumor- and chronic steroid therapy-related muscle losses. Here, we investigated the hypothesis that HMB may modulate the balance between protein synthesis and degradation in the PI3K/Akt-mediated mammalian target of rapamycin (mTOR) and FoxO1/FoxO3a-dependent mechanisms in differentiated C2C12 muscle cells. We also tested the effect of HMB on the expression of MuRF-1 and atrogin-1 in response to the inflammatory stress. β-Hydroxy- β-methylbutyrate up-regulated phosphorylation of Akt and mTOR, and these effects were completely abolished in the presence of PI3K inhibitor LY294002. β-Hydroxy- β-methylbutyrate also up-regulated FoxO1 and FoxO3a phosphorylation, and these changes were inhibited by LY294002. Although, unexpectedly, HMB failed to reduce the expressions of atrophy-related atrogin-1 messenger RNA and the protein response to the proinflammatory cytokines tumor necrosis factor α plus interferon γ, HMB did attenuate the MuRF-1 expression. Thus, HMB appears to restore the balance between intracellular protein synthesis and proteolysis, likely via activation of the PI3K/Akt-dependent mTOR and FoxO1/FoxO3a signaling pathway and the reduction of tumor necrosis factor α/interferon γ-induced MuRF-1 expression, thereby ameliorating aging-related muscle atrophy. © 2014 Elsevier Inc.
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Cathepsin K-Mediated Noich1 Activation Contributes to Neovascularization in Response to Hypoxia
Hu Lina, Cheng Xian Wu, Shi Guo-Ping, Jang Haiying, Inoue Aiko, Yamamura Yumiko, Wu Hongxian, Takeshita Kyosuke, Okumura Kenji, Murohara Toyoaki, Kuzuya Masafumi
CIRCULATION 128 巻 ( 22 ) 2013年11月
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HMG-CoA Reductase Inhibitor Pitavastatin Enhances Renoprotective Effects of Angiotensin Receptor1 Blocker Olmesartan In Salt-Sensitive Hypertensive Rats
Inoue Aiko, Cheng Xian Wu, Sasaki Takeshi, Hu Lina, Jang Haiying, Xiang Li, Kuzuya Masafumi, Murohara Toyoaki, Okumura Kenji
CIRCULATION 128 巻 ( 22 ) 2013年11月
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Akt is essential for adaptive response of systolic left-ventricular function and aging-induced intolerance to exercise
Aoyama M., Bando Y. Kureishi, Monji A., Cheng X. W., Inoue A., Monji A., Mitsui T., Kuzuya M., Murohara T.
EUROPEAN HEART JOURNAL 34 巻 頁： 927 - 927 2013年8月
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Mechanisms Underlying the Impairment of Ischemia-Induced Neovascularization in Cathepsin K-Deficient Mic
Jiang Haiying, Cheng Xian Wu, Shi Guo-Ping, Hu Lina, Song Haizhen, Inoue Aiko, Koike Teruhiko, Kuzuya Masafumi
CIRCULATION 126 巻 ( 21 ) 2012年11月
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Statins Enhance the Beneficial Effects of Olmesartan on Renal Injury in Salt-Sensitive Hypertensive Rats via the Reduction of an Angiotensin-Mineralocorticoid Receptor Signaling Interaction
Cheng Xian Wu, Inoue Aiko, Hu Lina, Song Haizhen, Sasaki Takeshi, Kuzuya Masafumi, Okumura Kenji, Murohara Toyoaki
CIRCULATION 124 巻 ( 21 ) 2011年11月
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Cheng Xian Wu, Song Haizhen, Sasaki Takeshi, Hu Lina, Inoue Aiko, Bando Yasuko K., Shi Guo-Ping, Kuzuya Masafumi, Okumura Kenji, Murohara Toyoaki
HYPERTENSION 57 巻 ( 5 ) 頁： 981 - U238 2011年5月
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記述言語：日本語 出版者・発行元：Hypertension
