顔写真

ウルノ アキラ
宇留野 晃
Akira Uruno
所属
東北メディカル・メガバンク機構 ゲノム解析部門
職名
准教授
学位
  • 博士(医学)(東北大学)

経歴 6

  • 2017年 ~ 継続中
    東北大学大学院東北メディカルメガバンク機構 准教授

  • 2012年 ~ 2017年
    東北大学大学院医学系研究科 講師

  • 2010年 ~ 2012年
    東北大学大学院医学系研究科 助教

  • 2009年 ~ 2010年
    東北大学大学院医学系研究科 日本学術振興会特別研究員(PD)

  • 2004年 ~ 2007年
    東北大学病院 医員

  • 1998年 ~ 2000年
    国家公務員共済組合連合会水府病院 初期臨床研修医

︎全件表示 ︎最初の5件までを表示

学歴 2

  • 東北大学大学院医学系研究科

    1998年4月 ~ 2004年3月

  • 東北大学 医学部 医学科

    1992年4月 ~ 1998年3月

所属学協会 5

  • 日本人類遺伝学会

  • 日本内科学会

  • 日本内分泌学会

  • 日本分子生物学会

  • 日本生化学会

研究キーワード 5

  • アルツハイマー病

  • Nrf2

  • 酸化ストレス

  • 糖尿病

  • 代謝

研究分野 5

  • ライフサイエンス / 基盤脳科学 /

  • ライフサイエンス / 代謝、内分泌学 /

  • ライフサイエンス / 医化学 /

  • ライフサイエンス / 栄養学、健康科学 /

  • ライフサイエンス / 病態医化学 /

受賞 9

  1. 平成29年度宮城県医師会医学奨励賞

    2018年

  2. 平成29年度坂田賞

    2018年

  3. 東北大学医学部奨学賞金賞

    2018年

  4. 日本生化学会東北支部奨励賞

    2017年

  5. 匂坂記念賞

    2011年

  6. International Symposium for Aldosterone and Related Substances in Hypertension Young Investigator’s award

    2010年

  7. 平成19年度宮城県医師会医学奨励賞

    2008年

  8. 平成19年度坂田賞

    2008年

  9. 東北大学医学部奨学賞銀賞

    2008年

︎全件表示 ︎最初の5件までを表示

論文 180

  1. The association between depressive symptoms and masked hypertension in participants with normotension measured at research center. 国際誌

    Sayuri Tokioka, Naoki Nakaya, Kumi Nakaya, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Hirohito Metoki, Takahisa Murakami, Michihiro Satoh, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Yohei Hamanaka, Masatsugu Orui, Tomoko Kobayashi, Akira Uruno, Eiichi N Kodama, Satoshi Nagaie, Soichi Ogishima, Yoko Izumi, Nobuo Fuse, Shinichi Kuriyama, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 47 (3) 586-597 2024年3月

    DOI: 10.1038/s41440-023-01484-8  

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    Masked hypertension is a risk factor for cardiovascular diseases. However, masked hypertension is sometimes overlooked owing to the requirement for home blood pressure measurements for diagnosing. Mental status influences blood pressure. To reduce undiagnosed masked hypertension, this study assessed the association between depressive symptoms and masked hypertension. This cross-sectional study used data from the Tohoku Medical Megabank Project Community-Based Cohort Study (conducted in Miyagi Prefecture, Japan, from 2013) and included participants with normotension measured at the research center (systolic blood pressure<140 mmHg and diastolic blood pressure <90 mmHg). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (Japanese version). Masked hypertension was defined as normotension measured at the research center and home hypertension (home systolic blood pressure ≥135 mmHg or home diastolic blood pressure ≥85 mmHg). The study comprised 6705 participants (mean age: 55.7 ± 13.7 years). Of these participants, 1106 (22.1%) without depressive symptoms and 393 (23.2%) with depressive symptoms were categorized to have masked hypertension. Sex-specific and age-adjusted least mean squares for home blood pressure, not for research blood pressure were significantly higher in the group with depressive symptoms in both sex categories. The multivariate odds ratio for masked hypertension in the patients with depressive symptoms was 1.72 (95% confidence interval: 1.26-2.34) in male participants and 1.30 (95% confidence interval: 1.06-1.59) in female ones. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at the research center. Depressive symptoms may be one of the risk factors for masked hypertension. Depressive symptoms were associated with masked hypertension in individuals with normotension measured at research center.

  2. Reduced glutathione level in the aqueous humor of patients with primary open-angle glaucoma and normal-tension glaucoma. 国際誌

    Kota Sato, Daisuke Saigusa, Taiki Kokubun, Amane Fujioka, Qiwei Feng, Ritsumi Saito, Akira Uruno, Naomi Matsukawa, Michiko Ohno-Oishi, Hiroshi Kunikata, Yu Yokoyama, Masayuki Yasuda, Noriko Himori, Kazuko Omodaka, Satoru Tsuda, Shigeto Maekawa, Masayuki Yamamoto, Toru Nakazawa

    npj aging 9 (1) 28-28 2023年11月21日

    DOI: 10.1038/s41514-023-00124-2  

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    Glaucoma is a leading cause of blindness worldwide in older people. Profiling the aqueous humor, including the metabolites it contains, is useful to understand physiological and pathological conditions in the eye. In the current study, we used mass spectrometry (MS) to characterize the aqueous humor metabolomic profile and biological features of patients with glaucoma. Aqueous humor samples were collected during trabeculectomy surgery or cataract surgery and analyzed with global metabolomics. We included 40 patients with glaucoma (32 with POAG, 8 with NTG) and 37 control subjects in a discovery study. VIP analysis revealed five metabolites that were elevated and three metabolites that were reduced in the glaucoma patients. The identified metabolomic profile had an area under the receiver operating characteristic curve of 0.953. Among eight selected metabolites, the glutathione level was significantly decreased in association with visual field defects. Moreover, in a validation study to confirm the reproducibility of our findings, the glutathione level was reduced in NTG and POAG patients compared with a cataract control group. Our findings demonstrate that aqueous humor profiling can help to diagnose glaucoma and that various aqueous humor metabolites are correlated with clinical parameters in glaucoma patients. In addition, glutathione is clearly reduced in the aqueous humor of glaucoma patients with both IOP-dependent and IOP-independent disease subtypes. These findings indicate that antioxidant agents in the aqueous humor reflect glaucomatous optic nerve damage and that excessive oxidative stress may be involved in the pathogenesis of glaucoma.

  3. The risk of withdrawal from hypertension treatment in coastal areas after the Great East Japan Earthquake: the TMM CommCohort Study

    Rieko Hatanaka, Naoki Nakaya, Mana Kogure, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Hideaki Hashimoto, Tomohiro Nakamura, Kotaro Nochioka, Taku Obara, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Akira Uruno, Eiichi N. Kodama, Nobuo Fuse, Shinichi Kuriyama, Atsushi Hozawa

    Hypertension Research 2023年10月13日

    出版者・発行元:Springer Science and Business Media LLC

    DOI: 10.1038/s41440-023-01454-0  

    ISSN:0916-9636

    eISSN:1348-4214

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    Abstract This study aimed to examine whether risk of withdrawal from HTTx was higher in coastal areas that were severely damaged by tsunami than in inland areas. We conducted a cross-sectional study of 9218 participants aged ≥20 years in Miyagi, Japan. The odds ratios (ORs) and confidence interval (CI) for withdrawal from HTTx in coastal and inland groups were compared using multivariate logistic regression analysis, adjusting for potential confounders. In total, 194 of 5860 and 146 of 3358 participants in the inland and coastal groups, respectively, withdrew from HTTx treatment. OR (95%CI) of withdrawal from HTTx in the coastal group was 1.46 (1.14–1.86) compared to the inland group. According to housing damage, ORs (95% CI) in the no damage, partially destroyed, and more than half destroyed coastal groups compared with the no damage inland group were 1.62 (1.04–2.50), 1.69 (1.17–2.45), and 1.08 (0.71–1.65), respectively. In conclusion, the risk of HTTx withdrawal for participants whose homes in coastal areas were relatively less damaged was significantly higher compared with those in inland areas, while the risk of HTTx withdrawal for participants whose homes were more than half destroyed was not. Post-disaster administrative support for disaster victims is considered vital for continuation of their treatment.

  4. Influence of Diabetes Family History on the Associations of Combined Genetic and Lifestyle Risks with Diabetes in the Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Akira Narita, Taku Obara, Mami Ishikuro, Akira Uruno, Tomoko Kobayashi, Eiichi N Kodama, Yohei Hamanaka, Masatsugu Orui, Soichi Ogishima, Satoshi Nagaie, Nobuo Fuse, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Gen Tamiya, Atsushi Hozawa, Masayuki Yamamoto

    Journal of atherosclerosis and thrombosis 2023年10月6日

    DOI: 10.5551/jat.64425  

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    AIM: The influence of family history of diabetes, probably reflecting genetic and lifestyle factors, on the association of combined genetic and lifestyle risks with diabetes is unknown. We examined these associations. METHODS: This cross-sectional study included 9,681 participants in the Tohoku Medical Megabank Community-based Cohort Study. A lifestyle score, which was categorized into ideal, intermediate, and poor lifestyles, was given. Family history was obtained through a self-reported questionnaire. A polygenic risk score (PRS) was constructed in the target data (n=1,936) using publicly available genome-wide association study summary statistics from BioBank Japan. For test data (n=7,745), we evaluated PRS performance and examined the associations of combined family history and genetic and lifestyle risks with diabetes. Diabetes was defined as non-fasting blood glucose ≥ 200 mmHg, HbA1c ≥ 6.5%, and/or self-reported diabetes treatment. RESULTS: In test data, 467 (6.0%) participants had diabetes. Compared with a low genetic risk and an ideal lifestyle without a family history, the odds ratio (OR) was 3.73 (95% confidence interval [CI], 1.92-7.00) for a lower genetic risk and a poor lifestyle without a family history. Family history was significantly associated with diabetes (OR, 3.58 [95% CI, 1.73-6.98]), even in those with a low genetic risk and an ideal lifestyle. Even among participants who had an ideal lifestyle without a family history, a high genetic risk was associated with diabetes (OR, 2.49 [95% CI, 1.65-3.85]). Adding PRS to family history and conventional lifestyle risk factors improved the prediction ability for diabetes. CONCLUSIONS: Our findings support the notion that a healthy lifestyle is important to prevent diabetes regardless of genetic risk.

  5. Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice 査読有り

    Ritsuko Shimizu, Ikuo Hirano, Atsushi Hasegawa, Mikiko Suzuki, Akihito Otsuki, Keiko Taguchi, Fumiki Katsuoka, Akira Uruno, Norio Suzuki, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Communications Biology 6 2023年8月25日

    DOI: 10.1038/s42003-023-05251-w  

  6. Association of Central Blood Pressure and Carotid Intima Media Thickness with New-Onset Hypertension in People with High Normal Blood Pressure.

    Sayuri Tokioka, Naoki Nakaya, Kumi Nakaya, Masato Takase, Mana Kogure, Rieko Hatanaka, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Hirohito Metoki, Takahisa Murakami, Michihiro Satoh, Tomohiro Nakamura, Taku Obara, Yohei Hamanaka, Tomoko Kobayashi, Akira Uruno, Junichi Sugawara, Eiichi N Kodama, Soichi Ogishima, Yoko Izumi, Nobuo Fuse, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 2023年7月5日

    DOI: 10.5551/jat.64151  

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    AIM: People with high normal blood pressure (BP) have a higher risk of cardiovascular events than those with normal BP; therefore, progression to hypertension (HT) should be prevented. We aimed to assess the HT risk using central BP and carotid intima media thickness (CIMT) in people with high normal BP. METHODS: This prospective cohort study used the Tohoku Medical Megabank Community-Based Project Cohort Study (conducted from 2013 in Miyagi Prefecture in Japan). The participants had a high normal BP, defined as a systolic BP of 120-139 mmHg and diastolic BP <90 mmHg using brachial BP measurement during the baseline survey. The outcome was new-onset HT during the secondary survey, conducted four years after the baseline survey. RESULTS: Overall, 4,021 participants with high normal BP during the baseline survey, with an average age of 58.7 years, were included; 1,030 (26%) were diagnosed with new-onset HT during the secondary survey, 3.5± 0.7 years after the baseline survey. The multivariable odds ratio (95% confidence interval) for HT in the highest versus lowest quartile of central BP was 1.7 (1.2-2.4, p=0.0030), and that of CIMT was 1.8 (1.4-2.4, p<0.001). Subgroup analysis according to age (<60 and ≥ 60 years) and sex revealed that the central BP was influential in groups with younger age and female individuals; CIMT was influential in all groups. CONCLUSIONS: Higher central BP and thicker CIMT at the baseline were correlated with new-onset HT in individuals with high normal BP, independent of brachial systolic BP and other cardiovascular risk factors.

  7. Tohoku Medical Megabank Brain Magnetic Resonance Imaging Study: Rationale, Design, and Background 査読有り

    JMA Journal 6 (3) 246-264 2023年7月

    出版者・発行元:None

    DOI: 10.31662/jmaj.2022-0220  

    ISSN:2433-328X

    eISSN:2433-3298

  8. The KEAP1-NRF2 System and Neurodegenerative Diseases

    Akira Uruno, Masayuki Yamamoto

    Antioxidants & Redox Signaling 2023年5月1日

    DOI: 10.1089/ars.2023.0234  

  9. Distributions of CHN compounds in meteorites record organic syntheses in the early solar system

    Yoshihiro Furukawa, Daisuke Saigusa, Kuniyuki Kano, Akira Uruno, Ritsumi Saito, Motoo Ito, Megumi Matsumoto, Junken Aoki, Masayuki Yamamoto, Tomoki Nakamura

    Scientific Reports 13 (1) 2023年4月24日

    出版者・発行元:Springer Science and Business Media LLC

    DOI: 10.1038/s41598-023-33595-0  

    eISSN:2045-2322

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    Abstract Carbonaceous meteorites contain diverse soluble organic compounds. These compounds formed in the early solar system from volatiles accreted on tiny dust particles. However, the difference in the organic synthesis on respective dust particles in the early solar system remains unclear. We found micrometer-scale heterogeneous distributions of diverse CHN<sub>1-2</sub> and CHN<sub>1-2</sub>O compounds in two primitive meteorites: the Murchison and NWA 801, using a surface-assisted laser desorption/ionization system connected to a high mass resolution mass spectrometer. These compounds contained mutual relationships of ± H<sub>2</sub>, ± CH<sub>2</sub>, ± H<sub>2</sub>O, and ± CH<sub>2</sub>O and showed highly similar distributions, indicating that they are the products of series reactions. The heterogeneity was caused by the micro-scale difference in the abundance of these compounds and the extent of the series reactions, indicating that these compounds formed on respective dust particles before asteroid accretion. The results of the present study provide evidence of heterogeneous volatile compositions and the extent of organic reactions among the dust particles that formed carbonaceous asteroids. The compositions of diverse small organic compounds associated with respective dust particles in meteorites are useful to understand different histories of volatile evolution in the early solar system.

  10. Combined fat mass and fat-free mass indices and lung function among Japanese population: The Tohoku Medical Megabank Community-based Cohort Study.

    Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of epidemiology 2023年4月8日

    DOI: 10.2188/jea.JE20220355  

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    BACKGROUND: Although fat mass index (FMI) and fat-free mass index (FFMI) affect lung function, FMI and FFMI are not independent of each other since FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. We aimed to examine the association of combined FMI and FFMI with lung function. METHODS: In this cross-sectional study, lung function was evaluated using forced expiratory volume at 1 s and forced vital capacity was measured using spirometry. Both FMI and FFMI were classified into sex-specific quartiles (16 groups). Analysis of covariance was used to assess the associations of combined FMI and FFMI with lung function. The trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1-4 (lowest-highest), and entering the number as a continuous term in the regression model. RESULTS: This study included 3,736 men and 8,821 women aged ≥20 years living in Miyagi Prefecture, Japan. The mean FEV1 (standard deviation) was 3.0 (0.7) L for men and 2.3 (0.5) L for women. The mean FVC was 3.8 (0.7) L for men and 2.8 (0.5) L for women. The FMI was inversely associated with lung function among all FFMI subgroups in both sexes. Conversely, FFMI was positively associated with lung function in all FMI subgroups in both sexes. CONCLUSIONS: Higher FMI was associated with lower lung function independent of FFMI; higher FFMI was associated with higher lung function independent of FMI. Reducing FMI and maintaining FFMI might be important for respiratory health.

  11. Association between lung function and hypertension and home hypertension in a Japanese population: the Tohoku Medical Megabank Community-Based Cohort Study. 国際誌

    Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of hypertension 41 (3) 443-452 2023年3月1日

    DOI: 10.1097/HJH.0000000000003356  

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    BACKGROUND: Although several studies have shown an inverse association between lung function and hypertension, few studies have examined the association between lung function and hypertension among never-smokers, and no study has investigated the association between lung function and home hypertension. We investigated the associations between lung function and hypertension in a Japanese population. INDIVIDUALS AND METHODS: We conducted a cross-sectional study of 3728 men and 8795 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was assessed using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC), measured by spirometry. Hypertension was defined as a casual blood pressure at least 140/90 mmHg and/or self-reported treatment for hypertension. Home hypertension was defined as morning home blood pressure at least 135/85 mmHg and/or self-reported treatment for hypertension. Multivariate logistic regression models adjusted for potential confounders were used to assess the association between lung function and hypertension. RESULTS: The mean ages (±SD) of men and women were 60.1 (±14.0) years and 56.2 (±13.4) years, respectively, and 1994 (53.5%) men and 2992 (34.0%) women had hypertension. In the multivariable models, FEV1 and FVC were inversely associated with hypertension. Inverse associations between lung function and hypertension were observed even among never-smokers. Furthermore, reduced lung function was associated with higher prevalence of home hypertension in men and women. CONCLUSION: Reduced lung function was associated with higher prevalence of hypertension, independent of smoking status. Assessment of the lung function or blood pressure may be required in individuals with reduced lung function or hypertension.

  12. Carotid Intima Media Thickness and Risk Factor for Atherosclerosis: Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Naoki Nakaya, Tomohiro Nakamura, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ippei Chiba, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 2023年2月11日

    DOI: 10.5551/jat.64039  

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    AIM: We examined the association between the carotid intima medica thickness (cIMT) and risk factors for atherosclerosis based on the Japan Atherosclerosis Society 2022 Atherosclerosis Prevention Guideline. METHODS: Using data from the Tohoku Medical Megabank Community-based Cohort Study, we performed a cross-sectional study that enrolled 13,366 participants (age ≥ 20 years) with an analysis of covariance to assess associations between cIMT and risk factors for atherosclerosis. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. Analysis was conducted in the model adjusted for age, sex, smoking status, drinking status, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), high-density lipoprotein-cholesterol (HDL-C), non-high-density lipoprotein-cholesterol (non-HDL-C), and height. RESULTS: In this study cohort, the average age and cIMT were 57.3 (13.8) years and 0.61 (0.13) mm, respectively, which included 3,988 males (29.8%). Males had a higher cIMT than did the females. Age, height, BMI, SBP, HbA1c, and non-HDL-C were positively associated with cIMT. HDL-C was inversely associated with cIMT. Compared with never drinkers, current drinkers (≥ 46.0 g/day) had a significantly decreased cIMT. CONCLUSIONS: The cIMT was associated with atherosclerosis risk factors including age, sex, BMI, SBP, HbA1c, non-HDL-C, and HDL-C, and adequate control of risks in high-risk individuals might be required to prevent atherosclerotic cardiovascular diseases.

  13. 東北メディカル・メガバンク計画地域住民コホート調査(宮城)詳細二次調査の概要

    中谷 久美, 中谷 直樹, 小暮 真奈, 畑中 里衣子, 千葉 一平, 菅野 郁美, 中村 智洋, 小原 拓, 宇留野 晃, 布施 昇男, 辻 一郎, 栗山 進一, 寳澤 篤

    Journal of Epidemiology 33 (Suppl.1) 173-173 2023年2月

    出版者・発行元:(一社)日本疫学会

    ISSN:0917-5040

    eISSN:1349-9092

  14. Improving the Signal Intensity of Cryosections Using a Conductive Adhesive Film in Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging

    Daisuke Saigusa, Ritsumi Saito, Komei Kawamoto, Akira Uruno, Kuniyuki Kano, Shuichi Shimma, Junken Aoki, Masayuki Yamamoto, Tadafumi Kawamoto

    Mass Spectrometry 2023年

    出版者・発行元:The Mass Spectrometry Society of Japan

    DOI: 10.5702/massspectrometry.a0137  

    ISSN:2187-137X

    eISSN:2186-5116

  15. Local Delivery of Nimustine Hydrochloride against Brain Tumors: Basic Characterization Study

    Xiaodong Shao, Ryuta Saito, Aya Sato, Saori Okuno, Daisuke Saigusa, Ritsumi Saito, Akira Uruno, Yoshinari Osada, Masayuki Kanamori, Teiji Tominaga

    The Tohoku Journal of Experimental Medicine 2023年

    出版者・発行元:Tohoku University Medical Press

    DOI: 10.1620/tjem.2023.j069  

    ISSN:0040-8727

    eISSN:1349-3329

  16. Design and Progress of Child Health Assessments at Community Support Centers in the Birth and Three-Generation Cohort Study of the Tohoku Medical Megabank Project.

    Tomoko Kobayashi, Mika Kobayashi, Naoko Minegishi, Masahiro Kikuya, Taku Obara, Mami Ishikuro, Chizuru Yamanaka, Tomomi Onuma, Keiko Murakami, Fumihiko Ueno, Aoi Noda, Akira Uruno, Junichi Sugawara, Kichiya Suzuki, Eiichi N Kodama, Yohei Hamanaka, Naho Tsuchiya, Mana Kogure, Naoki Nakaya, Makiko Taira, Mika Sakurai-Yageta, Toru Tamahara, Junko Kawashima, Maki Goto, Akihito Otsuki, Ritsuko Shimizu, Soichi Ogishima, Hiroaki Hashizume, Fuji Nagami, Tomohiro Nakamura, Atsushi Hozawa, Tadao Kobayashi, Nobuo Fuse, Shinichi Kuriyama, Shigeo Kure, Masayuki Yamamoto

    The Tohoku journal of experimental medicine 259 (2) 93-105 2022年12月1日

    DOI: 10.1620/tjem.2022.J103  

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    The Tohoku Medical Megabank Project (TMM) has been conducting a birth and three-generation cohort study (the BirThree Cohort Study). We recruited 73,529 pregnant women and their family members for this cohort study, which included 23,143 newborns and 9,459 of their siblings. We designed and are in the process of conducting three-step health assessments for each newborn at approximately ages of 5, 10 and 16. These health assessments are administered at seven community support centers. Trained genome medical research coordinators conduct physical examinations of and collect biological specimens from each participant. The Sendai Children's Health Square has been established as the headquarters for these child health assessments and is utilized to accumulate knowledge that can facilitate the proper practice of child health assessments. We designed all the relevant health assessments facilities to allow parents and their children to participate in the health assessments concomitantly. Our centers serve as places where child participants and their parents can feel at ease as a result of the implementation of safety measures and child hospitality measures. The TMM BirThree Cohort Study is in the process of conducting strategically detailed health assessments and genome analysis, which can facilitate studies concerning the gene-environment interactions relevant to noncommunicable diseases. Through these operations, our study allows for a significant depth of data to be collected in terms of the number of biospecimens under study and the comprehensiveness of both basic and clinical data alongside relevant family information.

  17. Nrf2 deficiency deteriorates diabetic kidney disease in Akita model mice

    Yexin Liu, Akira Uruno, Ritsumi Saito, Naomi Matsukawa, Eiji Hishinuma, Daisuke Saigusa, Hong Liu, Masayuki Yamamoto

    Redox Biology 58 102525-102525 2022年12月

    出版者・発行元:Elsevier BV

    DOI: 10.1016/j.redox.2022.102525  

    ISSN:2213-2317

  18. The Association of Lung Function and Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Mitsuhiro Yamada, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Tomoko Kobayashi, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 2022年11月4日

    DOI: 10.5551/jat.63826  

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    AIM: Impaired lung function is associated with atherosclerotic vascular events. Carotid intima-media thickness (cIMT) is a marker for subclinical atherosclerosis. However, few studies have examined the association between lung function and cIMT among never smokers or individuals stratified by age. We investigated the association between lung function and cIMT in the Japanese population. METHODS: We conducted a cross-sectional study of 3,716 men and 8,765 women aged 20 years or older living in Miyagi Prefecture, Japan. Lung function was evaluated using forced expiratory volume at 1 s (FEV1) and forced vital capacity (FVC) was measured using spirometry. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between lung function and cIMT and adjusted for potential confounders. A linear trend test was conducted by scoring the categories from 1 (lowest) to 4 (highest) and entering the score as a continuous term in the regression model. RESULTS: After adjusting for potential confounders including passive smoking, lower FEV1 and FVC were associated with higher cIMT in both men and women (P<0.001 for linear trend). This association was confirmed even when we restricted our study to never smokers. Furthermore, even when we stratified by age, an inverse association between lung function and cIMT was confirmed in middle-aged (40-64 years) and elderly participants (65-74 years). CONCLUSIONS: Lower lung function was associated with higher cIMT in the Japanese population independent of age and smoking. Assessment of atherosclerosis or lung function may be required for individuals with lower lung function or atherosclerosis.

  19. 東北メディカル・メガバンク計画・地域住民コホート調査詳細三次調査(宮城)の進捗

    中谷 直樹, 小暮 真奈, 畑中 里衣子, 中谷 久美, 千葉 一平, 菅野 郁美, 小原 拓, 中村 智洋, 宇留野 晃, 布施 昇男, 泉 陽子, 丹野 高三, 辻 一郎, 栗山 進一, 寳澤 篤

    東北公衆衛生学会誌 (71) 28-28 2022年7月

    出版者・発行元:東北公衆衛生学会

    ISSN:0915-549X

  20. Halofuginone micelle nanoparticles eradicate Nrf2-activated lung adenocarcinoma without systemic toxicity. 国際誌

    Harit Panda, Mikiko Suzuki, Mitsuru Naito, Ritsumi Saito, Huaichun Wen, Liam Baird, Akira Uruno, Kanjiro Miyata, Masayuki Yamamoto

    Free radical biology & medicine 187 92-104 2022年7月

    DOI: 10.1016/j.freeradbiomed.2022.05.017  

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    The Keap1-Nrf2 system is the master regulator of the cellular response against oxidative and xenobiotic stresses. Constitutive activation of Nrf2 is frequently observed in various types of cancers. Nrf2 hyperactivation induces metabolic reprogramming in cancer cells, which supports the increased energy demand required for rapid proliferation and confers high-level resistance against anticancer radio/chemotherapy. Hence, Nrf2 inhibition has emerged as an attractive therapeutic strategy to counter such acquired resistance in Nrf2-activated tumors. We previously identified Halofuginone (HF) as a promising Nrf2 inhibitor. In this study, we pursued preclinical characterization of HF and found that while HF markedly reduced the viability of cancer cells, it also caused severe hematopoietic and immune cell suppression in a dose-dependent manner. Hence, to overcome this toxicity, we decided to employ a nanomedicine approach to HF. We found that encapsulation of HF into a polymeric micelle (HF micelle; HFm) largely relieved the systemic toxicity exhibited by free HF while maintaining the tumor-suppressive properties of HF. LC-MS/MS analysis revealed that the reduction in the magnitude of adverse effects was the result of the ability to release HF from the HFm core in a slow and sustained manner. These results thus support the contention that HFm will potentially counteract Nrf2-activated cancers in the clinical settings.

  21. Associations between the Combined Fat Mass Index and Fat-Free Mass Index with Carotid Intima-Media Thickness in a Japanese Population: The Tohoku Medical Megabank Community-Based Cohort Study.

    Masato Takase, Tomohiro Nakamura, Naoki Nakaya, Mana Kogure, Rieko Hatanaka, Kumi Nakaya, Ikumi Kanno, Kotaro Nochioka, Naho Tsuchiya, Takumi Hirata, Yohei Hamanaka, Junichi Sugawara, Kichiya Suzuki, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Journal of atherosclerosis and thrombosis 30 (3) 255-273 2022年5月26日

    DOI: 10.5551/jat.63523  

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    AIM: Although many epidemiological studies have shown that obesity assessed by body mass index is associated with carotid intima-media thickness (cIMT), few studies have evaluated fat-free mass, which is a component of body composition. We investigated the associations between the combined fat mass index (FMI) and fat-free mass index (FFMI) with cIMT. METHODS: We conducted a cross-sectional study of 3,873 men and 9,112 women aged 20 years or older who lived in Miyagi prefecture, Japan. The FMI and FFMI were calculated as fat mass and fat-free mass divided by height squared, respectively. The indices were classified into sex-specific quartiles and were combined into 16 groups. The maximum common carotid artery was measured using high-resolution B-mode ultrasound. An analysis of covariance was used to assess associations between the combined FMI and FFMI with cIMT adjusted for age and smoking status. The linear trend test was conducted by stratifying the FMI and FFMI, scoring the categories from 1 (lowest) to 4 (highest), and entering the number as a continuous term in the regression model. RESULTS: In multivariable models, a higher FMI was not related to higher cIMT in men and women in most FFMI subgroups. Conversely, a higher FFMI was related to higher cIMT in all FMI subgroups (p<0.001 for linear trend). CONCLUSIONS: FMI was not associated with cIMT in most FFMI subgroups. Conversely, FFMI was positively associated with cIMT independently of FMI.

  22. Consideration of the reference value and number of measurements of the urinary sodium-to-potassium ratio based on the prevalence of untreated home hypertension: TMM Cohort Study. 国際誌

    Mana Kogure, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Kotaro Nochioka, Akira Narita, Rieko Hatanaka, Fumi Itabashi, Ikumi Kanno, Taku Obara, Michihiro Satoh, Hirohito Metoki, Ken Miyagawa, Hiroshi Koshimizu, Sho Nagayoshi, Akira Uruno, Masahiro Kikuya, Kichiya Suzuki, Naoki Nakaya, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 45 (5) 866-875 2022年5月

    DOI: 10.1038/s41440-021-00843-7  

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    The sodium-to-potassium (Na/K) ratio is known to be associated with blood pressure (BP). However, no reference value has been established since the urinary Na/K (uNa/K) ratio is known to have diurnal and day-to-day variations. Therefore, we investigated the number of days required to yield a better association between the morning uNa/K ratio and home BP (HBP) and determined a morning uNa/K ratio value that can be used as a reference value in participants who are not taking antihypertensive medication. This was a cross-sectional study using data from the Tohoku Medical Megabank Project Cohort Study. A total of 3122 participants borrowed HBP and uNa/K ratio monitors for 10 consecutive days. We assessed the relationship between the morning uNa/K ratio from 1 day to 10 days and home hypertension (HBP ≥ 135/85 mmHg) using multiple logistic regression models. Although a 1-day measurement of the morning uNa/K ratio was positively associated with home hypertension, multiple measurements of the morning uNa/K ratio were strongly related to home hypertension. The average morning uNa/K ratio was relatively stable after 3 days (adjusted odds ratio of home hypertension per unit increase in the uNa/K ratio for more than 3 days: 1.19-1.23). In conclusion, there was no threshold for the uNa/K ratio, and the morning uNa/K ratio was linearly associated with home hypertension. The Na/K ratio 2.0 calculated from the Dietary Reference Intakes for Japanese might be a good indication. Regarding the stability of the association between the morning uNa/K ratio and BP, more than 3 days of measurements is desirable.

  23. A Pilot Study for Return of Individual Pharmacogenomic Results to Population-Based Cohort Study Participants.

    Kinuko Ohneda, Masahiro Hiratsuka, Hiroshi Kawame, Fuji Nagami, Yoichi Suzuki, Kichiya Suzuki, Akira Uruno, Mika Sakurai-Yageta, Yohei Hamanaka, Makiko Taira, Soichi Ogishima, Shinichi Kuriyama, Atsushi Hozawa, Hiroaki Tomita, Naoko Minegishi, Junichi Sugawara, Inaho Danjoh, Tomohiro Nakamura, Tomoko Kobayashi, Yumi Yamaguchi-Kabata, Shu Tadaka, Taku Obara, Eiji Hishimuma, Nariyasu Mano, Masaki Matsuura, Yuji Sato, Masateru Nakasone, Yohei Honkura, Jun Suzuki, Yukio Katori, Yoichi Kakuta, Atsushi Masamune, Yoko Aoki, Masaharu Nakayama, Shigeo Kure, Kengo Kinoshita, Nobuo Fuse, Masayuki Yamamoto

    JMA journal 5 (2) 177-189 2022年4月15日

    DOI: 10.31662/jmaj.2021-0156  

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    Introduction: Pharmacogenomic (PGx) testing results provide valuable information on drug selection and appropriate dosing, maximization of efficacy, and minimization of adverse effects. Although the number of large-scale, next-generation-sequencing-based PGx studies has recently increased, little is known about the risks and benefits of returning PGx results to ostensibly healthy individuals in research settings. Methods: Single-nucleotide variants of three actionable PGx genes, namely, MT-RNR1, CYP2C19, and NUDT15, were returned to 161 participants in a population-based Tohoku Medical Megabank project. Informed consent was obtained from the participants after a seminar on the outline of this study. The results were sent by mail alongside sealed information letter intended for clinicians. As an exception, genetic counseling was performed for the MT-RNR1 m.1555A > G variant carriers by a medical geneticist, and consultation with an otolaryngologist was encouraged. Questionnaire surveys (QSs) were conducted five times to evaluate the participants' understanding of the topic, psychological impact, and attitude toward the study. Results: Whereas the majority of participants were unfamiliar with the term PGx, and none had undergone PGx testing before the study, more than 80% of the participants felt that they could acquire basic PGx knowledge sufficient to understand their genomic results and were satisfied with their potential benefit and use in future prescriptions. On the other hand, some felt that the PGx concepts or terminology was difficult to fully understand and suggested that in-person return of the results was desirable. Conclusions: These results collectively suggest possible benefits of returning preemptive PGx information to ostensibly healthy cohort participants in a research setting.

  24. 東北メディカル・メガバンク計画健康調査における眼軸長のゲノムワイド関連解析

    布施 昇男, 櫻井 美由紀, 元池 育子, 小島 要, 平良 摩紀子, 宇留野 晃, 濱中 洋平, 中村 智洋, 荻島 創一, 寳澤 篤, 栗山 進一, 呉 繁夫, 木下 賢吾, 山本 雅之

    日本眼科学会雑誌 126 (臨増) 216-216 2022年3月

    出版者・発行元:(公財)日本眼科学会

    ISSN:0029-0203

  25. Genome-wide Association Study of Axial Length in Population-based Cohorts in Japan

    Nobuo Fuse, Miyuki Sakurai, Ikuko N. Motoike, Kaname Kojima, Takako Takai-Igarashi, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Mami Ishikuro, Taku Obara, Akiko Miyazawa, Kei Homma, Keisuke Ido, Makiko Taira, Tomoko Kobayashi, Ritsuko Shimizu, Akira Uruno, Eiichi N. Kodama, Kichiya Suzuki, Yohei Hamanaka, Hiroaki Tomita, Junichi Sugawara, Yoichi Suzuki, Fuji Nagami, Soichi Ogishima, Fumiki Katsuoka, Naoko Minegishi, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Yaegashi, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto

    Ophthalmology Science 2 (1) 100113-100113 2022年3月

    出版者・発行元:Elsevier BV

    DOI: 10.1016/j.xops.2022.100113  

    ISSN:2666-9145

  26. 東北メディカル・メガバンク計画・地域住民コホート調査詳細三次調査(宮城)の進捗

    中谷 直樹, 小暮 真奈, 畑中 里衣子, 中谷 久美, 菅野 郁美, 小原 拓, 中村 智洋, 宇留野 晃, 布施 昇男, 泉 陽子, 丹野 高三, 辻 一郎, 栗山 進一, 呉 繁夫, 寳澤 篤

    Journal of Epidemiology 32 (Suppl.1) 162-162 2022年1月

    出版者・発行元:(一社)日本疫学会

    ISSN:0917-5040

    eISSN:1349-9092

  27. dbTMM: an integrated database of large-scale cohort, genome and clinical data for the Tohoku Medical Megabank Project. 国際誌

    Soichi Ogishima, Satoshi Nagaie, Satoshi Mizuno, Ryosuke Ishiwata, Keita Iida, Kazuro Shimokawa, Takako Takai-Igarashi, Naoki Nakamura, Sachiko Nagase, Tomohiro Nakamura, Naho Tsuchiya, Naoki Nakaya, Keiko Murakami, Fumihiko Ueno, Tomomi Onuma, Mami Ishikuro, Taku Obara, Shunji Mugikura, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Akito Tsuboi, Shu Tadaka, Fumiki Katsuoka, Akira Narita, Mika Sakurai, Satoshi Makino, Gen Tamiya, Yuichi Aoki, Ritsuko Shimizu, Ikuko N Motoike, Seizo Koshiba, Naoko Minegishi, Kazuki Kumada, Takahiro Nobukuni, Kichiya Suzuki, Inaho Danjoh, Fuji Nagami, Kozo Tanno, Hideki Ohmomo, Koichi Asahi, Atsushi Shimizu, Atsushi Hozawa, Shinichi Kuriyama, Nobuo Fuse, Teiji Tominaga, Shigeo Kure, Nobuo Yaegashi, Kengo Kinoshita, Makoto Sasaki, Hiroshi Tanaka, Masayuki Yamamoto

    Human genome variation 8 (1) 44-44 2021年12月10日

    DOI: 10.1038/s41439-021-00175-5  

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    To reveal gene-environment interactions underlying common diseases and estimate the risk for common diseases, the Tohoku Medical Megabank (TMM) project has conducted prospective cohort studies and genomic and multiomics analyses. To establish an integrated biobank, we developed an integrated database called "dbTMM" that incorporates both the individual cohort/clinical data and the genome/multiomics data of 157,191 participants in the Tohoku Medical Megabank project. To our knowledge, dbTMM is the first database to store individual whole-genome data on a variant-by-variant basis as well as cohort/clinical data for over one hundred thousand participants in a prospective cohort study. dbTMM enables us to stratify our cohort by both genome-wide genetic factors and environmental factors, and it provides a research and development platform that enables prospective analysis of large-scale data from genome cohorts.