The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of angiotensin II type 1 receptor antagonism in the pathogenesis of atherosclerosis in apolipoprotein E-deficient (ApoE) mice with a special focus on plaque neovascularization. ApoE mice fed a high-fat diet were randomly assigned to 1 of 2 groups and administered vehicle or olmesartan for 12 weeks. Quantification of plaque areas at the aortic root and in the thoracic and abdominal aorta revealed that, in all 3 of the regions, olmesartan reduced intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. Olmesartan increased the levels of collagen and elastin, reduced the level of macrophages in the aortic root, and reduced the mRNA and the activity of matrix metalloproteinase (MMP) 2 in aortic roots and thoracic aortas. Aortic ring assay revealed that olmesartan-treated ApoE mice had a markedly lower angiogenic response than that of untreated ApoE mice. Bone marrow-derived endothelial progenitor cell-like c-Kit cells from olmesartan-treated ApoE mice showed marked impairment of cellular functions and lower expression of TLR2/TLR4 and MMP-2 compared with those of untreated controls. MMP-2 deficiency reduced intimal neovessel density and atherosclerotic lesion formation. Olmesartan and small-interfering RNA targeting TLR2 reduced the levels of TLR2, and MMP-2 mRNA induced angiotensin II in cultured endothelial cells. Angiotensin II type 1 receptor antagonism appears to inhibit intimal neovascularization in ApoE mice, partly by reducing TLR2/TLR4-mediated inflammatory action and MMP activation, thus decreasing atherosclerotic plaque growth and increasing plaque instability. © 2011 American Heart Association, Inc.
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Cheng Xian Wu, Kuzuya Masafumi, Sasaki Takeshi, Inoue Aiko, Hu Lina, Song Haizhen, Huang Zhe, Li Ping, Takeshita Kyosuke, Hirashiki Akihiro, Sato Kohji, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki
JOURNAL OF HYPERTENSION 29 巻 ( 3 ) 頁： 542 - 552 2011年3月
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記述言語：日本語 出版者・発行元：Journal of Hypertension
Objective: The mineralocorticoid receptor has been implicated in the pathogenesis of chronic cardiorenal disease. Statins improve renal remodeling and dysfunction in patients with proteinuric kidney diseases. We aimed to clarify the beneficial effects and mechanisms of action of statins in renal insufficiency. Methods and Results: Dahl salt-sensitive rats fed a high-salt diet were treated from 12 to 20 weeks of age with vehicle, the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin, the synthetic cathepsin inhibitor E64d, or a low or high dosage of pitavastatin (1 or 3 mg/kg daily). Rats fed a low-salt diet served as controls. Rats on the high-salt diet developed massive proteinuria and glomerulosclerosis; these changes were attenuated by both doses of pitavastatin. The amounts of mRNAs or proteins for mineralocorticoid receptor, angiotensin-converting enzyme, angiotensin II type 1 receptor (AT1R), monocyte chemoattractant protein-1, osteopontin, macrophage infiltration, and NADPH subunits (gp91, p22, and Rac1) were significantly higher in the failing kidneys of vehicle-treated rats than in the kidneys of control rats. Either dose of pitavastatin significantly attenuated these changes. These effects of pitavastatin were mimicked by those of apocynin and E64d. Pretreatment with pitavastatin and apocynin inhibited mRNA and protein of mineralocorticoid receptor induced by angiotensin II in cultured podocytes. Conclusion: The beneficial effects of pitavastatin are likely attributable, at least in part, to attenuation of the mineralocorticoid receptor-dependent inflammatory mediator, matrix protein, and cathepsin expressions induced by AT1R-mediated NADPH oxidase activation in the kidneys of a salt-induced hypertensive Dahl salt-sensitive rat model. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.
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Statin Inhibits Apoptosis of Vascular Smooth Muscle Cells in Atherogenic Plaque via eNOs/HIF-1 alpha-Mediated IAP-2 Activation: Implication for Plaque Stability
Cheng Xian Wu, Song Haizhen, Hu Lina, Inoue Aiko, Kuzuya Masfumi, Nakamura Kae, Kim Weon, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki
CIRCULATION 122 巻 ( 21 ) 2010年11月
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Superoxide-Dependent Cathepsin Activation is Associated with Hypertensive Renal Remodeling and Dysfunction and Represents a Target for Angiotensin Type 1 Receptor Blocker
Cheng Xian Wu, Sasaki Takeshi, Song Haizhen, Inoue Aiko, Fan Janglin, Hirashiki Akihiro, Shi Guo-Ping, Okumura Kenji, Kuzuya Masafumi, Murohara Toyoaki
CIRCULATION 122 巻 ( 21 ) 2010年11月
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Kimura Kaoru, Cheng Xian Wu, Nakamura Kae, Inoue Aiko, Hu Lina, Song Haizhen, Okumura Kenji, Iguchi Akihisa, Murohara Toyoaki, Kuzuya Masafumi
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY 37 巻 ( 11 ) 頁： 1096 - 1101 2010年11月
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記述言語：日本語 出版者・発行元：Clinical and Experimental Pharmacology and Physiology
1. Matrix metalloproteinases (MMP) are associated with the vascular remodelling seen in atherosclerosis and aneurysm. The activation and activity of MMP-2 are regulated by the intrinsic tissue inhibitor of MMP-2 (TIMP-2). The aim of the present study was to examine whether, conversely, MMP-2 can affect the gene and protein expression of TIMP-2. 2. In the present study, we examined the mRNA and protein expression of MMP-2 and TIMP-2 in cultured smooth muscle cells (SMC) from the aortas of MMP-2+/+ and MMP-2 / mice. We also examined the roles of MMP-2 in SMC cellular events. 3. Western blotting showed that less TIMP-2 protein was present in the conditioned medium of MMP-2 / SMC than in that of MMP-2+/+ SMC. Real-time reverse transcription polymerase chain reaction analysis showed that MMP-2 deficiency reduced TIMP-2 mRNA expression in SMC. Recombinant MMP-2 enhanced the expression of TIMP-2 protein in cultured SMC from MMP-2 / mice. Furthermore, a siRNA targeting MMP-2 impaired the gene and protein expression of MMP-2 in cultured SMC from MMP-2+/+ mice. MMP-2 deficiency impaired SMC invasion, but not their proliferation, adhesion or migration. 4. Our findings suggest that MMP-2 is likely to be responsible, at least in part, for regulating TIMP-2 expression and is thus a potential target, in addition to TIMP-2, for therapeutics aimed at preventing cardiovascular remodelling in response to injury. © 2010 The Authors. Clinical and Experimental Pharmacology and Physiology © 2010 Blackwell Publishing Asia Pty Ltd.