  28. Nrf2 plays a critical role in the metabolic response during and after spaceflight. 国際誌

    Akira Uruno, Daisuke Saigusa, Takafumi Suzuki, Akane Yumoto, Tomohiro Nakamura, Naomi Matsukawa, Takahiro Yamazaki, Ristumi Saito, Keiko Taguchi, Mikiko Suzuki, Norio Suzuki, Akihito Otsuki, Fumiki Katsuoka, Eiji Hishinuma, Risa Okada, Seizo Koshiba, Yoshihisa Tomioka, Ritsuko Shimizu, Masaki Shirakawa, Thomas W Kensler, Dai Shiba, Masayuki Yamamoto

    Communications biology 4 (1) 1381-1381 2021年12月9日

    DOI: 10.1038/s42003-021-02904-6  

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    Space travel induces stresses that contribute to health problems, as well as inducing the expression of Nrf2 (NF-E2-related factor-2) target genes that mediate adaptive responses to oxidative and other stress responses. The volume of epididymal white adipose tissue (eWAT) in mice increases during spaceflight, a change that is attenuated by Nrf2 knockout. We conducted metabolome analyses of plasma from wild-type and Nrf2 knockout mice collected at pre-flight, in-flight and post-flight time points, as well as tissues collected post-flight to clarify the metabolic responses during and after spaceflight and the contribution of Nrf2 to these responses. Plasma glycerophospholipid and sphingolipid levels were elevated during spaceflight, whereas triacylglycerol levels were lower after spaceflight. In wild-type mouse eWAT, triacylglycerol levels were increased, but phosphatidylcholine levels were decreased, and these changes were attenuated in Nrf2 knockout mice. Transcriptome analyses revealed marked changes in the expression of lipid-related genes in the liver and eWAT after spaceflight and the effects of Nrf2 knockout on these changes. Based on these results, we concluded that space stress provokes significant responses in lipid metabolism during and after spaceflight; Nrf2 plays critical roles in these responses.

  29. Association between fat mass index, fat-free mass index, and hemoglobin A1c in a Japanese population: The Tohoku Medical Megabank Community-based Cohort Study.

    Masato Takase, Tomohiro Nakamura, Takumi Hirata, Naho Tsuchiya, Mana Kogure, Fumi Itabashi, Naoki Nakaya, Yohei Hamanaka, Junichi Sugawara, Kichiya Suzuki, Nobuo Fuse, Uruno Akira, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Journal of diabetes investigation 13 (5) 858-867 2021年12月3日

    DOI: 10.1111/jdi.13729  

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    AIMS/INTRODUCTION: Fat mass and fat-free mass affect glycated hemoglobin A1c (HbA1c) levels and blood glucose levels, respectively. The aim of the present study was to examine the association between fat mass index and fat-free mass index with HbA1c. MATERIALS AND METHODS: We conducted a cross-sectional study that included 3,731 men and 9,191 women aged 20 years or older, living in Miyagi Prefecture, Japan, who were not treated for diabetes. The fat mass index and fat-free mass index were calculated as fat mass and fat-free mass divided by the height squared, respectively. The indices were classified into sex-specific quartiles and combined into 16 groups. An ANCOVA was used to assess associations between the combined fat mass index and fat-free mass index with HbA1c adjusted for potential confounder. The linear trend test was conducted by stratifying the fat mass index and fat free mass index, entering the number as a continuous term in the regression model. RESULTS: In multivariable models, a higher fat mass index was related to higher HbA1c levels in men and women in all fat-free mass index subgroups (P<0.001 for linear trend). When we excluded the participants who had been pointed out to have diabetes, fat-free mass index was also related to higher HbA1c levels in most fat mass index subgroups (P<0.05 for linear trend). CONCLUSIONS: Fat mass index was positively related to HbA1c levels. Fat free mass index was also related to HbA1c levels when we excluded participants who had been pointed out to have diabetes.

  30. Genetic loci for lung function in Japanese adults with adjustment for exhaled nitric oxide levels as airway inflammation indicator. 国際誌

    Mitsuhiro Yamada, Ikuko N Motoike, Kaname Kojima, Nobuo Fuse, Atsushi Hozawa, Shinichi Kuriyama, Fumiki Katsuoka, Shu Tadaka, Matsuyuki Shirota, Miyuki Sakurai, Tomohiro Nakamura, Yohei Hamanaka, Kichiya Suzuki, Junichi Sugawara, Soichi Ogishima, Akira Uruno, Eiichi N Kodama, Naoya Fujino, Tadahisa Numakura, Tomohiro Ichikawa, Ayumi Mitsune, Takashi Ohe, Kengo Kinoshita, Masakazu Ichinose, Hisatoshi Sugiura, Masayuki Yamamoto

    Communications biology 4 (1) 1288-1288 2021年11月15日

    DOI: 10.1038/s42003-021-02813-8  

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    Lung function reflects the ability of the respiratory system and is utilized for the assessment of respiratory diseases. Because type 2 airway inflammation influences lung function, genome wide association studies (GWAS) for lung function would be improved by adjustment with an indicator of the inflammation. Here, we performed a GWAS for lung function with adjustment for exhaled nitric oxide (FeNO) levels in two independent Japanese populations. Our GWAS with genotype imputations revealed that the RNF5/AGER locus including AGER rs2070600 SNP, which introduces a G82S substitution of AGER, was the most significantly associated with FEV1/FVC. Three other rare missense variants of AGER were further identified. We also found genetic loci with three candidate genes (NOS2, SPSB2 and RIPOR2) associated with FeNO levels. Analyses with the BioBank-Japan GWAS resource revealed genetic links of FeNO and asthma-related traits, and existence of common genetic background for allergic diseases and their biomarkers. Our study identified the genetic locus most strongly associated with airway obstruction in the Japanese population and three genetic loci associated with FeNO, an indicator of type 2 airway inflammation in adults.

  31. Gene expression changes related to bone mineralization, blood pressure and lipid metabolism in mouse kidneys after space travel. 国際誌

    Norio Suzuki, Yuma Iwamura, Taku Nakai, Koichiro Kato, Akihito Otsuki, Akira Uruno, Daisuke Saigusa, Keiko Taguchi, Mikiko Suzuki, Ritsuko Shimizu, Akane Yumoto, Risa Okada, Masaki Shirakawa, Dai Shiba, Satoru Takahashi, Takafumi Suzuki, Masayuki Yamamoto

    Kidney international 101 (1) 92-105 2021年11月9日

    DOI: 10.1016/j.kint.2021.09.031  

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    Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.

  32. 東北メディカル・メガバンク計画・地域住民コホート調査詳細三次調査(宮城)の概要

    中谷 直樹, 小暮 真奈, 畑中 里衣子, 菅野 郁美, 中谷 久美, 小原 拓, 中村 智洋, 宇留野 晃, 布施 昇男, 泉 陽子, 丹野 高三, 辻 一郎, 栗山 進一, 呉 繁夫, 寳澤 篤

    日本公衆衛生学会総会抄録集 80回 219-219 2021年11月

    出版者・発行元:日本公衆衛生学会

    ISSN:1347-8060

  33. Association between the combined fat mass and fat-free mass index and hypertension: The Tohoku Medical Megabank Community-based Cohort Study. 国際誌

    Masato Takase, Tomohiro Nakamura, Naho Tsuchiya, Mana Kogure, Fumi Itabashi, Akira Narita, Takumi Hirata, Naoki Nakaya, Yohei Hamanaka, Junichi Sugawara, Kichiya Suzuki, Nobuo Fuse, Akira Uruno, Eiichi N Kodama, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Clinical and experimental hypertension (New York, N.Y. : 1993) 43 (7) 610-621 2021年10月3日

    DOI: 10.1080/10641963.2021.1925681  

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    BACKGROUND: A  higher body fat percentage is associated with hypertension, even in non-obese individuals. The difference in body composition may be related to hypertension. The fat mass index (FMI) and fat-free mass index (FFMI) are proposed indicators of body composition. This study aimed to examine the relationship of a combination of FMI and FFMI with hypertension. METHODS: We conducted a cross-sectional study of 5,058 men and 11,842 women aged ≥ 20 years in the Miyagi Prefecture, northeastern Japan. The FMI and FFMI were calculated as the fat mass and fat-free mass divided by the height squared, respectively. The indices were classified into quartiles and combined into 16 groups. Hypertension was defined as casual blood pressure ≥ 140/90 mmHg and/or self-reported treatment for hypertension. Multivariable logistic regression models, adjusted for potential confounders, were used to assess the relationship of a combination of FMI and FFMI with hypertension. RESULTS: Higher FMI was associated with hypertension in most of the FFMI subgroups. Similarly, a higher FFMI was associated with hypertension in most of FMI subgroups. For men, the association between FFMI and hypertension in the lowest FMI group was not significant. CONCLUSIONS: Reducing the FMI and FFMI may be important in preventing hypertension. For men, the relationship between the FFMI and hypertension in the lowest FMI group might be weak.

  34. The return of individual genomic results to research participants: design and pilot study of Tohoku Medical Megabank Project. 国際誌

    Hiroshi Kawame, Akimune Fukushima, Nobuo Fuse, Fuji Nagami, Yoichi Suzuki, Mika Sakurai-Yageta, Jun Yasuda, Yumi Yamaguchi-Kabata, Kengo Kinoshita, Soichi Ogishima, Takako Takai, Shinichi Kuriyama, Atsushi Hozawa, Naoki Nakaya, Tomohiro Nakamura, Naoko Minegishi, Junichi Sugawara, Kichiya Suzuki, Hiroaki Tomita, Akira Uruno, Tomoko Kobayashi, Yayoi Aizawa, Tomoharu Tokutomi, Kayono Yamamoto, Kinuko Ohneda, Shigeo Kure, Yoko Aoki, Hideki Katagiri, Yasushi Ishigaki, Shojiro Sawada, Makoto Sasaki, Masayuki Yamamoto

    Journal of human genetics 67 (1) 9-17 2021年7月8日

    DOI: 10.1038/s10038-021-00952-8  

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    Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

  35. ゲノムコホート研究におけるBRCA1/2遺伝情報返却とその後の医療機関との連携の取組み

    濱中 洋平, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 江幡 明子, 大根田 絹子, 布施 昇男, 川目 裕, 鈴木 洋一, 長神 風二, 鈴木 吉也, 佐藤 政文, 平塚 真弘, 櫻井 美佳, 宇留野 晃, 山口 由美, 平良 摩紀子, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集 29回 21-21 2021年7月

    出版者・発行元:(一社)日本乳癌学会

  36. ゲノムコホート研究におけるBRCA1/2遺伝情報返却とその後の医療機関との連携の取組み

    濱中 洋平, 多田 寛, 宮下 穣, 原田 成美, 佐藤 章子, 江幡 明子, 大根田 絹子, 布施 昇男, 川目 裕, 鈴木 洋一, 長神 風二, 鈴木 吉也, 佐藤 政文, 平塚 真弘, 櫻井 美佳, 宇留野 晃, 山口 由美, 平良 摩紀子, 山本 雅之, 石田 孝宣

    日本乳癌学会総会プログラム抄録集 29回 21-21 2021年7月

    出版者・発行元:(一社)日本乳癌学会

  37. Impacts of the urinary sodium-to-potassium ratio, sleep efficiency, and conventional risk factors on home hypertension in a general Japanese population. 国際誌

    Takumi Hirata, Mana Kogure, Naho Tsuchiya, Ken Miyagawa, Akira Narita, Kotaro Nochioka, Akira Uruno, Taku Obara, Tomohiro Nakamura, Naoki Nakaya, Hirohito Metoki, Masahiro Kikuya, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 44 (7) 858-865 2021年7月

    DOI: 10.1038/s41440-021-00628-y  

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    Recently, a high urinary sodium-to-potassium (Na/K) ratio and reduced sleep efficiency, in addition to conventional risk factors (obesity and excess alcohol intake), have been identified as risk factors for hypertension. We estimated the population attributable fraction (PAF) for home hypertension due to these risk factors in a general Japanese population. We conducted a cross-sectional study including 1384 participants (393 men and 991 women) to estimate the odds ratio (OR) and 95% confidence interval (CI) for the presence of any of the conventional risk factors using multivariable logistic regression analyses. The models were adjusted for sex, age, smoking status, and log-transformed average daily steps. We also estimated the OR and 95% CI for the presence of any of the overall risk factors. Furthermore, we calculated the PAF due to these risk factors. The results showed that the prevalence of home hypertension was 39.0% (540/1384). The presence of any of the conventional risk factors, as well as any of the overall risk factors, was significantly associated with an increased prevalence of hypertension (OR 2.80, 95% CI 2.15-3.65; OR 2.50, 95% CI 1.93-3.22, respectively). The PAF for hypertension due to the presence of any of the conventional risk factors and the PAF due to the presence of any of the overall risk factors were 30.2% and 39.0%, respectively. In conclusion, the impact of the overall risk factors, including the urinary Na/K ratio and sleep efficiency, on home hypertension was higher than that of conventional risk factors alone. The management of the urinary Na/K ratio and sleep efficiency as well as conventional risk factors might be important in the management of blood pressure.

  38. Japonica Array NEO with increased genome-wide coverage and abundant disease risk SNPs

    Mika Sakurai-Yageta, Kazuki Kumada, Chinatsu Gocho, Satoshi Makino, Akira Uruno, Shu Tadaka, Ikuko N Motoike, Masae Kimura, Shin Ito, Akihito Otsuki, Akira Narita, Hisaaki Kudo, Yuichi Aoki, Inaho Danjoh, Jun Yasuda, Hiroshi Kawame, Naoko Minegishi, Seizo Koshiba, Nobuo Fuse, Gen Tamiya, Masayuki Yamamoto, Kengo Kinoshita

    The Journal of Biochemistry 2021年5月13日

    出版者・発行元:Oxford University Press (OUP)

    DOI: 10.1093/jb/mvab060  

    ISSN:0021-924X

    eISSN:1756-2651

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    <title>Abstract</title> Ethnic-specific SNP arrays are becoming more important to increase the power of genome-wide association studies in diverse population. In the Tohoku Medical Megabank Project, we have been developing a series of Japonica Arrays (JPA) for genotyping participants based on reference panels constructed from whole-genome sequence data of the Japanese population. Here, we designed a novel version of the SNP array for the Japanese population, called Japonica Array NEO (JPA NEO), comprising a total of 666,883 markers. Among them, 654,246 tag SNPs of autosomes and X chromosome were selected from an expanded reference panel of 3,552 Japanese, 3.5KJPNv2, using pairwise r2 of linkage disequilibrium measures. Additionally, 28,298 markers were included for the evaluation of previously identified disease risk markers from the literature and databases, and those present in the Japanese population were extracted using the reference panel. Through genotyping 286 Japanese samples, we found that the imputation quality r2 and INFO score in the minor allele frequency bin &amp;gt;2.5–5% were &amp;gt;0.9 and &amp;gt;0.8, respectively, and &amp;gt;12 million markers were imputed with an INFO score &amp;gt;0.8. From these results, JPA NEO is a promising tool for genotyping the Japanese population with genome-wide coverage, contributing to the development of genetic risk scores.

  39. 環境・衛生部会シンポジウム〜多様なストレスに対する生体適応の仕組みと疾患制御〜 KEAP1-NRF2制御系の活性化とアルツハイマー病病態(Nrf2 suppresses oxidative stress and inflammation in App knock-in Alzheimer's disease model mice)

    松丸 大輔, 宇留野 晃, 領家 梨恵, 齋藤 律水, 門口 詩織, 三枝 大輔, 斉藤 貴志, 西道 隆臣, 川島 隆太, 山本 雅之

    日本薬学会年会要旨集 141年会 S16-3 2021年3月

    出版者・発行元:(公社)日本薬学会

    ISSN:0918-9823

  40. Novel method for evaluating the health condition of mice in space through a video downlink.

    Akane Yumoto, Toshiaki Kokubo, Ryutaro Izumi, Michihiko Shimomura, Osamu Funatsu, Motoki N Tada, Naoko Ota-Murakami, Kayoko Iino, Masaki Shirakawa, Hiroyasu Mizuno, Takashi Kudo, Satoru Takahashi, Takafumi Suzuki, Akira Uruno, Masayuki Yamamoto, Dai Shiba

    Experimental animals 70 (2) 236-244 2021年1月22日

    DOI: 10.1538/expanim.20-0102  

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    Clarification of the criteria for managing animal health is essential to increase the reliability of experiments and ensure transparency in animal welfare. For experiments performed in space, there is no consensus on how to care for animals owing to technical issues, launch mass limitation, and human resources. Some biological processes in mammals, such as musculoskeletal or immune processes, are altered in the space environment, and mice in space can be used to simulate morbid states, such as senescence acceleration. Thus, there is a need to establish a novel evaluation method and evaluation criteria to monitor animal health. Here, we report a novel method to evaluate the health of mice in space through a video downlink in a series of space experiments using the Multiple Artificial-gravity Research System (MARS). This method was found to be more useful in evaluating animal health in space than observations and body weight changes of the same live mice following their return to Earth. We also developed criteria to evaluate health status via a video downlink. These criteria, with "Fur condition" and "Respiratory" as key items, provided information on the daily changes in the health status of mice and helped to identify malfunctions at an early stage. Our method and criteria led to the success of our missions, and they will help establish appropriate rules for space experiments in the future.