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Statin-Induced Prevention of Hypertensive Renal Insufficiency Through Reduction of Local Angiotensin Synthesis and NADPH Oxidase-Dependent Activation of the Mineralocorticoid Receptor
Cheng Xian Wu, Okumura Kenji, Inoue Aiko, Hu Lina, Song Haizhen, Sasaki Takeshi, Kuzuya Masafumi, Murohara Toyoaki
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 30 巻 ( 11 ) 頁： E232 - E232 2010年11月
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Mechanisms Underlying the Exercise Training-Induced Improvement of Neovascularization in Response to Ischemia in Advanced Age
Cheng Xian Wu, Okumura Kenji, Hu Lina, Song Haizhen, Inoue Aiko, Kuzuya Masafumi, Murohara Toyoaki
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 30 巻 ( 11 ) 頁： E247 - E247 2010年11月
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Cheng Xian Wu, Kuzuya Masafumi, Kim Weon, Song Haizhen, Hu Lina, Inoue Aiko, Nakamura Kae, Di Qun, Sasaki Takeshi, Tsuzuki Michitaka, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki
CIRCULATION 122 巻 ( 7 ) 頁： 707 - 716 2010年8月
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記述言語：日本語 出版者・発行元：Circulation
Background: Exercise stimulates the vascular response in pathological conditions, including ischemia; however, the molecular mechanisms by which exercise improves the impaired hypoxia-induced factor (HIF)-1α-mediated response to hypoxia associated with aging are poorly understood. Here, we report that swimming training (ST) modulates the vascular response to ischemia in aged (24-month-old) mice. Methods and Results: Aged wild-type mice (MMP-2 +/+) that maintained ST (swimming 1 h/d) from day 1 after surgery were randomly assigned to 4 groups that were treated with either vehicle, LY294002, or deferoxamine for 14 days. Mice that were maintained in a sedentary condition served as controls. ST increased blood flow, capillary density, and levels of p-Akt, HIF-1α, vascular endothelial growth factor, Fit-1, and matrix metalloproteinase-2 (MMP-2+/+) in MMP-2 mice. ST also increased the numbers of circulating endothelial progenitor cells and their function associated with activation of HIF-1α. All of these effects were diminished by LY294002, an inhibitor of phosphatidylinositol 3-kinase; enhanced by deferoxamine, an HIF-1α stabilizer; and impaired by knockout of MMP-2. Finally, bone marrow transplantation confirmed that ST enhanced endothelial progenitor cell homing to ischemic sites in aged mice. Conclusions-: ST can improve neovascularization in response to hypoxia via a phosphatidylinositol 3-kinase-dependent mechanism that is mediated by the HIF-1α/vascular endothelial growth factor/MMP-2 pathway in advanced age. © 2010 American Heart Association, Inc.
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Exercise Training Stimulates Neovascularization in Response to Ischemia via HIF-1 alpha-VEGF-mediated Activation of MMP-2 in Advanced Age
Cheng Xian Wu, Kuzuya Masafumi, Hu Lina, Kim Weon, Song Haizhen, Inoue Aiko, Shi Guo-Ping, Okumura Kenji, Murohara Toyoaki
CIRCULATION 120 巻 ( 18 ) 頁： S532 - S532 2009年11月
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TREATMENT OF APO E-DEFICIENT MICE WITH STATIN INHIBITS THE OXIDATIVE STRESS-DEPENDENT LYSOSMAL PROTEASE CATHEPSIN ACTIVATION SYSTEM: IMPLICATION FOR PLAQUE STABILITY
Cheng X. W., Kuuzya M., Sasaki T., Nakamura K., Song H., Hu L., Inoue A., Shi G-P, Murohara T., Okumura K.
ATHEROSCLEROSIS SUPPLEMENTS 10 巻 ( 2 ) 2009年6月
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Treatment of ApoE-Deficient Mice with Statin Inhibits the Oxidative Stress-Dependent Lysosomal Protease Cathepsin Activation System: Implication for Plaque Stability
Cheng Xian Wu, Kuzuya Masafumi, Okumura Kenjl, Nakamura Kae, Inoue Aiko, Sasaki Takeshi, Song Haizhen, Takeshita Kyosuke, Kim Weon, Shi Guo-Ping, Murohara Toyoaki
CIRCULATION 118 巻 ( 18 ) 頁： S559 - S559 2008年10月
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Angiogenic activity of bFGF and VEGF suppressed by proteolytic cleavage by neutrophil elastase
Ai Shingo, Cheng Xian Wu, Inoue Aiko, Nakamura Kae, Okumura Kenji, Iguchi Akihisa, Murohara Toyoaki, Kuzuya Masafumi
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 364 巻 ( 2 ) 頁： 395 - 401 2007年12月
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記述言語：日本語 出版者・発行元：Biochemical and Biophysical Research Communications
Neutrophil elastase (NE), a serine protease released from the azurophil granules of activated neutrophil, proteolytically cleaves multiple cytokines, and cell surface proteins. In the present study, we examined whether NE affects the biological abilities of angiogenic growth factors such as basic-fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). NE degraded bFGF and VEGF in a time- and concentration-dependent manner, and these degradations were suppressed by sivelestat, a synthetic inhibitor of NE. The bFGF- or VEGF-mediated proliferative activity of human umbilical vein endothelial cells was inhibited by NE, and the activity was recovered by sivelestat. Furthermore, NE reduced the bFGF- or VEGF-induced tubulogenic response of the mice aortas, ex vivo angiogenesis assay, and these effects were also recovered by sivelestat. Neutrophil-derived NE degraded potent angiogenic factors, resulting in loss of their angiogenic activity. These findings provide additional insight into the role played by neutrophils in the angiogenesis process at sites of inflammation. © 2007 Elsevier Inc. All rights reserved.