  41. Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study.

    Atsushi Hozawa, Kozo Tanno, Naoki Nakaya, Tomohiro Nakamura, Naho Tsuchiya, Takumi Hirata, Akira Narita, Mana Kogure, Kotaro Nochioka, Ryohei Sasaki, Nobuyuki Takanashi, Kotaro Otsuka, Kiyomi Sakata, Shinichi Kuriyama, Masahiro Kikuya, Osamu Tanabe, Junichi Sugawara, Kichiya Suzuki, Yoichi Suzuki, Eiichi N Kodama, Nobuo Fuse, Hideyasu Kiyomoto, Hiroaki Tomita, Akira Uruno, Yohei Hamanaka, Hirohito Metoki, Mami Ishikuro, Taku Obara, Tomoko Kobayashi, Kazuyuki Kitatani, Takako Takai-Igarashi, Soichi Ogishima, Mamoru Satoh, Hideki Ohmomo, Akito Tsuboi, Shinichi Egawa, Tadashi Ishii, Kiyoshi Ito, Sadayoshi Ito, Yasuyuki Taki, Naoko Minegishi, Naoto Ishii, Masao Nagasaki, Kazuhiko Igarashi, Seizo Koshiba, Ritsuko Shimizu, Gen Tamiya, Keiko Nakayama, Hozumi Motohashi, Jun Yasuda, Atsushi Shimizu, Tsuyoshi Hachiya, Yuh Shiwa, Teiji Tominaga, Hiroshi Tanaka, Kotaro Oyama, Ryoichi Tanaka, Hiroshi Kawame, Akimune Fukushima, Yasushi Ishigaki, Tomoharu Tokutomi, Noriko Osumi, Tadao Kobayashi, Fuji Nagami, Hiroaki Hashizume, Tomohiko Arai, Yoshio Kawaguchi, Shinichi Higuchi, Masaki Sakaida, Ryujin Endo, Satoshi Nishizuka, Ichiro Tsuji, Jiro Hitomi, Motoyuki Nakamura, Kuniaki Ogasawara, Nobuo Yaegashi, Kengo Kinoshita, Shigeo Kure, Akio Sakai, Seiichiro Kobayashi, Kenji Sobue, Makoto Sasaki, Masayuki Yamamoto

    Journal of epidemiology 31 (1) 65-76 2021年1月5日

    DOI: 10.2188/jea.JE20190271  

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    BACKGROUND: We established a community-based cohort study to assess the long-term impact of the Great East Japan Earthquake on disaster victims and gene-environment interactions on the incidence of major diseases, such as cancer and cardiovascular diseases. METHODS: We asked participants to join our cohort in the health check-up settings and assessment center based settings. Inclusion criteria were aged 20 years or over and living in Miyagi or Iwate Prefecture. We obtained information on lifestyle, effect of disaster, blood, and urine information (Type 1 survey), and some detailed measurements (Type 2 survey), such as carotid echography and calcaneal ultrasound bone mineral density. All participants agreed to measure genome information and to distribute their information widely. RESULTS: As a result, 87,865 gave their informed consent to join our study. Participation rate at health check-up site was about 70%. The participants in the Type 1 survey were more likely to have psychological distress than those in the Type 2 survey, and women were more likely to have psychological distress than men. Additionally, coastal residents were more likely to have higher degrees of psychological distress than inland residents, regardless of sex. CONCLUSION: This cohort comprised a large sample size and it contains information on the natural disaster, genome information, and metabolome information. This cohort also had several detailed measurements. Using this cohort enabled us to clarify the long-term effect of the disaster and also to establish personalized prevention based on genome, metabolome, and other omics information.

  42. 東北メディカル・メガバンク計画(宮城)における頸動脈エコーについて

    寳澤 篤, 土屋 菜歩, 中村 智洋, 宇留野 晃, 栗山 進一, 菅原 準一, 呉 繁夫, 布施 昇男, 山本 雅之

    超音波医学 47 (Suppl.) S532-S532 2020年11月

    出版者・発行元:(公社)日本超音波医学会

    ISSN:1346-1176

    eISSN:1881-9311

  43. Maternal Baseline Characteristics and Perinatal Outcomes: the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study.

    Junichi Sugawara, Mami Ishikuro, Taku Obara, Tomomi Onuma, Keiko Murakami, Masahiro Kikuya, Fumihiko Ueno, Aoi Noda, Satoshi Mizuno, Tomoko Kobayashi, Yohei Hamanaka, Kichiya Suzuki, Eiichi Kodama, Naho Tsuchiya, Akira Uruno, Yoichi Suzuki, Osamu Tanabe, Hideyasu Kiyomoto, Akito Tsuboi, Atsushi Shimizu, Seizo Koshiba, Naoko Minegishi, Soichi Ogishima, Gen Tamiya, Hirohito Metoki, Atsushi Hozawa, Nobuo Fuse, Kengo Kinoshita, Shigeo Kure, Nobuo Yaegashi, Shinichi Kuriyama, Masayuki Yamamoto

    Journal of epidemiology 32 (2) 69-79 2020年10月10日

    DOI: 10.2188/jea.JE20200338  

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    BACKGROUND: The Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study was launched in 2013 to evaluate the complex interactions of genetic and environmental factors in multifactorial diseases. The present study describes the maternal baseline profile and perinatal data of participating mothers and infants. METHODS: Expectant mothers living in Miyagi prefecture were recruited from obstetric facilities or affiliated centers between 2013 and 2017. Three sets of self-administered questionnaires were collected, and the medical records were reviewed to obtain precise information about each antenatal visit and each delivery. Biospecimens, including blood, urine, umbilical cord blood, and breast milk, were collected for the study biobank. The baseline maternal sociodemographic characteristics, results of screening tests, and obstetric outcomes were analyzed according to the maternal age group. RESULTS: A total of 23 406 pregnancies involving 23 730 fetuses resulted in 23 143 live births. Younger maternal participants had a tendency toward a higher incidence of threatened abortion and threatened premature labor, while older age groups exhibited a significantly higher rate of low lying placenta, placenta previa, gestational diabetes and hypertensive disorders of pregnancy. CONCLUSIONS: The present study clearly shows the distribution of maternal baseline characteristics and the range of perinatal outcomes according to maternal age group. This cohort study can provide strategic information for creating breakthroughs in the pathophysiology of perinatal, developmental, and noncommunicable diseases by collaborative data visiting or sharing.

  44. Author Correction: Nrf2 contributes to the weight gain of mice during space travel. 国際誌

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications biology 3 (1) 566-566 2020年10月7日

    DOI: 10.1038/s42003-020-01292-7  

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  45. Nrf2 contributes to the weight gain of mice during space travel. 国際誌

    Takafumi Suzuki, Akira Uruno, Akane Yumoto, Keiko Taguchi, Mikiko Suzuki, Nobuhiko Harada, Rie Ryoke, Eriko Naganuma, Nanae Osanai, Aya Goto, Hiromi Suda, Ryan Browne, Akihito Otsuki, Fumiki Katsuoka, Michael Zorzi, Takahiro Yamazaki, Daisuke Saigusa, Seizo Koshiba, Takashi Nakamura, Satoshi Fukumoto, Hironobu Ikehata, Keizo Nishikawa, Norio Suzuki, Ikuo Hirano, Ritsuko Shimizu, Tetsuya Oishi, Hozumi Motohashi, Hirona Tsubouchi, Risa Okada, Takashi Kudo, Michihiko Shimomura, Thomas W Kensler, Hiroyasu Mizuno, Masaki Shirakawa, Satoru Takahashi, Dai Shiba, Masayuki Yamamoto

    Communications biology 3 (1) 496-496 2020年9月8日

    DOI: 10.1038/s42003-020-01227-2  

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    Space flight produces an extreme environment with unique stressors, but little is known about how our body responds to these stresses. While there are many intractable limitations for in-flight space research, some can be overcome by utilizing gene knockout-disease model mice. Here, we report how deletion of Nrf2, a master regulator of stress defense pathways, affects the health of mice transported for a stay in the International Space Station (ISS). After 31 days in the ISS, all flight mice returned safely to Earth. Transcriptome and metabolome analyses revealed that the stresses of space travel evoked ageing-like changes of plasma metabolites and activated the Nrf2 signaling pathway. Especially, Nrf2 was found to be important for maintaining homeostasis of white adipose tissues. This study opens approaches for future space research utilizing murine gene knockout-disease models, and provides insights into mitigating space-induced stresses that limit the further exploration of space by humans.

  46. ゲノムコホート調査におけるゲノム薬理学(PGx)遺伝情報返却(回付)のパイロット研究

    濱中 洋平, 大根田 絹子, 布施 昇男, 川目 裕, 長神 風二, 平塚 真弘, 宇留野 晃, 櫻井 美佳, 平良 摩紀子, 鈴木 吉也, 鈴木 洋一, 山本 雅之

    日本遺伝カウンセリング学会誌 41 (2) 122-122 2020年6月

    出版者・発行元:(一社)日本遺伝カウンセリング学会

    ISSN:1347-9628

  47. Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach. 国際誌 査読有り

    Sherif Rashad, Daisuke Saigusa, Takahiro Yamazaki, Yotaro Matsumoto, Yoshihisa Tomioka, Ritsumi Saito, Akira Uruno, Kuniyasu Niizuma, Masayuki Yamamoto, Teiji Tominaga

    Scientific reports 10 (1) 6507-6507 2020年4月16日

    DOI: 10.1038/s41598-020-63483-w  

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    Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.

  48. Nrf2 Suppresses Oxidative Stress and Inflammation in App Knock-In Alzheimer's Disease Model Mice. 国際誌 査読有り

    Akira Uruno, Daisuke Matsumaru, Rie Ryoke, Ritsumi Saito, Shiori Kadoguchi, Daisuke Saigusa, Takashi Saito, Takaomi C Saido, Ryuta Kawashima, Masayuki Yamamoto

    Molecular and cellular biology 40 (6) 2020年2月27日

    DOI: 10.1128/MCB.00467-19  

    ISSN:0270-7306

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    Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer's disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF ) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF ::Keap1FA/FA mice. Matrix-assisted laser desorption ionization-mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF ::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.

  49. Multiple measurements of the urinary sodium-to-potassium ratio strongly related home hypertension: TMM Cohort Study. 国際誌 査読有り

    Mana Kogure, Takumi Hirata, Naoki Nakaya, Naho Tsuchiya, Tomohiro Nakamura, Akira Narita, Ken Miyagawa, Hiroshi Koshimizu, Taku Obara, Hirohito Metoki, Akira Uruno, Masahiro Kikuya, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 43 (1) 62-71 2020年1月

    DOI: 10.1038/s41440-019-0335-2  

    ISSN:0916-9636

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    Previous studies have reported a positive association between the urinary sodium-to-potassium (Na/K) ratio and hypertension, and multiple measurements of the casual urinary Na/K ratio are more strongly correlated with the 24-h urinary Na/K ratio than a single measurement. Multiple measurements of the urinary Na/K ratio might be more strongly associated with hypertension. We aimed to determine the association between multiple measurements of the casual urinary Na/K ratio and home hypertension compared with a single measurement. A population-based cross-sectional study was performed in Miyagi Prefecture, Japan. Subjects were over 20 years old and participated in the Tohoku Medical Megabank Project Cohort Study. We targeted 3273 subjects who borrowed home blood pressure (HBP) monitors and urinary Na/K ratio monitors for 10 consecutive days. The association between the urinary Na/K ratio and home hypertension (HBP ≥ 135/85 mmHg or under treatment for hypertension) was examined using multiple logistic regression models. To compare the prediction of home hypertension using multiple measurements with that using a single measurement, we calculated the area under the receiver operating characteristic curve (AUROC). Multiple measurements of the urinary Na/K ratio strongly related to home hypertension were better than 1 or 2 days of measurement (adjusted odds ratio of home hypertension per unit increase in urinary Na/K ratio over 6 days: 1.13-1.15). The AUROC of the urinary Na/K ratio measurement for home hypertension was stable after 5 days (AUROC = 0.779). In conclusion, multiple measurements of the urinary Na/K ratio are strongly related to home hypertension. This finding suggests that multiple measurements of the urinary Na/K ratio are useful for evaluating home hypertension.

  50. Reduced sleep efficiency, measured using an objective device, was related to an increased prevalence of home hypertension in Japanese adults. 国際誌 査読有り

    Takumi Hirata, Tomohiro Nakamura, Mana Kogure, Naho Tsuchiya, Akira Narita, Ken Miyagawa, Kotaro Nochioka, Akira Uruno, Taku Obara, Naoki Nakaya, Hirohito Metoki, Masahiro Kikuya, Junichi Sugawara, Shinichi Kuriyama, Ichiro Tsuji, Shigeo Kure, Atsushi Hozawa

    Hypertension research : official journal of the Japanese Society of Hypertension 43 (1) 23-29 2020年1月

    DOI: 10.1038/s41440-019-0329-0  

    ISSN:0916-9636

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    Few studies have reported the relationship between reduced sleep efficiency and the prevalence of hypertension independent of sleep duration in Japan. This study aimed to evaluate whether reduced sleep efficiency, measured using an objective device for >1 week, was related to an increased prevalence of hypertension independent of sleep duration in the general Japanese population. We conducted a cross-sectional study of 904 participants aged ≥20 years who lived in Miyagi Prefecture, Japan. Sleep efficiency was measured using a contactless biomotion sleep sensor for 10 continuous days. The participants were classified into two groups according to their sleep efficiency: reduced (<90%) or not reduced (≥90%). Hypertension was defined as morning home blood pressure ≥135/85 mmHg or self-reported treatment for hypertension. Multivariable logistic regression models were used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationship between sleep efficiency and hypertension adjusted for potential confounders. The results showed that two hundred and ninety-four individuals (32.5%) had reduced sleep efficiency, and 331 (36.6%) had hypertension. Individuals with reduced sleep efficiency had a higher body mass index and shorter sleep duration. In the multivariable analysis, reduced sleep efficiency was significantly related to an increased prevalence of hypertension (OR, 1.62; 95% CI, 1.15-2.28). In conclusion, reduced sleep efficiency was significantly related to an increased prevalence of hypertension in Japanese adults. Improvements in sleep efficiency may be important to reduce blood pressure in Japanese adults.

  51. Alteration of the lysophosphatidic acid and its precursor lysophosphatidylcholine levels in spinal cord stenosis: A study using a rat cauda equina compression model. 国際誌 査読有り

    Baasanjav Uranbileg, Nobuko Ito, Makoto Kurano, Daisuke Saigusa, Ritsumi Saito, Akira Uruno, Kuniyuki Kano, Hitoshi Ikeda, Yoshitsugu Yamada, Masahiko Sumitani, Miho Sekiguchi, Junken Aoki, Yutaka Yatomi

    Scientific reports 9 (1) 16578-16578 2019年11月12日

    DOI: 10.1038/s41598-019-52999-5  

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    Cauda equina compression (CEC) is a major cause of neurogenic claudication and progresses to neuropathic pain (NP). A lipid mediator, lysophosphatidic acid (LPA), is known to induce NP via the LPA1 receptor. To know a possible mechanism of LPA production in neurogenic claudication, we determined the levels of LPA, lysophosphatidylcholine (LPC) and LPA-producing enzyme autotaxin (ATX), in the cerebrospinal fluid (CSF) and spinal cord (SC) using a CEC as a possible model of neurogenic claudication. Using silicon blocks within the lumbar epidural space, we developed a CEC model in rats with motor dysfunction. LPC and LPA levels in the CSF were significantly increased from day 1. Importantly, specific LPA species (16:0, 18:2, 20:4) were upregulated, which have been shown to produce by ATX detected in the CSF, without changes on its level. In SC, the LPC and LPA levels did not change, but mass spectrometry imaging analysis revealed that LPC was present in a region where the silicon blocks were inserted. These results propose a model for LPA production in SC and CSF upon neurogenic claudication that LPC produced locally by tissue damages is converted to LPA by ATX, which then leak out into the CSF.