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Azelnidipine enhances beneficial effects of olmesartan on left ventricular remodeling during the development of hypertension-induced heart failure
Cheng Xian Wu, Okumura Kenji, Nagata Kohzo, Inoue Aiko, Zhang Jie, Nishizawa Takao, Yamada Takashi, Murase Yosuke, Izawa Hideo, Asano Hiroyuki, Obata Koji, Kuzuya Masafumi, Shi Guo-Ping, Murohara Toyoaki, Yokota Mitsuhiro
CIRCULATION 116 巻 ( 16 ) 頁： 557 - 557 2007年10月
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Superoxide-dependent cathepsin activation system is associated with hypertensive myocardial remodeling and represents a target for angiotesin II type 1 receptor blocker therapy
Cheng Xian Wu, Okumura Kenji, Nagata Kohzo, Izawa Hideo, Obata Koji, Sasaki Takeshi, Inoue Aiko, Nishizawa Takao, Yamada Takashi, Kobayashi Masakazu, Inden Yasuya, Murase Yosuke, Kuzuya Mafumi, Shi Guo-Ping, Murohara Toyoaki, Yokota Mitsuhiro
CIRCULATION 116 巻 ( 16 ) 頁： 742 - 742 2007年10月
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Mechanisms underlying the impairment of ischemia-induced Neovascularization in aging mice: the pivotal role for matirx-metalloproteinase-2
Cheng Man Wu, Kuzuya Masafumi, Okumura Kenji, Inoue Aiko, Kim Weon, Yokota Mitsuhiro, Murohara Toyoaki
CIRCULATION 116 巻 ( 16 ) 頁： 24 - 25 2007年10月
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書籍等出版物
書籍等出版物 1
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最先端ナノライフシステム研究
（ 担当： 分担執筆 , 範囲: 4章 健康寿命の延伸に関する実装研究）
丸善プラネット株式会社 2022年3月 （ ISBN:978-4-86345-520-7 ）
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総ページ数：215 担当ページ：63-69 記述言語：日本語 著書種別：教科書・概説・概論
MISC
MISC 4
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(特集 老化・フレイルとサルコペニア) フレイル・サルコペニアとバイオマーカー
井上愛子、葛谷雅文、成 憲武
CLINICAL CALCIUM28 巻 ( 9 ) 頁： 1191 - 1200 2018年8月
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担当区分：筆頭著者 記述言語：日本語
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(老年医学の展望) サルコペニアの分子メカニズム
井上愛子、成 憲武、五籐大貴、葛谷雅文
日本老年医学会雑誌55 巻 頁： 13 - 24 2018年
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冠動脈硬化の新しい分子機序:炎症•免疫からみた最新の知見
成 憲武、井上愛子
医学の歩み259 巻 ( 6 ) 頁： 590 - 596 2016年
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(特集 高齢者医療におけるサルコペニア・フレイル対策) サルコペニア・フレイルのバイオマーカー
井上愛子、成 憲武、葛谷雅文
医薬ジャーナル51 巻 ( 9 ) 頁： 67 - 71 2015年9月
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講演・口頭発表等
講演・口頭発表等 16
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Cathepsin K activity controls injury-related vascular repair in mice
Hu L., Cheng X.W., Song H., Inoue A., Jiang H., Li X., Shi G.P., Kozawa E., Okumura K., Kuzuya M.