  52. 睡眠の測定機器から得られた睡眠状況と心理的苦痛との関連

    五十嵐 有香, 小暮 真奈, 中村 智洋, 土屋 菜歩, 平田 匠, 成田 暁, 宮川 健, 宇留野 晃, 中谷 直樹, 菅原 準一, 栗山 進一, 呉 繁夫, 寳澤 篤

    日本公衆衛生学会総会抄録集 78回 223-223 2019年10月

    出版者・発行元:日本公衆衛生学会

    ISSN:1347-8060

  53. 高血圧有病率からみた尿ナトカリ比の目標値と必要測定回数の検討 東北メディカル・メガバンク計画コホート調査の成果から

    小暮 真奈, 平田 匠, 土屋 菜歩, 中村 智洋, 宮川 健, 小清水 宏, 小原 拓, 目時 弘仁, 宇留野 晃, 菊谷 昌浩, 菅原 準一, 栗山 進一, 辻 一郎, 呉 繁夫, 寳澤 篤

    日本高血圧学会総会プログラム・抄録集 42回 287-287 2019年10月

    出版者・発行元:(NPO)日本高血圧学会

  54. 非喫煙者における受動喫煙の有無と家庭高血圧の関連

    平田 匠, 小暮 真奈, 成田 暁, 佐藤 倫広, 土屋 菜歩, 中村 智洋, 宇留野 晃, 小原 拓, 目時 弘仁, 中谷 直樹, 菅原 準一, 栗山 進一, 呉 繁夫, 寳澤 篤

    日本高血圧学会総会プログラム・抄録集 42回 288-288 2019年10月

    出版者・発行元:(NPO)日本高血圧学会

  55. 高血圧有病率からみた尿ナトカリ比の目標値と必要測定回数の検討 東北メディカル・メガバンク計画コホート調査の成果から 査読有り

    小暮 真奈, 平田 匠, 土屋 菜歩, 中村 智洋, 宮川 健, 小清水 宏, 小原 拓, 目時 弘仁, 宇留野 晃, 菊谷 昌浩, 菅原 準一, 栗山 進一, 辻 一郎, 呉 繁夫, 寳澤 篤

    日本高血圧学会総会プログラム・抄録集 42回 287-287 2019年10月

    出版者・発行元:(NPO)日本高血圧学会

  56. 非喫煙者における受動喫煙の有無と家庭高血圧の関連 査読有り

    平田 匠, 小暮 真奈, 成田 暁, 佐藤 倫広, 土屋 菜歩, 中村 智洋, 宇留野 晃, 小原 拓, 目時 弘仁, 中谷 直樹, 菅原 準一, 栗山 進一, 呉 繁夫, 寳澤 篤

    日本高血圧学会総会プログラム・抄録集 42回 288-288 2019年10月

    出版者・発行元:(NPO)日本高血圧学会

  57. MALDI-MSI分析における導電性粘着フィルムで作製した生体組織切片の有用性について

    三枝 大輔, 齋藤 律水, 川本 孔明, 宇留野 晃, 可野 邦行, 青木 淳賢, 山本 雅之, 川本 忠文

    JSBMS Letters 44 (Suppl.) 122-122 2019年8月

    出版者・発行元:(一社)日本医用マススペクトル学会

    ISSN:1881-5464

  58. Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension. 国際誌 査読有り

    Ryo Kurosawa, Kimio Satoh, Nobuhiro Kikuchi, Haruhisa Kikuchi, Daisuke Saigusa, Md Elias Al-Mamun, Mohammad A H Siddique, Junichi Omura, Taijyu Satoh, Shinichiro Sunamura, Masamichi Nogi, Kazuhiko Numano, Satoshi Miyata, Akira Uruno, Kuniyuki Kano, Yotaro Matsumoto, Takayuki Doi, Junken Aoki, Yoshiteru Oshima, Masayuki Yamamoto, Hiroaki Shimokawa

    Circulation research 125 (3) 309-327 2019年7月19日

    DOI: 10.1161/CIRCRESAHA.119.315229  

    ISSN:0009-7330

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    RATIONALE: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) accompanying increased production of inflammatory factors and adaptation of the mitochondrial metabolism to a hyperproliferative state. However, all the drugs in clinical use target pulmonary vascular dilatation, which may not be effective for patients with advanced PAH. OBJECTIVE: We aimed to discover a novel drug for PAH that inhibits PASMC proliferation. METHODS AND RESULTS: We screened 5562 compounds from original library using high-throughput screening system to discover compounds which inhibit proliferation of PASMCs from patients with PAH (PAH-PASMCs). We found that celastramycin, a benzoyl pyrrole-type compound originally found in a bacteria extract, inhibited the proliferation of PAH-PASMCs in a dose-dependent manner with relatively small effects on PASMCs from healthy donors. Then, we made 25 analogs of celastramycin and selected the lead compound, which significantly inhibited cell proliferation of PAH-PASMCs and reduced cytosolic reactive oxygen species levels. Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine. Importantly, celastramycin treatment reduced reactive oxygen species levels in PAH-PASMCs with increased protein levels of Nrf2 (nuclear factor erythroid 2-related factor 2), a master regulator of cellular response against oxidative stress. Furthermore, celastramycin treatment improved mitochondrial energy metabolism with recovered mitochondrial network formation in PAH-PASMCs. Moreover, these celastramycin-mediated effects were regulated by ZFC3H1 (zinc finger C3H1 domain-containing protein), a binding partner of celastramycin. Finally, celastramycin treatment ameliorated pulmonary hypertension in 3 experimental animal models, accompanied by reduced inflammatory changes in the lungs. CONCLUSIONS: These results indicate that celastramycin ameliorates pulmonary hypertension, reducing excessive proliferation of PAH-PASMCs with less inflammation and reactive oxygen species levels, and recovered mitochondrial energy metabolism. Thus, celastramycin is a novel drug for PAH that targets antiproliferative effects on PAH-PASMCs.

  59. Conductive Adhesive Film Expands the Utility of Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging. 国際誌 査読有り

    Daisuke Saigusa, Ritsumi Saito, Komei Kawamoto, Akira Uruno, Kuniyuki Kano, Junken Aoki, Masayuki Yamamoto, Tadafumi Kawamoto

    Analytical chemistry 91 (14) 8979-8986 2019年7月16日

    DOI: 10.1021/acs.analchem.9b01159  

    ISSN:0003-2700

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    The matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique is a promising approach for detecting the distribution of small molecules in a section of biological tissue. However, when a cryosection is created from fragile, hard, or whole-body samples, obtaining a high-quality section that maintains the distribution of the various components has been difficult. Since adhesive films have the potential to obtain high-quality cryosections, we attempted to utilize a conductive adhesive film for MALDI-MSI. To this end, cryosections of the whole body of a 9-day-old mouse were directly prepared on indium tin oxide (ITO) glass slides, nonconductive adhesive films, or conductive adhesive films, and the signal intensities from each section were measured by MALDI-MSI. We measured the differences in the ion intensity among these three slides/films by means of multivariate analyses and found that both the nonconductive and conductive adhesive films gave rise to high-quality sections in comparison with the ITO glass slide. The conductive adhesive film gave higher signals that were comparable to those of the ITO glass slide in comparison with the nonconductive adhesive film. We divided the frozen sections into two groups, a freeze-dried group and a thawed group, to examine the freeze-thaw effect on the signals of representative compounds of amino acids, cholesterol, and phosphatidylcholines. The freeze-dried samples were found to be useful for the analysis. These results indicate that the sections made with the conductive adhesive film under a freeze-dried condition can expand the utility of the MALDI-MSI analysis.

  60. 遺伝教育は血縁者の健康管理のために自身の遺伝学的検査結果を共有する意識を強くする

    徳富 智明, 吉田 明子, 福島 明宗, 山本 佳世乃, 石垣 泰, 川目 裕, 布施 昇男, 長神 風二, 鈴木 吉也, 宇留野 晃, 櫻井 美佳, 沼田 早苗, 中山 文予, 山本 雅之, 佐々木 真理

    日本遺伝カウンセリング学会誌 40 (2) 76-76 2019年7月

    出版者・発行元:(一社)日本遺伝カウンセリング学会

    ISSN:1347-9628

  61. Nrf2 activation in myeloid cells and endothelial cells differentially mitigates sickle cell disease pathology in mice. 国際誌 査読有り

    Nadine Keleku-Lukwete, Mikiko Suzuki, Harit Panda, Akihito Otsuki, Fumiki Katsuoka, Ritsumi Saito, Daisuke Saigusa, Akira Uruno, Masayuki Yamamoto

    Blood advances 3 (8) 1285-1297 2019年4月23日

    DOI: 10.1182/bloodadvances.2018017574  

    ISSN:2473-9529

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    Sickle cell disease (SCD) is caused by a monogenic mutation of the β-globin gene and affects millions of people worldwide. SCD is associated with sustained hemolytic anemia, vasoocclusion, ischemia-reperfusion injury, oxidative tissue damage, inflammatory cell activation, and systemic endothelial dysfunction. The transcription factor Nrf2 coordinates the expression of a wide variety of genes encoding antioxidant, detoxification, and metabolic enzymes. Nrf2 participates in suppressing proinflammatory cytokines and organ protection in SCD. However, little is known regarding the mechanisms by which Nrf2 ameliorates SCD pathology or how some cells respond to Nrf2 stimuli to alleviate SCD pathology. Here, we asked whether monocytes/granulocytes and/or endothelial cells are particularly critical in alleviating the pathology of SCD. By targeting these cells with a Cre recombinase system, we generated SCD::Keap1F/F::LysM-Cre and Tie1-Cre mice with constitutive Nrf2 activation in monocytes/granulocytes and endothelial cells, respectively. Analyses of SCD::Keap1F/F::LysM-Cre and SCD::Keap1F/F::Tie1-Cre mice revealed significantly reduced inflammation, along with decreased white blood cell counts and lower Tnfα and Il1β expression in the lungs. Notably, SCD::Keap1F/F::LysM-Cre mice exhibited reduced heme distribution in the liver, consistent with a decrease in the damaged areas. Vascular function in SCD::Keap1F/F::Tie1-Cre mice was significantly improved, with a 50% decrease in vascular leakage and low expression of the adhesion molecules Vcam1 and P-selectin. Thus, Nrf2 activation in monocytes/granulocytes and endothelial cells contributes differentially and cooperatively to the improvement of SCD pathology.

  62. 疾患モデル動物のメタボローム組織分布解析による疾患発症リスク因子の同定

    三枝 大輔, 齋藤 律水, 宇留野 晃

    日本内分泌学会雑誌 95 (1) 326-326 2019年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  63. Estimating carrier frequencies of newborn screening disorders using a whole-genome reference panel of 3552 Japanese individuals. 国際誌 査読有り

    Yumi Yamaguchi-Kabata, Jun Yasuda, Akira Uruno, Kazuro Shimokawa, Seizo Koshiba, Yoichi Suzuki, Nobuo Fuse, Hiroshi Kawame, Shu Tadaka, Masao Nagasaki, Kaname Kojima, Fumiki Katsuoka, Kazuki Kumada, Osamu Tanabe, Gen Tamiya, Nobuo Yaegashi, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure

    Human genetics 138 (4) 389-409 2019年4月

    DOI: 10.1007/s00439-019-01998-7  

    ISSN:0340-6717

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    Incidence rates of Mendelian diseases vary among ethnic groups, and frequencies of variant types of causative genes also vary among human populations. In this study, we examined to what extent we can predict population frequencies of recessive disorders from genomic data, and explored better strategies for variant interpretation and classification. We used a whole-genome reference panel from 3552 general Japanese individuals constructed by the Tohoku Medical Megabank Organization (ToMMo). Focusing on 32 genes for 17 congenital metabolic disorders included in newborn screening (NBS) in Japan, we identified reported and predicted pathogenic variants through variant annotation, interpretation, and multiple ways of classifications. The estimated carrier frequencies were compared with those from the Japanese NBS data based on 1,949,987 newborns from a previous study. The estimated carrier frequency based on genomic data with a recent guideline of variant interpretation for the PAH gene, in which defects cause hyperphenylalaninemia (HPA) and phenylketonuria (PKU), provided a closer estimate to that by the observed incidence than the other methods. In contrast, the estimated carrier frequencies for SLC25A13, which causes citrin deficiency, were much higher compared with the incidence rate. The results varied greatly among the 11 NBS diseases with single responsible genes; the possible reasons for departures from the carrier frequencies by reported incidence rates were discussed. Of note, (1) the number of pathogenic variants increases by including additional lines of evidence, (2) common variants with mild effects also contribute to the actual frequency of patients, and (3) penetrance of each variant remains unclear.

  64. Nrf2 represses the onset of type 1 diabetes in non-obese diabetic mice. 国際誌 査読有り

    Yoko Yagishita, Akira Uruno, Dionysios V Chartoumpekis, Thomas W Kensler, Masayuki Yamamoto

    The Journal of endocrinology 240 (3) 403-416 2019年1月1日

    DOI: 10.1530/JOE-18-0355  

    ISSN:0022-0795

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    The transcription factor Nrf2 (NF-E2-related factor 2) plays a critical role in oxidative stress responses. While activation of Nrf2 signaling is known to exert anti-inflammatory effects, Nrf2 function in inflammation-mediated autoimmune disorders, such as type 1 diabetes, is not well established. To address the roles of Nrf2 in protection against autoreactive T-cell-induced type 1 diabetes, we used non-obese diabetic (NOD) mice, a polygenic model of human type 1 diabetes, to generate a genetic model that allowed us to assess the contribution of Nrf2 activation to preventing and/or treating type 1 diabetes. As Keap1 negatively regulates Nrf2, we used Keap1 gene knockdown driven by either hypomorphic or knockout alleles of Keap1,which enhances Nrf2 signaling to moderate and excess levels, respectively. We found that Nrf2 activation in NOD::Keap1FA/- mice inhibited T-cell infiltration within or near the islets, ameliorated impairment of insulin secretion, and prevented development of diabetes mellitus in the NOD mice. Notably, Nrf2 activation decreased both plasma interferon-γ (IFN-γ) levels and IFN-γ-positive cell numbers in the pancreatic islets. These findings were also observed in mice with two hypomorphic Keap1 alleles (Keap1FA/FA). Both NOD::Keap1FA/- and NOD::Keap1FA/FA mice had decreased incidence of diabetes mellitus, demonstrating that the activation of Nrf2 signaling prevents the onset of type 1 diabetes mellitus in NOD mice. Thus, Nrf2 appears to be a potential target for preventing and treating type 1 diabetes.

  65. Metabolomic Analysis of Mouse Brain after a Transient Middle Cerebral Artery Occlusion by Mass Spectrometry Imaging. 査読有り

    Takatsugu Abe, Kuniyasu Niizuma, Atsushi Kanoke, Daisuke Saigusa, Ritsumi Saito, Akira Uruno, Miki Fujimura, Masayuki Yamamoto, Teiji Tominaga

    Neurologia medico-chirurgica 58 (9) 384-392 2018年9月15日

    DOI: 10.2176/nmc.oa.2018-0054  

    ISSN:0470-8105

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    We performed metabolomic analyses of mouse brain using a transient middle cerebral artery occlusion (tMCAO) model with Matrix Assisted Laser Desorption/Ionization (MALDI)-mass spectrometry imaging (MSI) to reveal metabolite changes after cerebral ischemia. We selected and analyzed three metabolites, namely creatine (Cr), phosphocreatine (P-Cr), and ceramides (Cer), because these metabolites contribute to cell life and death. Eight-week-old male C57BL/6J mice were subjected to tMCAO via the intraluminal blockade of the middle cerebral artery (MCA) and reperfusion 60 min after the induction of ischemia. Each mouse was randomly assigned to one of the three groups; the groups were defined by the survival period after reperfusion: control, 1 h, and 24 h. Corrected samples were analyzed using MALDI-MSI. Results of MSI analysis showed the presence of several ionized substances and revealed spatial changes in some metabolites identified as precise substances, including Cr, P-Cr, Cer d18:1/18:0, phosphatidylcholine, L-glutamine, and L-histidine. Cr, P-Cr, and Cer d18:1/18:0 were changed after tMCAO, and P-Cr and Cer d18:1/18:0 accumulated over time in ischemic cores and surrounding areas following ischemia onset. The upregulation of P-Cr and Cer d18:1/18:0 was detected 1 h after tMCAO when no changes were evident on hematoxylin and eosin staining and immunofluorescence assay. P-Cr and Cer d18:1/18:0 can serve as neuroprotective therapies because they are biomarker candidates for cerebral ischemia.

  66. Metabolomic changes in the mouse retina after optic nerve injury. 国際誌 査読有り

    Kota Sato, Daisuke Saigusa, Ritsumi Saito, Amane Fujioka, Yurika Nakagawa, Koji M Nishiguchi, Taiki Kokubun, Ikuko N Motoike, Kazuichi Maruyama, Kazuko Omodaka, Yukihiro Shiga, Akira Uruno, Seizo Koshiba, Masayuki Yamamoto, Toru Nakazawa

    Scientific reports 8 (1) 11930-11930 2018年8月9日

    DOI: 10.1038/s41598-018-30464-z  

    ISSN:2045-2322

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    In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.

  67. Intracellular S1P Levels Dictate Fate of Different Regions of the Hippocampus following Transient Global Cerebral Ischemia. 国際誌 査読有り

    Sherif Rashad, Kuniyasu Niizuma, Daisuke Saigusa, Xiaobo Han, Mika Sato-Maeda, Ritsumi Saito, Akira Uruno, Miki Fujimura, Shuntaro Ikawa, Masayuki Yamamoto, Teiji Tominaga

    Neuroscience 384 188-202 2018年8月1日

    出版者・発行元:Elsevier Ltd

    DOI: 10.1016/j.neuroscience.2018.05.015  

    ISSN:1873-7544 0306-4522

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    Sphingosine-1-phosphate (S1P) is a sphingolipid molecule produced by the action of sphingosine kinases (SphK) on sphingosine. It possesses various intracellular functions through its interactions with intracellular proteins or via its action on five G-protein-coupled cell membrane receptors. Following transient global cerebral ischemia (tGCI), only the CA1 subregion of the hippocampus undergoes apoptosis. In this study, we evaluated S1P levels and S1P-processing enzyme expression in different hippocampal areas following tGCI in rats. We found that S1P was upregulated earlier in CA3 than in CA1. This was associated with upregulation of SphK1 in both regions; however, SphK2 was downregulated quickly in CA3. S1P lyase was also downregulated in CA3, but not in CA1. Spinster 2, the S1P exporter, was upregulated early in both regions, but was quickly downregulated in CA3. Together, these effects explain the variable levels of S1P in the CA1 and CA3 areas and indicate that S1P levels play a role in the preferential resistance of the CA3 subregion to tGCI-induced ischemia. FTY720 did not improve neuronal survival in the CA1 subregion, indicating that these effects were due to intracellular S1P accumulation. In conclusion, the findings suggest that intracellular S1P levels affect neuronal cell fate following tGCI.

  68. High glucose stimulates expression of aldosterone synthase (CYP11B2) and secretion of aldosterone in human adrenal cells. 国際誌 査読有り

    Hiroki Shimada, Naotaka Kogure, Erika Noro, Masataka Kudo, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Makoto Kobayashi, Dai Suzuki, Rehana Parvin, Takako Saito-Ito, Akira Uruno, Akiko Saito-Hakoda, William E Rainey, Sadayoshi Ito, Atsushi Yokoyama, Akira Sugawara

    FEBS open bio 7 (9) 1410-1421 2017年9月

    出版者・発行元:WILEY

    DOI: 10.1002/2211-5463.12277  

    ISSN:2211-5463

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    Aldosterone synthase is the key rate-limiting enzyme in adrenal aldosterone production, and induction of its gene (CYP11B2) results in the progression of hypertension. As hypertension is a frequent complication among patients with diabetes, we set out to elucidate the link between diabetes mellitus and hypertension. We examined the effects of high glucose on CYP11B2 expression and aldosterone production using human adrenal H295R cells and a stable H295R cell line expressing a CYP11B2 5'-flanking region/luciferase cDNA chimeric construct. d-glucose (d-glu), but not its enantiomer l-glucose, dose dependently induced CYP11B2 transcription and mRNA expression. A high concentration (450 mg·dL-1) of d-glu time dependently induced CYP11B2 transcription and mRNA expression. Moreover, high glucose stimulated secretion of aldosterone into the media. Transient transfection studies using deletion mutants/nerve growth factor-induced clone B (NGFIB) response element 1 (NBRE-1) point mutant of CYP11B2 5'-flanking region revealed that the NBRE-1 element, known to be activated by transcription factors NGFIB and NURR1, was responsible for the high glucose-mediated effect. High glucose also induced the mRNA expression of these transcription factors, especially that of NURR1, but NURR1 knockdown using its siRNA did not affect high glucose-induced CYP11B2 mRNA expression. Taken together, it is speculated that high glucose may induce CYP11B2 transcription via the NBRE-1 element in its 5'-flanking region, resulting in the increase in aldosterone production although high glucose-induced NURR1 is not directly involved in the effect. Additionally, glucose metabolism and calcium channels were found to be involved in the high glucose effect. Our observations suggest one possible explanation for the high incidence of hypertension in patients with diabetes.