Hypertension 2014年3月 Hypertension
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記述言語：日本語
Cathepsin K (CatK) is one of the most potent mammalian collagenases. We showed previously the increased expression of CatK in human and animal atherosclerotic lesions. Here, we hypothesized that ablation of CatK mitigates injury-induced neointimal hyperplasia. Male wild-type (CatK) and CatK-deficient (CatK) mice underwent ligation or a combination of ligation and polyethylene cuff-replacement injuries to the right common carotid artery just proximal to its bifurcation, and they were then processed for morphological and biochemical studies at specific time points. On operative day 28, CatK significantly reduced neointimal formation and neovessel formation in both single- and combination-injured arteries compared with the Cat K mice. At early time points, CatK reduced the lesion macrophage contents and medial smooth muscle cell proliferation, the mRNA levels of monocyte chemoattractant protein-1, toll-like receptor-2, toll-like receptor-4, chemokine ligand-12, and the gelatinolytic activity related to matrix metalloproteinase-2/-9. An aorta-explant assay revealed that smooth muscle cell movement was impaired in the CatK mice compared with the CatK mice. In addition, the smooth muscle cells and macrophages from CatK mice had less invasive ability through a reconstituted basement membrane barrier. This vasculoprotective effect was mimicked by Cat inhibition with trans-epoxysuccinyl-L-leucylamido-{4-guanidino} butane (E64d). These results demonstrate an essential role of CatK in neointimal lesion formation in response to injury, possibly via the reduction of toll-like receptor-2/-4-mediated inflammation and smooth muscle cell proliferation, suggesting a novel therapeutic strategy for the control of endovascular treatment-related restenosis by regulating CatK activity. © 2013 American Heart Association, Inc.
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Cheng X.W., Okumura K., Kuzuya M., Jin Z., Nagata K., Obata K., Inoue A., Hirashiki A., Takeshita K., Unno K., Harada K., Shi G.P., Yokota M., Murohara T.
Journal of Cardiovascular Pharmacology 2009年7月 Journal of Cardiovascular Pharmacology
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記述言語：日本語
OBJECTIVE: To investigate the mechanism responsible for the increased cardiac stiffness associated with hypertensive heart failure in Dahl salt-sensitive (DS) rats and the effects of treatment with the combination of a calcium channel blocker [azelnidipine (AZE)] and angiotensin II type 1 receptor blocker [olmesartan (OLM)]. METHODS: DS rats fed a high-salt diet from 7 weeks of age were treated (or not) from 12 to 19 weeks of age with the vasodilator hydralazine, OLM plus AZE, or the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin. Rats fed a low-salt diet served as controls. RESULTS: Treatment with OLM plus AZE attenuated changes in the expression of collagen isoforms and a decrease in the ratio of elastin to collagen in the left ventricle and prevented the increase in myocardial stiffness and diastolic dysfunction in DS rats in a manner independent of the hypotensive effect of these drugs. Such treatment also inhibited the expression and activation of elastolytic proteases (including cathepsins S and K and metalloproteinases-2, -9, and -12), NADPH oxidase-dependent superoxide production, and inflammatory changes in the failing myocardium. All these effects were mimicked by treatment with apocynin. CONCLUSIONS: The changes in collagen isoform expression and the decrease in the elastin to collagen ratio in the failing myocardium likely account for the increase in diastolic stiffness in this model of hypertensive heart failure. Administration of angiotensin receptor and calcium channel blockers prevented these changes in a manner independent of the hypotensive effect of these drugs by inhibiting the increase in elastolytic activity induced by activation of NADPH oxidase. © 2009 Lippincott Williams & Wilkins, Inc.