  69. The novel Nrf2 inducer TFM-735 ameliorates experimental autoimmune encephalomyelitis in mice. 国際誌 査読有り

    Chika Higashi, Atsuko Kawaji, Naoto Tsuda, Makiko Hayashi, Ryota Saito, Yoko Yagishita, Takafumi Suzuki, Akira Uruno, Masaki Nakamura, Kazunari Nakao, Shoji Furusako, Masayuki Yamamoto

    European journal of pharmacology 802 76-84 2017年5月5日

    出版者・発行元:ELSEVIER SCIENCE BV

    DOI: 10.1016/j.ejphar.2017.02.044  

    ISSN:0014-2999

    eISSN:1879-0712

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    The transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of cellular defense mechanisms against oxidative stress. Multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system, is characterized by progressive demyelination and neurodegeneration induced by inflammation and oxidative stress. The induction of Nrf2 signaling has been shown to inhibit disease development and progression in the experimental autoimmune encephalomyelitis (EAE) model of MS in mice. In the present study, we performed a high-throughput screening assay using a chimeric construct of the N-terminal portion of Nrf2 fused to LacZ. Using this approach, we identified the novel Nrf2 inducer TFM-735. Using human primary cell profiling systems, we found that TFM-735 inhibited T cell proliferation and exerted immuno-modulatory effects by inhibiting the production of IL-6 and IL-17. TFM-735 also inhibited IL-17 secretion from human peripheral blood mononuclear cells stimulated with anti-CD3 and anti-CD28. In EAE mice treated with TFM-735, the expression of the Nrf2 target gene Nqo1 increased in the brain and spleen, disease severity was ameliorated, and plasma IL-17 levels decreased. Furthermore, TFM-735 inhibited luciferase activity in Wim-6 transgenic EAE mice expressing the human interleukin 6-luciferase (hIL6-BAC-Luc) reporter. Therefore, these findings indicate that TFM-735 is a potent Nrf2 inducer that inhibits inflammatory cytokine production and disease progression in mice with EAE and that TFM-735 is a promising therapeutic agent for MS.

  70. Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress. 国際誌 査読有り

    Yoko Yagishita, Akira Uruno, Toshiaki Fukutomi, Ritsumi Saito, Daisuke Saigusa, Jingbo Pi, Akiyoshi Fukamizu, Fumihiro Sugiyama, Satoru Takahashi, Masayuki Yamamoto

    Cell reports 18 (8) 2030-2044 2017年2月21日

    出版者・発行元:CELL PRESS

    DOI: 10.1016/j.celrep.2017.01.064  

    ISSN:2211-1247

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    The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic β cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast, Trsp-KO mice (TrspIns1KO) expressing Cre specifically in pancreatic β cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.

  71. Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism 査読有り

    Akira Uruno, Yoko Yagishita, Fumiki Katsuoka, Yasuo Kitajima, Aki Nunomiya, Ryoichi Nagatomi, Jingbo Pi, Shyam S. Biswal, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY 36 (11) 1655-1672 2016年6月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/MCB.01095-15  

    ISSN:0270-7306

    eISSN:1098-5549

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    Nrf2 (NF-E2-related factor 2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic beta cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nrf2 in their SkM and then examined Nrf2 target gene expression in that tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated and the levels of the glycogen branching enzyme (Gbe1) and muscle-type PhK alpha subunit (Phka1) mRNAs, along with those of the glycogen branching enzyme (GBE) and the phosphorylase b kinase alpha subunit (PhK alpha) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2 inducers promoted Gbe1 and Phka1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 and Phka1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2 induction in SkM increases GBE and PhK alpha expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Our results also indicate that Nrf2 differentially regulates glycogen metabolism in SkM and the liver.

  72. Effects of RXR Agonists on Cell Proliferation/Apoptosis and ACTH Secretion/Pomc Expression 査読有り

    Akiko Saito-Hakoda, Akira Uruno, Atsushi Yokoyama, Kyoko Shimizu, Rehana Parvin, Masataka Kudo, Takako Saito-Ito, Ikuko Sato, Naotaka Kogure, Dai Suzuki, Hiroki Shimada, Takeo Yoshikawa, Ikuma Fujiwara, Hiroyuki Kagechika, Yasumasa Iwasaki, Shigeo Kure, Sadayoshi Ito, Akira Sugawara

    PLOS ONE 10 (12) 2015年12月

    出版者・発行元:PUBLIC LIBRARY SCIENCE

    DOI: 10.1371/journal.pone.0141960  

    ISSN:1932-6203

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    Various retinoid X receptor (RXR) agonists have recently been developed, and some of them have shown anti-tumor effects both in vivo and in vitro. However, there has been no report showing the effects of RXR agonists on Cushing's disease, which is caused by excessive ACTH secretion in a corticotroph tumor of the pituitary gland. Therefore, we examined the effects of synthetic RXR pan-agonists HX630 and PA024 on the proliferation, apoptosis, ACTH secretion, and pro-opiomelanocortin (Pomc) gene expression of murine pituitary corticotroph tumor AtT20 cells. We demonstrated that both RXR agonists induced apoptosis dose-dependently in AtT20 cells, and inhibited their proliferation at their higher doses. Microarray analysis identified a significant gene network associated with caspase 3 induced by high dose HX630. On the other hand, HX630, but not PA024, inhibited Pomc transcription, Pomc mRNA expression, and ACTH secretion dose-dependently. Furthermore, we provide new evidence that HX630 negatively regulates the Pomc promoter activity at the transcriptional level due to the suppression of the transcription factor Nur77 and Nurr1 mRNA expression and the reduction of Nur77/Nurr1 heterodimer recruiting to the Pomc promoter region. We also demonstrated that the HX630-mediated suppression of the Pomc gene expression was exerted via RXR alpha. Furthermore, HX630 inhibited tumor growth and decreased Pomc mRNA expression in corticotroph tumor cells in female nude mice in vivo. Thus, these results indicate that RXR agonists, especially HX630, could be a new therapeutic candidate for Cushing's disease.

  73. ベラプロストは腎不全時腎機能改善と尿毒症物質減少をもたらす

    大庭 悠貴, 松山 由香, 鈴木 康介, 宇留野 晃, 秋山 泰利, 三島 英換, 島 久登, 菊地 晃一, 伊藤 貞嘉, 阿部 高明

    日本腎臓学会誌 57 (3) 487-487 2015年4月

    出版者・発行元:(一社)日本腎臓学会

    ISSN:0385-2385

    eISSN:1884-0728

  74. レチノイドX受容体アゴニストPA024が副腎CYP11B2発現・アルドステロン分泌に及ぼす影響の検討

    鈴木 大, 箱田 明子, 清水 恭子, パービン・レハナ, 宇留野 晃, 青木 聡, 佐藤 郁子, 島田 洋樹, 小暮 直敬, 藤原 幾磨, 伊藤 貞嘉, 影近 弘之, 横山 敦, 菅原 明

    日本内分泌学会雑誌 91 (1) 400-400 2015年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  75. Pomc遺伝子のグルココルチコイドによるネガティブ・レギュレーションにおけるNeuroD1の関与

    パービン・レハナ, 箱田 明子, 清水 恭子, 宇留野 晃, 鈴木 大, 青木 聡, 島田 洋樹, 小暮 直敬, 工藤 正孝, 岩崎 泰正, 伊藤 貞嘉, 横山 敦, 菅原 明

    日本内分泌学会雑誌 91 (1) 266-266 2015年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  76. 種々のレチノイドX受容体アゴニストは、AtT20細胞の増殖・アポトーシス・Pomc発現・ACTH分泌に異なる影響を及ぼす

    箱田 明子, 宇留野 晃, 清水 恭子, パービン・レハナ, 横山 敦, 吉川 雄朗, 工藤 正孝, 影近 弘之, 岩崎 泰正, 伊藤 貞嘉, 菅原 明

    日本内分泌学会雑誌 91 (1) 269-269 2015年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  77. NRF2-Mediated Gene Regulation and Glucose Homeostasis 査読有り

    Yoko Yagishita, Akira Uruno, Masayuki Yamamoto

    Molecular Nutrition and Diabetes: A Volume in the Molecular Nutrition Series 331-348 2015年

    出版者・発行元:Elsevier Inc.

    DOI: 10.1016/B978-0-12-801585-8.00027-0  

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    Transcription factor nuclear factor-erythroid-related factor 2 (NRF2) plays a central role in cytoprotection from various environmental stresses. In unstressed conditions, kelch-like ECH-associated protein 1 suppresses NRF2 activity through leading to degradation in the ubiquitin-proteasome pathway. Upon exposure to the environmental stresses, kelch-like ECH-associated protein 1 cysteine residues are modified and its activity is abrogated. Thereafter, NRF2 escapes from the protein degradation and accumulates in the nucleus, inducing target gene expressions. This system exerts not only cytoprotective effects against stresses but also cellular metabolic regulations. Several NRF2-inducing compounds in plants show antidiabetic effects in human and animal diabetic models, and derivatives of these compounds display strong NRF2 induction and antidiabetic effects, indicating that NRF2 is a promising target of drug development.

  78. The Keap1-Nrf2 system and diabetes mellitus 査読有り

    Akira Uruno, Yoko Yagishita, Masayuki Yamamoto

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 566 76-84 2015年1月

    出版者・発行元:ELSEVIER SCIENCE INC

    DOI: 10.1016/j.abb.2014.12.012  

    ISSN:0003-9861

    eISSN:1096-0384

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    Nrf2 (NF-E2-related factor 2) plays a key role in the protection of vertebrates against environmental stress by contributing to the inducible expression of detoxification and antioxidant enzymes. Keap1 (Kelch-like ECH-associated protein 1) is a sensor for oxidative and electrophilic stresses. Keap1 also acts as an E3 ubiquitin ligase substrate-recognition subunit that specifically targets Nrf2. Keap1 causes Nrf2 to be degraded through the ubiquitin-proteasome pathway and thus ensures that Nrf2 is constitutively suppressed under unstressed conditions. Upon exposure to oxidative or electrophilic stress, Keap1 loses its ability to ubiquitinate Nrf2. Many lines of evidence have recently clarified that the Keap1-Nrf2 system also plays critical roles in the maintenance of cellular homeostasis. One of the most salient examples is the contribution of Keap1-Nrf2 to metabolic and energy-balance regulation. In particular, how the Keap1-Nrf2 system protects the body against diabetes mellitus and how perturbations in this system provoke the disease condition are now under intense investigation. This review will summarize the recent progress made in this area. (C) 2014 Elsevier Inc. All rights reserved.

  79. Nrf2 induces fibroblast growth factor 21 in diabetic mice 査読有り

    Yuki Furusawa, Akira Uruno, Yoko Yagishita, Chika Higashi, Masayuki Yamamoto

    GENES TO CELLS 19 (12) 864-878 2014年12月

    出版者・発行元:WILEY-BLACKWELL

    DOI: 10.1111/gtc.12186  

    ISSN:1356-9597

    eISSN:1365-2443

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    Transcription factor Nrf2 (nuclear factor E2-related factor 2) is a master regulator of cellular defense system against oxidative and electrophilic stresses and is negatively regulated by an adaptor protein Keap1 (Kelch-like ECH-associated protein 1). Nrf2 also plays a pivotal role in metabolic homeostasis, such as lipid metabolism and energy expenditure as well as redox homeostasis. FGF21 (fibroblast growth factor 21) is known as a key mediator of glucose and lipid metabolism. Here, we found that Nrf2 is involved in FGF21 regulation in diabetic model mice. Nrf2 induction by genetic knockdown of Keap1 increased plasma FGF21 level and hepatic Fgf21 expression in diabetic db/db mice and high-calorie-diet-induced obesity model mice. Administration of CDDO-Im (oleanolic triterpenoid 1-[2-cyano-3,12-dioxooleane-1, 9(11)-dien-28-oyl] imidazole), a potent Nrf2 inducer, up-regulated plasma FGF21 level and hepatic Fgf21 expression in db/db mice, whereas CDDO-Im did not induce FGF21 in db/db mice with Nrf2 knockout background. Furthermore, in Keap1-knockdown db/db mice, Nrf2 enhanced expression of glucose-and lipid-metabolism-related genes in adipose tissues, which improved plasma lipid profiles. These results show that Nrf2 positively regulates FGF21 expression in diabetic mice. We propose that FGF21 is a potential efficacy biomarker that mediates metabolic regulation by the Keap1-Nrf2 system.

  80. Retinoic acid receptor-a up-regulates proopiomelanocortin gene expression in AtT20 corticotroph cells 査読有り

    Akira Uruno, Akiko Saito-Hakoda, Atsushi Yokoyama, Naotaka Kogure, Ken Matsuda, Rehana Parvin, Kyoko Shimizu, Ikuko Sato, Masataka Kudo, Takeo Yoshikawa, Hiroyuki Kagechika, Yasumasa Iwasaki, Sadayoshi Ito, Akira Sugawara

    ENDOCRINE JOURNAL 61 (11) 1105-1114 2014年11月

    出版者・発行元:JAPAN ENDOCRINE SOC

    DOI: 10.1507/endocrj.EJ14-0115  

    ISSN:0918-8959

    eISSN:1348-4540

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    Cushing's disease is a disorder caused by excessive ACTH secretion from a corticotroph tumor of the pituitary gland. Although its standard therapy is a transsphenoidal surgery, innovation of novel medical treatments for the disease is urgently necessary. Retinoic acid (RA) has been reported to suppress adrenocorticotropic hormone (ACTH) secretion in Cushing's disease. However, the role of RA receptor (RAR) in proopiomelanocortin (Pomc) gene expression remains uncertain. We here examined the involvement of RARa in Pomc regulation using AtT20 corticotroph cells. Surprisingly, a synthetic RARa agonist Am80 increased Pomc mRNA expression, CRH-induced ACTH secretion, and Pomc promoter activity. Small interfering RNA-mediated RARa-knockdown suppressed both basal and Am80-induced Pomc promoter activity. RARa-overexpression dose-dependently increased Porric promoter activity. Pomc promoter mutation analysis revealed that both Tpit and NeuroD1 binding elements were responsible for the Am80-mediated effect. Am80 increased Tpit expression while RAR antagonist LE540 suppressed the increase. Tpit-overexpression increased Pomc promoter activity. Mammalian two-hybrid assay revealed that Am80 induced NeuroD1-RAR alpha interaction. NeuroDl-overexpression enhanced the Am80-induced Pomc promoter activity, which was suppressed by NeuroD1 truncated mutant-overexpression. RARa thus positively regulates ACTH secretion/Pomc gene expression through interaction with NeuroD1 and Tpit expression increase. The present observation will be useful for the future development of the RA/retinoid-derived therapeutics of the disease.

  81. 高血糖刺激による副腎アルドステロン合成酵素遺伝子(CYP11B2)発現亢進の分子機構

    小暮 直敬, 菅原 香織, 松田 謙, 宇留野 晃, 佐藤 郁子, 清水 恭子, レハナ・パービン, 島田 洋樹, 吉川 雄朗, 工藤 正孝, 箱田 明子, 伊藤 亮, 横山 敦, 伊藤 貞嘉, 菅原 明

    日本高血圧学会総会プログラム・抄録集 37回 333-333 2014年10月

    出版者・発行元:(NPO)日本高血圧学会

  82. アルドステロン合成酵素遺伝子(CYP11B2)をターゲットとした新規創薬

    伊藤 亮, 島田 洋樹, 松田 謙, 宇留野 晃, 横山 敦, 菅原 明

    日本高血圧学会総会プログラム・抄録集 37回 393-393 2014年10月

    出版者・発行元:(NPO)日本高血圧学会

  83. 高血糖刺激は副腎11β-水酸化酵素遺伝子(CYP11B1)の発現を誘導する

    菅原 香織, 小暮 直敬, 松田 謙, 宇留野 晃, 佐藤 郁子, 清水 恭子, レハナ・パービン, 島田 洋樹, 吉川 雄朗, 工藤 正孝, 箱田 明子, 伊藤 亮, 横山 敦, 伊藤 貞嘉, 菅原 明

    日本高血圧学会総会プログラム・抄録集 37回 399-399 2014年10月

    出版者・発行元:(NPO)日本高血圧学会

  84. Transcription Factor Nrf1 Negatively Regulates the Cystine/Glutamate Transporter and Lipid-Metabolizing Enzymes 査読有り

    Tadayuki Tsujita, Vivian Peirce, Liam Baird, Yuka Matsuyama, Misaki Takaku, Shawn V. Walsh, Julian L. Griffin, Akira Uruno, Masayuki Yamamoto, John D. Hayes

    MOLECULAR AND CELLULAR BIOLOGY 34 (20) 3800-3816 2014年10月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/MCB.00110-14  

    ISSN:0270-7306

    eISSN:1098-5549

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    Liver-specific Nrf1 (NF-E2-p45-related factor 1) knockout mice develop nonalcoholic steatohepatitis. To identify postnatal mechanisms responsible for this phenotype, we generated an inducible liver-specific Nrf1 knockout mouse line using animals harboring an Nrf1(flox) allele and a rat CYP1A1-Cre transgene (Nrf1(flox)/(flox)::CYP1A1-Cre mice). Administration of 3-methylcholanthrene (3-MC) to these mice (Nrf1(flox/flox)::CYP1A1-Cre+3MC mice) resulted in loss of hepatic Nrf1 expression. The livers of mice lacking Nrf1 accumulated lipid, and the hepatic fatty acid (FA) composition in such animals differed significantly from that in the Nrf1(flox/flox)::CYP1A1-Cre control. This change was provoked by upregulation of several FA metabolism genes. Unexpectedly, we also found that the level of glutathione was increased dramatically in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice. While expression of glutathione biosynthetic enzymes was unchanged, xCT, a component of the cystine/glutamate antiporter system xc-, was significantly upregulated in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice, suggesting that Nrf1 normally suppresses xCT. Thus, stress-inducible expression of xCT is a two-step process: under homeostatic conditions, Nrf1 effectively suppresses nonspecific transactivation of xCT, but when cells encounter severe oxidative/electrophilic stress, Nrf1 is displaced from an antioxidant response element (ARE) in the gene promoter while Nrf2 is recruited to the ARE. Thus, Nrf1 controls both the FA and the cystine/cysteine content of hepatocytes by participating in an elaborate regulatory network.