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食事摂取と体位が健常者の核心温ならびに血圧に及ぼす影響 : 炭水化物摂取と仰臥位・長坐位における検討
長谷川 愛子, 伊藤 剛, 石津 みゑ子, 花輪 壽彦
自律神経 = The Autonomic nervous system 2005年6月15日
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Mechanisms underlying the impairment of ischemia-induced neovascularization in MMP-2-deficient mice
Circulation journal : official journal of the Japanese Circulation Society 2007年10月20日 Japanese Circulation Society
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Mechanisms underlying the impairment of ischemia-induced neovascularization in MMP-2-deficient mice
Cheng Xian-Wu, Kuzuya Masafumi, Nakamura Kae, Inoue Aiko, Hirata Makiko, Tsuzuki Michitaka, Kondo Takahisa, Kim Woen, Okumura Kenji, Yokota Mitsuhiro, Murohara Toyoaki, Iguchi Akihisa
Circulation journal : official journal of the Japanese Circulation Society 2007年3月1日 Japanese Circulation Society
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裏寒と手足厥寒における四逆湯の温熱生理学的検討(EBM, 第58回日本東洋医学会学術総会)
伊藤 剛, 井上 愛子, 若杉 安希乃, 及川 哲郎, 花輪 壽彦
第58回日本東洋医学会学術総会 2007年5月 社団法人日本東洋医学会
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長谷川 愛子, 伊藤 剛, 石野 尚吾, 花輪 壽彦
日本東洋醫學雜誌 2001年5月1日 社団法人日本東洋医学会
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温熱生理学的にみた漢方薬の生理作用 : 当帰四逆加呉茱萸生姜湯について
伊藤 剛, 井上 愛子, 若杉 安希乃, 及川 哲郎, 花輪 壽彦
第57回日本東洋医学会学術総会 2006年5月31日 社団法人日本東洋医学会
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サーモグラフィと尿温による冷え症のパターンと裏寒の温熱生理学的検討
伊藤 剛, 井上 愛子, 若杉 安希乃, 及川 哲郎, 花輪 壽彦
第59回日本東洋医学会学術総会 2008年5月7日 社団法人日本東洋医学会
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中核温からみた「冷え症」の病態解析(04病態(現代医学)(1))
伊藤 剛, 長谷川 愛子, 高橋 裕子, 花輪 壽彦
日本東洋醫學雜誌 2003年4月 社団法人日本東洋医学会
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中核温ならびに自律神経機能よりみた「四肢型冷え症」の病態(03 病態(現代医学)(1))
伊藤 剛, 長谷川 愛子, 高橋 裕子, 花輪 壽彦
日本東洋醫學雜誌 2004年5月 社団法人日本東洋医学会
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「食後佳眠倦怠」の病態解析(第1報) : 健常者における食後傾眠について(02病態(伝統医学)(1))
長谷川 愛子, 伊藤 剛, 花輪 壽彦
日本東洋醫學雜誌 2003年4月 社団法人日本東洋医学会
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Cheng Xian Wu, Kuzuya Masafumi, Okumura Kenji, Inoue Aiko, Nakamura Kae, Sasaki Takeshi, Kim Veon, Yokota Mitsuhiro, Murohara Toyoaki
The 72nd Annual Scientific Meeting of the Japanese Circulation Society 2008年3月1日 Japanese Circulation Society
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Cheng Xian Wu, Kuzuya Masafumi, Nakamura Kae, Okumura Kenji, Inoue Aiko, Sasaki Takeshi, Yokota Mitsuhiro, Murohara Toyoaki
The 72nd Annual Scientific Meeting of the Japanese Circulation Society 2008年3月1日 Japanese Circulation Society
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[Aging-related frailty and sarcopenia. Frailty - Sarcopenia and biomarker.].
Inoue A, Kuzuya M, Cheng X
Clinical calcium 2018年
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Development of a Smart Speaker Application to Promote Continuous Exercise in the Elderly
Kurokawa S., Urata M., Endo M., Yasuda T., Inoue A.