  85. Transcription factor NF-E2-related factor 1 impairs glucose metabolism in mice 査読有り

    Yosuke Hirotsu, Chika Higashi, Toshiaki Fukutomi, Fumiki Katsuoka, Tadayuki Tsujita, Yoko Yagishita, Yuka Matsuyama, Hozumi Motohashi, Akira Uruno, Masayuki Yamamoto

    GENES TO CELLS 19 (8) 650-665 2014年8月

    出版者・発行元:WILEY-BLACKWELL

    DOI: 10.1111/gtc.12165  

    ISSN:1356-9597

    eISSN:1365-2443

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    Nrf1 (NF-E2-related factor 1) is a basic region leucine zipper-type transcription factor belonging to the CNC (cap-'n'-collar) family. Major pathophysiological contribution of Nrf1 remains unclear. As single nucleotide polymorphism rs3764400 in 50-flanking region of NRF1 gene appears to associate with obesity, in this study, we focused on the Nrf1 function on metabolism. We found that the risk C allele of rs3764400 increased NRF1 gene transcriptional activity compared with the T allele in hepatoma cell lines. Therefore, we newly established Nrf1 transgenic (Nrf1-Tg) mouse lines and examined roles that Nrf1 plays on the obesity and metabolism. Unexpectedly, Nrf1 over-expression repressed bodyweight gain in both lean and diet-induced obesity mice. Of note, Nrf1-Tg mice showed rise in blood glucose levels; Nrf1 strongly reduced glucose infusion rate in euglycemic-hyperinsulinemic clamp test and increased blood glucose levels in insulin tolerance test, indicating that Nrf1 induces insulin resistance in mice. Nrf1 repressed insulin-regulated glycolysis-related gene expression and gave rise to loss of glucose-6-phosphate and fructose-6-phosphate contents in liver. Consistently, Nrf1 heterozygote improved impaired glucose regulations in diet-induced obesity model. These results showed that Nrf1 contributes to metabolic regulation, which gain-of-function develops diabetes mellitus in mice.

  86. Isocitrate dehydrogenase mutation is frequently observed in giant cell tumor of bone 査読有り

    Mika Kato Kaneko, Xing Liu, Hiroharu Oki, Satoshi Ogasawara, Takuro Nakamura, Noriko Saidoh, Yuta Tsujimoto, Yuka Matsuyama, Akira Uruno, Masato Sugawara, Takashi Tsuchiya, Mitsunori Yamakawa, Masayuki Yamamoto, Michiaki Takagi, Yukinari Kato

    CANCER SCIENCE 105 (6) 744-748 2014年6月

    出版者・発行元:WILEY

    DOI: 10.1111/cas.12413  

    ISSN:1349-7006

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    Giant cell tumors of bone (GCTB) are benign and locally destructive tumors that include osteoclast-type multinuclear giant cells. No available treatment is definitively effective in curing GCTB, especially in surgically unresectable cases. Isocitrate dehydrogenase (IDH) mutations have been reported not only in gliomas and acute myeloid leukemias, but also in cartilaginous tumors and osteosarcomas. However, IDH mutations in GCTB have not been investigated. The IDH mutations are remarkably specific to arginine 132 (R132) in IDH1 and arginine 172 (R172) or arginine 140 (R140) in IDH2; IDH1/2 mutations are known to convert -ketoglutarate to oncometabolite R(-)-2-hydroxyglutarate. We recently reported that the most frequent IDH mutation in osteosarcomas is IDH2-R172S, which was detected by MsMab-1, a multispecific anti-IDH1/2 mAb. Herein, we newly report the IDH mutations in GCTB, which were stained by MsMab-1 in immunohistochemistry. DNA direct sequencing and subcloning identified IDH mutations of GCTB as IDH2-R172S (16 of 20; 80%). This is the first report to describe IDH mutations in GCTB, and MsMab-1 can be anticipated for use in immunohistochemical determination of IDH1/2 mutation-bearing GCTB.

  87. Nrf2 Positively Regulates FGF21 in Diabetic Mice: A Potential Efficacy Biomarker of Nrf2 Induction 査読有り

    Yuki Furusawa, Akira Uruno, Yoko Yagishita, Masayuki Yamamoto

    DIABETES 63 A485-A485 2014年6月

    出版者・発行元:AMER DIABETES ASSOC

    ISSN:0012-1797

    eISSN:1939-327X

  88. Generation of a Stable H295R Cell Line Expressing 11beta-Hydroxylase Gene Promoter and the Effect of High-Glucose on Its Expression 査読有り

    Kaori Sugawara, Ken Matsuda, Naotaka Kogure, Akira Uruno, Ikuko Sato, Kyoko Shimizu, Rehana Parvin, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Ryo Ito, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

    ENDOCRINE REVIEWS 35 (3) 2014年6月

    出版者・発行元:ENDOCRINE SOC

    ISSN:0163-769X

    eISSN:1945-7189

  89. Effects of RXR Agonist HX630 on Pomc Promoter Activity and in Vivo Tumor Formation 査読有り

    Akiko Saito-Hakoda, Akira Uruno, Kyoko Shimizu, Naotaka Kogure, Rehana Parvin, Ikuko Sato, Ikuma Fujiwara, Hiroyuki Kagechika, Yasumasa Iwasaki, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

    ENDOCRINE REVIEWS 35 (3) 2014年6月

    出版者・発行元:ENDOCRINE SOC

    ISSN:0163-769X

    eISSN:1945-7189

  90. The Innovation of a Novel Drug Screening System for the Inhibitors of Aldosterone Synthase Gene (CYP11B2) Expression 査読有り

    Ryo Ito, Ken Matsuda, Akira Uruno, Atsushi Yokoyama, Akira Sugawara

    ENDOCRINE REVIEWS 35 (3) 2014年6月

    出版者・発行元:ENDOCRINE SOC

    ISSN:0163-769X

    eISSN:1945-7189

  91. High-Glucose Stimulates Aldosterone Synthase Gene (CYP11B2) Expression Via the Induction of T-Type Calcium Channels in H295R Cells 査読有り

    Naotaka Kogure, Ken Matsuda, Akira Uruno, Kaori Sugawara, Ikuko Sato, Kyoko Shimizu, Rehana Parvin, Takeo Yoshikawa, Masataka Kudo, Akiko Saito-Hakoda, Ryo Ito, Atsushi Yokoyama, Sadayoshi Ito, Akira Sugawara

    ENDOCRINE REVIEWS 35 (3) 2014年6月

    出版者・発行元:ENDOCRINE SOC

    ISSN:0163-769X

    eISSN:1945-7189

  92. HPA系の基礎研究Update 高血糖刺激による副腎11β-水酸化酵素遺伝子(CYP11B1)の発現誘導

    菅原 香織, 小暮 直敬, 宇留野 晃, 松田 謙, 佐藤 郁子, 清水 恭子, 工藤 正孝, 箱田 明子, 島田 洋樹, 伊藤 亮, 横山 敦, 伊藤 貞嘉, 菅原 明

    ACTH RELATED PEPTIDES 25 20-21 2014年3月

    出版者・発行元:間脳・下垂体・副腎系研究会

    ISSN:1340-4512

  93. レチノイドX受容体アゴニストHX630によるPomc遺伝子転写抑制機構の解明ならびにin vivo腫瘍抑制効果の検討

    箱田 明子, 宇留野 晃, 清水 恭子, 小暮 直敬, 佐藤 郁子, 藤原 幾磨, 影近 弘之, 岩崎 泰正, 横山 敦, 伊藤 貞嘉, 菅原 明

    ACTH RELATED PEPTIDES 25 28-29 2014年3月

    出版者・発行元:間脳・下垂体・副腎系研究会

    ISSN:1340-4512

  94. Angiotensin II receptor blockers differentially affect CYP11B2 expression in human adrenal H295R cells 査読有り

    Ken Matsuda, Akira Uruno, Naotaka Kogure, Kaori Sugawara, Hiroki Shimada, Masahiro Nezu, Takako Saito-Ito, Yuko Iki, Masataka Kudo, Kyoko Shimizu, Ikuko Sato, Takeo Yoshikawa, Fumitoshi Satoh, Ryo Ito, Atsushi Yokoyama, William E. Rainey, Akiko Saito-Hakoda, Sadayoshi Ito, Akira Sugawara

    MOLECULAR AND CELLULAR ENDOCRINOLOGY 383 (1-2) 60-68 2014年3月

    出版者・発行元:ELSEVIER IRELAND LTD

    DOI: 10.1016/j.mce.2013.12.004  

    ISSN:0303-7207

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    We generated a stable H295R cell line expressing aldosterone synthase gene (CYP11B2) promoter/luciferase chimeric reporter construct that is highly sensitive to angiotensin II (All) and potassium, and defined All receptor blocker (ARB) effects. In the presence of All, all ARBs suppressed All-induced CYP11B2 transcription. However, telmisartan alone increased CYP11B2 transcription in the absence of All. Telmisartan dose-dependently increased CYP11B2 transcription/mRNA expression and aldosterone secretion. Experiments using CYP11B2 promoter mutants indicated that the Ad5 element was responsible. Among transcription factors involved in the element, telmisartan significantly induced NGFIB/NURRI expression. KN-93, a CaMK inhibitor, abrogated the telmisartan-mediated increase of CYP11B2 transcription/mRNA expression and NURR1 mRNA expression, but not NGFIB mRNA expression. NURRI over-expression significantly augmented the telmisartan-mediated CYP11B2 transcription, while high-dose olmesartan did not affect it. Taken together, telmisartan may stimulate CYP11B2 transcription via NGFIB and the CaMK-mediated induction of NURR1 that activates the Ad5 element, independent of All type 1 receptor. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  95. Nrf2 Protects Pancreatic beta-Cells From Oxidative and Nitrosative Stress in Diabetic Model Mice 査読有り

    Yoko Yagishita, Toshiaki Fukutomi, Akira Sugawara, Hiroshi Kawamura, Tetsu Takahashi, Jingbo Pi, Akira Uruno, Masayuki Yamamoto

    DIABETES 63 (2) 605-618 2014年2月

    出版者・発行元:AMER DIABETES ASSOC

    DOI: 10.2337/db13-0909  

    ISSN:0012-1797

    eISSN:1939-327X

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    Transcription factor Nrf2 (NF-E2-related factor 2) regulates wide-ranging cytoprotective genes in response to environmental stress. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for Cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. The Keap1-Nrf2 system plays important roles in the oxidative stress response and metabolism. However, the roles Nrf2 plays in prevention of pancreatic -cell damage remain elusive. To demonstrate the roles of Nrf2 in pancreatic -cells, we used four genetically engineered mouse models: 1) -cell-specific Keap1-conditional knockout mice, 2) -cell-specific Nos2 transgenic mice, 3) conventional Nrf2-heterozygous knockout mice, and 4) -cell-specific Nrf2-conditional knockout mice. We found that Nrf2 induction suppressed the oxidative DNA-adduct formation in pancreatic islets of iNOS-Tg mice and strongly restored insulin secretion from pancreatic -cells in the context of reactive species (RS) damage. Consistently, Nrf2 suppressed accumulation of intracellular RS in isolated islets and pancreatic -cell lines and also decreased nitrotyrosine levels. Nrf2 induced glutathione-related genes and reduced pancreatic -cell apoptosis mediated by nitric oxide. In contrast, Nrf2 depletion in Nrf2-heterozygous knockout and -cell-specific Nrf2-conditional knockout mice strongly aggravated pancreatic -cell damage. These results demonstrate that Nrf2 induction prevents RS damage in pancreatic -cells and that the Keap1-Nrf2 system is the crucial defense pathway for the physiological and pathological protection of pancreatic beta-cells.

  96. Is heparan sulfate in the glomerular basement membrane necessary for the etiology of diabetic nephropathy? 査読有り

    Saito-Hakoda A, Kogure N, Yoshikawa T, Shimizu K, Iki Y, Sato I, Kudo M, Uruno A, Matsuda K, Parvin R, Sugawara K, Yokoyama A, Ito S, Sugawara A

    J Biomol Res Ther 3 (e127) 2014年

    DOI: 10.4172/2167-7956.1000e127  

  97. Isocitrate dehydrogenase mutation is frequently observed in giant cell tumor of bone 査読有り

    Mika Kato Kaneko, Xing Liu, Hiroharu Oki, Satoshi Ogasawara, Takuro Nakamura, Noriko Saidoh, Yuta Tsujimoto, Yuka Matsuyama, Akira Uruno, Masato Sugawara, Takashi Tsuchiya, Mitsunori Yamakawa, Masayuki Yamamoto, Michiaki Takagi, Yukinari Kato

    Cancer Science 105 (6) 744-748 2014年

    出版者・発行元:Blackwell Publishing Ltd

    DOI: 10.1111/cas.12413  

    ISSN:1349-7006 1347-9032

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    Giant cell tumors of bone (GCTB) are benign and locally destructive tumors that include osteoclast-type multinuclear giant cells. No available treatment is definitively effective in curing GCTB, especially in surgically unresectable cases. Isocitrate dehydrogenase (IDH) mutations have been reported not only in gliomas and acute myeloid leukemias, but also in cartilaginous tumors and osteosarcomas. However, IDH mutations in GCTB have not been investigated. The IDH mutations are remarkably specific to arginine 132 (R132) in IDH1 and arginine 172 (R172) or arginine 140 (R140) in IDH2 IDH1/2 mutations are known to convert α-ketoglutarate to oncometabolite R(-)-2-hydroxyglutarate. We recently reported that the most frequent IDH mutation in osteosarcomas is IDH2-R172S, which was detected by MsMab-1, a multispecific anti-IDH1/2 mAb. Herein, we newly report the IDH mutations in GCTB, which were stained by MsMab-1 in immunohistochemistry. DNA direct sequencing and subcloning identified IDH mutations of GCTB as IDH2-R172S (16 of 20 80%). This is the first report to describe IDH mutations in GCTB, and MsMab-1 can be anticipated for use in immunohistochemical determination of IDH1/2 mutation-bearing GCTB. This is the first report to describe IDH mutations in giant cell tumor of bone (GCTB), and MsMab-1 can be anticipated for use in immunohistochemical determination of IDH1/2 mutation-bearing GCTB. © 2014 The Authors.

  98. ARB affects nicotine-induced gene expression profile in human coronary artery endothelial cells 査読有り

    Kudo M, Matsuda K, Sugawara K, Iki Y, Kogure N, Saito-Ito T, Shimizu K, Sato I, Yoshikawa T, Uruno A, Ito R, Yokoyama A, Saito-Hakoda A, Ito S, Sugawara A

    World J Hypertens 4 (1) 7-14 2014年

  99. The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus 査読有り

    Akira Uruno, Yuki Furusawa, Yoko Yagishita, Toshiaki Fukutomi, Hiroyuki Muramatsu, Takaaki Negishi, Akira Sugawara, Thomas W. Kensler, Masayuki Yamamoto

    MOLECULAR AND CELLULAR BIOLOGY 33 (15) 2996-3010 2013年8月

    出版者・発行元:AMER SOC MICROBIOLOGY

    DOI: 10.1128/MCB.00225-13  

    ISSN:0270-7306

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    Transcription factor Nrf2 (NF-E2-related factor 2) regulates a broad cytoprotective response to environmental stresses. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. Whereas the Keap1-Nrf2 system plays important roles in oxidative stress response and metabolism, the roles Nrf2 plays in the prevention of diabetes mellitus remain elusive. Here we show that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic knockdown (Keap1(flox/-)) markedly suppresses the onset of diabetes. When Keap1(flox/-) mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1(flox/-) also prevented high-calorie-diet-induced diabetes. Oral administration of the Nrf2 inducer CDDO-Im {oleanolic acid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole} also attenuated diabetes in db/db mice. Nrf2 induction altered antioxidant-, energy consumption-, and gluconeogenesis-related gene expression in metabolic tissues. Thus, the Keap1-Nrf2 system is a critical target for preventing the onset of diabetes mellitus.

  100. 高血糖刺激は副腎アルドステロン合成酵素の発現をT型Caチャネルの発現増加を介して誘導する

    小暮 直敬, 伊藤 貴子, 菅原 香織, 松田 謙, 壹岐 裕子, 佐藤 郁子, 皆川 敬治, 勝木 将人, 清水 恭子, 吉川 雄朗, 工藤 正孝, 宇留野 晃, 箱田 明子, 伊藤 貞嘉, 菅原 明

    日本内分泌学会雑誌 89 (1) 278-278 2013年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  101. 高血糖刺激はヒト副腎H295R細胞における11β-水酸化酵素遺伝子(CYP11B1)発現を誘導する

    菅原 香織, 伊藤 貴子, 小暮 直敬, 皆川 敬治, 壹岐 裕子, 勝木 将人, 宇留野 晃, 佐藤 郁子, 田中 智博, 太田 翔, 木谷 優介, 塚田 晃也, 大熊 崇生, 角田 亮, 清水 恭子, 工藤 正孝, 松田 謙, 箱田 明子, 伊藤 貞嘉, 菅原 明

    日本内分泌学会雑誌 89 (1) 278-278 2013年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  102. ニコチンのヒト冠動脈血管内皮細胞の遺伝子発現に及ぼす影響ならびにそれに対するARBの効果

    壹岐 裕子, 工藤 正孝, 伊藤 貴子, 菅原 香織, 松田 謙, 小暮 直敬, 皆川 敬治, 勝木 将人, 佐藤 郁子, 宇留野 晃, 清水 恭子, 吉川 雄朗, 箱田 明子, 伊藤 貞嘉, 菅原 明

    日本内分泌学会雑誌 89 (1) 313-313 2013年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  103. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma 査読有り

    Daisuke Inoue, Takashi Suzuki, Yoichiro Mitsuishi, Yasuhiro Miki, Satoshi Suzuki, Shunichi Sugawara, Mika Watanabe, Akira Sakurada, Chiaki Endo, Akira Uruno, Hironobu Sasano, Takayuki Nakagawa, Kennichi Satoh, Nobuyuki Tanaka, Hiroshi Kubo, Hozumi Motohashi, Masayuki Yamamoto

    CANCER SCIENCE 103 (4) 760-766 2012年4月

    出版者・発行元:WILEY-BLACKWELL

    DOI: 10.1111/j.1349-7006.2012.02216.x  

    ISSN:1347-9032

    eISSN:1349-7006

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    p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non-small-cell lung cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer-specific survival (P = 0.0003 for NRF2; P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer-specific survival (P &lt; 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. (Cancer Sci 2012; 103: 760766)

  104. Accumulation of p62/SQSTM1 is associated with poor prognosis in patients with lung adenocarcinoma 査読有り

    Daisuke Inoue, Takashi Suzuki, Yoichiro Mitsuishi, Yasuhiro Miki, Satoshi Suzuki, Shunichi Sugawara, Mika Watanabe, Akira Sakurada, Chiaki Endo, Akira Uruno, Hironobu Sasano, Takayuki Nakagawa, Kennichi Satoh, Nobuyuki Tanaka, Hiroshi Kubo, Hozumi Motohashi, Masayuki Yamamoto

    Cancer Science 103 (4) 760-766 2012年4月

    DOI: 10.1111/j.1349-7006.2012.02216.x  

    ISSN:1347-9032 1349-7006

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    p62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non-small-cell lung cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer-specific survival (P = 0.0003 for NRF2 P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer-specific survival (P &lt 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. © 2012 Japanese Cancer Association.