GCCE 2023 - 2023 IEEE 12th Global Conference on Consumer Electronics 2023年 GCCE 2023 - 2023 IEEE 12th Global Conference on Consumer Electronics
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Continuous exercise is essential for healthy aging. In recent years, there have been efforts to enable the elderly to engage in continuous exercise at home by utilizing Information and Communication Technology (ICT) devices. Among ICT devices, smart speakers are gaining attention due to their easy voice control, and applications for smart speakers, operating on their screens, are also being developed to assist with exercise. However, there is still a lack of understanding regarding the most effective features of smart speaker applications that support the continuation of exercise. This study aims to identify the key features for sustaining exercise. We have developed a smart speaker application with two features to support this goal. The first feature provides stamps based on the smart speaker application usage. The second feature suggests personalized exercises based on the user's fitness level. Four elderly women were invited to use the smart speaker application continuously at home and to evaluate the proposed features by a questionnaire. The research result suggests that the proposed features could improve self-efficacy, promoting continuous exercise. It also indicates the need for feature adjustment based on the participant's exercise status.
科研費
科研費 3
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独居高齢者に対するICTを活用した包括的フレイル予防システムの運用による介入効果
研究課題/研究課題番号：21K17436 2021年4月 - 2024年3月
科学研究費助成事業 若手研究
井上 愛子
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担当区分：研究代表者
配分額：4680000円 （ 直接経費：3600000円 、 間接経費：1080000円 ）
世界に類を見ないスピードで超高齢社会を迎えている我が国において、ケアが必要な高齢者の絶対数の増加と現役世代の減少により医療・介護を担う人的資源が枯渇していく中で、持続可能なフレイルへの対策が急務となっている。
本研究では、申請者らが2019年度に構築した循環型健康寿命延伸プログラムをスマートスピーカーを活用した独居高齢者向けのフレイル予防アプリケーション（独居高齢者見守りシステム）として新たに改良し、包括的フレイル予防支援システムによる独居高齢者の心身機能の維持・向上やフレイル予防効果ならびに健康行動促進要因を明らかにする。 -
超高齢社会における健康増進のためのICT/IoT利活用に関する研究
研究課題/研究課題番号：21K12593 2021年4月 - 2024年3月
科学研究費助成事業 基盤研究(C)
浦田 真由, 安田 孝美, 井上 愛子
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担当区分：研究分担者
超高齢社会において，高齢者の社会的孤立をいかに防ぐかは自治体の大きな課題となっているが，新型コロナウイルス感染症の影響により，地域での高齢者支援サービスの実施が困難となっている。本研究では，地域在住高齢者の健康増進のためのICT/IoT利活用を社会情報学と老年医学の学際研究として取り組み，地域への実装によってその効果を検証する。健康寿命を延ばすためのモデルを構築し，地域のICT/IoT 利活用を支える担い手の育成を行うことで，研究期間後も取り組みを継続させることを目指している。
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フレイルおよびサルコペニア予防のための骨格筋リモデリングと再生機構解明
研究課題/研究課題番号：18K15414 2018年4月 - 2021年3月
科学研究費助成事業 若手研究
井上 愛子
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担当区分：研究代表者
配分額：4290000円 （ 直接経費：3300000円 、 間接経費：990000円 ）
高齢期の骨格筋は障害を伴っていることが多く（サルコペニア、フレイルなど）、治療には骨格筋再生へのアプローチが必要である。細胞の分化・増殖、及びアポトーシスにおいて重要な役割を果たし、老化に伴いそのシグナル伝達の不活化が起こることが報告されているNotch シグナルとその活性化に関与するカテプシンKに着目し、サルコペニア形成、骨格筋のリモデリングや再生への関与を検討した。カテプシンKは、サルコペニアを代表とする骨格筋障害に関与することを明らかにした。
カテプシンKが、カヘキシアモデルマウスの骨格筋の萎縮と機能障害にも関与している可能性が示唆されたことにより、今後は高齢者のQOLやADLの低下予防や、フレイルなどの改善のための新たな分子標的になる可能性が示唆された。