  105. 種々のレチノイドX受容体(RXR)アゴニストは、AtT20細胞の増殖・アポトーシス・POMC発現・ACTH分泌に異なる影響を及ぼす 査読有り

    箱田明子, 宇留野晃, 清水恭子, 伊藤貴子, 吉川雄朗, 藤原幾磨, 松田謙, 工藤正孝, 影近弘之, 岩崎泰正, 伊藤貞嘉, 菅原明

    ACTH RELATED PEPTIDES 23 15-16 2012年3月

  106. Effects of PPARγ agonists against vascular and renal dysfunction 査読有り

    Akira Sugawara, Akira Uruno, Ken Matsuda, Takako Saito-Ito, Tadao Funato, Akiko Saito-Hakoda, Masataka Kudo, Sadayoshi Ito

    Current Molecular Pharmacology 5 (2) 248-254 2012年

    出版者・発行元:Bentham Science Publishers B.V.

    DOI: 10.2174/1874467211205020248  

    ISSN:1874-4702 1874-4672

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    Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear hormone receptor, is activated by its agonists including anti-diabetic thiazolidinediones, and has recently been reported to exert beneficial effects in the vasculature independently of its anti-diabetic effects. We here discuss our recent findings on the beneficial pleiotropic effects of PPARγ agonists. PPARγ agonists have been shown to lower blood pressure in both animals and humans, which may possibly be mediated via the PPARγ agonist-mediated inhibition of the renin-angiotensin-aldosterone system (RAAS) including the suppression of angiotensin (Ang) II type 1 receptor expression/Ang II-mediated signaling pathways and Ang II-induced adrenal aldosterone synthesis/secretion. PPARγ agonists also inhibited the progression of atherosclerosis in both animals and humans. PPARγ agonist-mediated inhibition of the RAAS and the thromboxane A2 system as well as endothelial protection may possibly be involved in the inhibitory effects on blood pressure and atherosclerosis. Furthermore, PPARγ agonists were demonstrated to have reno-protective effects, especially in reducing proteinuria in diabetic nephropathy in both animals and humans. The reno-protective effects of PPARγ agonists were also observed in non-diabetic renal dysfunctions. The effects may possibly be mediated via the PPARγ agonist-mediated blood pressure lowering, endothelial protection, and vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPARγ agonists have recently received much attention. PPARγ agonists, may therefore, be useful and effective against lifestyle-related diseases. © 2012 Bentham Science Publishers.

  107. All-trans retinoic acid and a novel synthetic retinoid tamibarotene (Am80) differentially regulate CD38 expression in human leukemia HL-60 cells: possible involvement of protein kinase C-delta 査読有り

    Akira Uruno, Naoya Noguchi, Ken Matsuda, Koji Nata, Takeo Yoshikawa, Youichiro Chikamatsu, Hiroyuki Kagechika, Hideo Harigae, Sadayoshi Ito, Hiroshi Okamoto, Akira Sugawara

    JOURNAL OF LEUKOCYTE BIOLOGY 90 (2) 235-247 2011年8月

    出版者・発行元:FEDERATION AMER SOC EXP BIOL

    DOI: 10.1189/jlb.0109025  

    ISSN:0741-5400

    eISSN:1938-3673

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    ATRA and a synthetic RAR agonist tamibarotene (Am80) induce granulocytic differentiation of human acute leukemia HL-60 cells and have been used in antineoplastic therapy. ATRA induces CD38 antigen during HL-60 cell differentiation, which interacts with CD31 antigen on the vascular EC surface and may induce disadvantages in the therapy. We here examined the mechanisms of the ATRA-mediated CD38 induction and compared the difference between ATRA-and tamibarotene-mediated induction. Tamibarotene-induced HL-60 cell adhesion to ECs was 38% lower than ATRA, and NB4 cell adhesion to ECs by tamibarotene was equivalent to ATRA, which induced CD38 gene transcription biphasically in HL-60 cells, the early-phase induction via DR-RARE containing intron 1, and the delayed-phase induction via RARE lacking the 5&apos;-flanking region. In contrast to ATRA, tamibarotene induced only the early-phase induction, resulting in its lower CD38 induction than ATRA. A PKC delta inhibitor, rottlerin, and siRNA-mediated PKC delta knockdown suppressed the ATRA-induced CD38 promoter activity of the 5&apos;-flanking region, whereas a RAR antagonist, LE540, or RAR knockdown did not affect it. Cycloheximide and rottlerin suppressed the delayed-phase induction of CD38 expression by ATRA but did not affect the early-phase induction. Moreover, ATRA, but not tamibarotene, induced PKC delta expression without affecting its mRNA stability. The diminished effect of tamibarotene on CD38-mediated HL-60 cell adhesion to ECs compared with ATRA is likely a result of the lack of its delayed-phase induction of CD38 expression, which may be advantageous in antineoplastic therapy. J. Leukoc. Biol. 90: 235-247; 2011.

  108. The Keap1-Nrf2 system as an in vivo sensor for electrophiles 査読有り

    Akira Uruno, Hozumi Motohashi

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY 25 (2) 153-160 2011年8月

    出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI: 10.1016/j.niox.2011.02.007  

    ISSN:1089-8603

    eISSN:1089-8611

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    The Keap1-Nrf2 regulatory system plays a central role in cytoprotection from electrophilic and oxidative stress. In unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3-Keap1 ubiquitin E3 ligase complex and is degraded in the proteasome. Upon the exposure to electrophilic and oxidative stress, reactive cysteine residues in Keap1 are covalently modified, which abrogates the E3 ligase activity of the Cul3-Keap1 complex. Consequently Nrf2 is stabilized and induces the transcription of various cytoprotective genes. Structural analyses have revealed the overall structure of the Keap1 homodimer as well as structural features of the association between Keap1 and Nrf2, which has greatly enhanced our understanding of the molecular mechanisms involved in the regulation of the Keap1-Nrf2 system. Recently nitric oxide signaling has been shown to activate Nrf2, suggesting that Nrf2 is a mediator of the cytoprotective effect of nitric oxide. Analyses of Nip-null mice have revealed a critical contribution of Nrf2 to the protection from various diseases caused by electrophilic and oxidative stress. In contrast, constitutive activation of Nrf2 has been found in many cancers, resulting in resistance against chemotherapy and radiotherapy in cancer cells. Thus, Nrf2 is a promising target for drug development. The development of Nrf2 inducers and inhibitors is an important challenge for enhancing therapies for stress-induced diseases and cancers, respectively. (C) 2011 Elsevier Inc. All rights reserved.

  109. PPARγ Agonist Beyond Glucose Lowering Effect 査読有り

    Akira Sugawara, Akira Uruno, Masataka Kudo, Ken Matsuda, Chul Woo Yang, Sadayoshi Ito

    Korean Journal of Internal Medicine 26 (1) 19-24 2011年3月

    DOI: 10.3904/kjim.2011.26.1.19  

    ISSN:1226-3303 2005-6648

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    The nuclear hormone receptor PPARγ is activated by several agonists, including members of the thiazolidinedione group of insulin sensitizers. Pleiotropic beneficial effects of these agonists, independent of their blood glucose- lowering effects, have recently been demonstrated in the vasculature. PPARγ agonists have been shown to lower blood pressure in animals and humans, perhaps by suppressing the renin-angiotensin (Ang)-aldosterone system (RAAS), including the inhibition of Ang II type 1 receptor expression, Ang-II-mediated signaling pathways, and Ang-II-induced adrenal aldosterone synthesis/secretion. PPARγ agonists also inhibit the progression of atherosclerosis in animals and humans, possibly through a pathway involving the suppression of RAAS and the thromboxane A2 system, as well as the protection of endothelial function. Moreover, PPARγ-agonist-mediated renal protection, especially the reduction of albuminuria, has been observed in diabetic nephropathy, including animal models of the disease, and in non-diabetic renal dysfunction. The renal protective activities may reflect, at least in part, the ability of PPARγ agonists to lower blood pressure, protect endothelial function, and cause vasodilation of the glomerular efferent arterioles. Additionally, anti-neoplastic effects of PPARγ agonists have recently been described. Based on the multiple therapeutic actions of PPARγ agonists, they will no doubt lead to novel approaches in the treatment of lifestyle-related and other diseases.

  110. Peroxisome proliferator-activated receptor-gamma suppresses CYP11B2 expression and aldosterone production 査読有り

    Akira Uruno, Ken Matsuda, Naoya Noguchi, Takeo Yoshikawa, Masataka Kudo, Fumitoshi Satoh, William E. Rainey, Xiao-Gang Hui, Jun-ichi Akahira, Yasuhiro Nakamura, Hironobu Sasano, Hiroshi Okamoto, Sadayoshi Ito, Akira Sugawara

    JOURNAL OF MOLECULAR ENDOCRINOLOGY 46 (1) 37-49 2011年2月

    出版者・発行元:BIOSCIENTIFICA LTD

    DOI: 10.1677/JME-10-0088  

    ISSN:0952-5041

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    Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear receptor for the antidiabetic agent thiazolidinedione, which exerts various physiological activities, independent of lowering blood glucose. However, the role of PPAR gamma in aldosterone production has not been clarified. The objective of this study was to investigate the effect of PPAR gamma on aldosterone synthase gene (CYP11B2) expression and aldosterone production. Localization of PPAR gamma expression in normal adrenal cortex was determined by immunohistochemistry. Aldosterone production and CYP11B2 expression levels were determined using human adrenocortical carcinoma H295R cells. Pioglitazone suppressed angiotensin II-induced aldosterone secretion and CYP11B2 expression. PPAR gamma was expressed in zona glomerulosa in human normal adrenal gland. PPAR gamma overexpression enhanced pioglitazone-mediated CYP11B2 transrepression. The pioglitazone-mediated suppression of aldosterone secretion and CYP11B2 expression were canceled by PPARg L466A/E469A mutant. Pioglitazone also suppressed potassium-mediated CYP11B2 induction, but not N6-2&apos;-O-dibutyladenosine- 3&apos;,5&apos;-cyclic monophosphate stimulation. Rosiglitazone and GW1929 also suppressed CYP11B2 transactivation. Mutation analysis revealed that the Ad1/CRE element in CYP11B2 5&apos;-flanking region was responsible for the pioglitazone-mediated transrepression. Pioglitazone suppressed ionomycin and a truncated constitutively active form Ca(2+)/calmodulin-dependent kinase I (CaMKI)-mediated CYP11B2 transcriptional activation. A CaMK inhibitor KN-93 attenuated pioglitazone-mediated CYP11B2 transrepression. PPAR gamma suppresses CYP11B2 expression and aldosterone secretion.

  111. Upregulation of REG I alpha accelerates tumor progression in pancreatic cancer with diabetes 査読有り

    Lin Zhou, Ruifeng Zhang, Lishun Wang, Shaoming Shen, Hiroshi Okamoto, Akira Sugawara, Li Xia, Xiaoling Wang, Naoya Noguchi, Takeo Yoshikawa, Akira Uruno, Weiyan Yao, Yaozong Yuan

    INTERNATIONAL JOURNAL OF CANCER 127 (8) 1795-1803 2010年10月

    出版者・発行元:WILEY-BLACKWELL

    DOI: 10.1002/ijc.25188  

    ISSN:0020-7136

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    Diabetes is now generally accepted as a crucial event in the process of pancreatic cancer (PaC). However, molecular mechanisms underlying the relationship between diabetes and PaC are not fully understood. Regenerating gene (REG) I alpha is a growth factor affecting pancreatic islet beta cells, and it has been shown to be involved in the carcinogenesis in gastrointestinal tract. It is rational to speculate that REG I alpha plays a potential role in the pathogenesis of PaC with diabetes. The aim of this study was to evaluate the REG I alpha protein expression profile in PaC with and without diabetes, and define the contribution of REG I alpha on PaC development. We found that REG I alpha protein preferentially expressed in cancerous tissues of PaC patients with diabetes by Western blot. REG I alpha positive cancer cells in PaC with diabetes (n = 38) was significantly higher than that in subjects without diabetes (n = 42, p &lt; 0.05) by immunohistochemical analysis. Furthermore, we found that overexpression of REG I alpha protein in PaC cell lines resulted in accelerated cell proliferation and consequently tumor growth, both in vitro and in vivo. The findings suggest that REG I alpha may act as one of the tumor promoter and contribute to the aggressive nature of PaC, especially in the subpopulation with diabetes. This study would shed new insights for understanding the molecular mechanisms underlying the link between diabetes and PaC.

  112. Effects of PPAR gamma on hypertension, atherosclerosis, and chronic kidney disease 査読有り

    Akira Sugawara, Akira Uruno, Masataka Kudo, Ken Matsuda, Chul Woo Yang, Sadayoshi Ito

    ENDOCRINE JOURNAL 57 (10) 847-852 2010年10月

    出版者・発行元:JAPAN ENDOCRINE SOC

    DOI: 10.1507/endocrj.K10E-281  

    ISSN:0918-8959

    eISSN:1348-4540

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    Peroxisome proliferator-activated receptor (PPAR)gamma is a nuclear hormone receptor that is trans-activated by its ligands including insulin-sensitizing thiazolidinediones. PPAR gamma has recently been reported to demonstrate pleiotropic beneficial effects in the vasculatures, independent of its blood glucose-lowering effects. Firstly, PPAR gamma ligands have been shown to lower blood pressure in both animals and human. The effect may possibly be mediated via the PPAR gamma-mediated inhibition of the angiotensin (Ang) II type I receptor expression as well as Ang II-mediated signaling pathways, which may result in the suppression of the renin-angiotensin system (RAS). Secondly, the progression of atherosclerosis was also prevented by PPAR gamma ligands in both animals and human. In addition to the PPAR gamma-mediated suppression of the RAS and the thromboxane A(2) system, protective effects of PPAR gamma ligands on endothelial function may also be involved. Thirdly, reno-protective effects of PPAR gamma ligands, especially on reducing urinary albumin, have been observed in both animals and human not only in diabetic nephropathy but also in non-diabetic renal diseases. The reno-protective effects may be mediated, at least in part, via the PPAR gamma ligand-induced blood pressure-lowering effects, protective effects on endothelial function, and vasodilating effects on the glomerular efferent arterioles. Additionally, anti-cancer effects of PPAR gamma ligands have recently been reported. Taken together, usefulness and effectiveness of PPAR gamma ligands on lifestyle related diseases will be increasingly appreciated.

  113. Role of Heparan Sulfate in Glucose-Induced Insulin Secretion in MIN6 Cells 査読有り

    Takeo Yoshikawa, Shiori Takayanagi, Naoya Noguchi, Akira Uruno, Hiroshi Okamoto, Akira Sugawara, Kazuhiko Yanai

    DIABETES 59 A456-A456 2010年6月

    出版者・発行元:AMER DIABETES ASSOC

    ISSN:0012-1797

  114. Novel effects of beraprost sodium on vasculatures 査読有り

    A. Sugawara, M. Kudo, A. Saito, K. Matsuda, A. Uruno, S. Ito

    INTERNATIONAL ANGIOLOGY 29 (2) 28-32 2010年4月

    出版者・発行元:EDIZIONI MINERVA MEDICA

    ISSN:0392-9590

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    Beraprost sodium (BPS) is a stable orally active prostacyclin analogue with vasodilatory and anti-platelet effects, and has been widely used as therapeutics for pulmonary artery hypertension and chronic arterial obstruction. In order to elucidate its effects on endothelium, we first examined the short-term effects of BPS on nitric oxide (NO) production and endothelial NO synthase (eNOS) activation using bovine aortic endothelial cells. Short-term treatment of BPS induced NO production as well as eNOS phosphorylation at Ser-1179 mediated via cAMP/protein kinase A (PKA) pathway. The effects of BPS on capillary-like tube formation were next determined using human umbilical vein ECs (HUVECs)/normal human dermal fibroblasts co-culture system. BPS was observed to induce capillary-like tube formation mediated via cAMP/PKA pathway, but not via NO generation. Finally, we performed DNA microarray analyses using RNA extracted from BPS treated HUVECs. Interestingly, BPS up-regulated several genes involved in angiogenesis, anti-atherosclerosis, and endothelial function, while down-regulated several genes involved in atherosclerosis. Our data therefore indicate that BPS may be useful not only for patients with pulmonary artery hypertension and chronic arterial obstruction, but also for general atherosclerotic patients complicated with endothelial dysfunction. Further studies are needed to clarify molecular mechanisms of these BPS effects including the involvement of peroxisome proliferator-activated receptor-delta. [Int Aniol 2010;29(Suppl. 1 to No. 1):28-32]

  115. Role of retinoic acid receptor on ACTH secretion and POMC gene expression in AtT20 corticotroph cells 査読有り

    Akira Uruno, Akira Sugawara, Ken Matsuda, Yasumasa Iwasaki, Akiko Saito, Masataka Kudo, Sadayoshi Ito

    ENDOCRINE JOURNAL 57 S328-S328 2010年3月

    出版者・発行元:JAPAN ENDOCRINE SOC

    ISSN:0918-8959

  116. Negative regulation of CYP11B2 expression and aldosterone production in adrenocortical carcinoma H295R cells by PPAR gamma 査読有り

    Akira Uruno, Ken Matsuda, Naoya Noguchi, Takeo Yoshikawa, Masataka Kudo, Fumitoshi Satoh, William E. Rainey, Sadayoshi Ito, Hiroshi Okamoto, Akira Sugawara

    ENDOCRINE JOURNAL 57 S351-S351 2010年3月

    出版者・発行元:JAPAN ENDOCRINE SOC

    ISSN:0918-8959

  117. Prostacyclin analogs rapidly stimulates endothelial nitric oxide synthase phosphorylation through cAMP/PKA pathway in vascular endothelial cells 査読有り

    Masataka Kudo, Akira Sugawara, Akiko Saito, Fumitoshi Satoh, Akira Uruno, Sadayoshi Ito

    ENDOCRINE JOURNAL 57 S572-S573 2010年3月

    出版者・発行元:JAPAN ENDOCRINE SOC

    ISSN:0918-8959

  118. Measurements of aldosterone in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry(LC-ESI-MS/MS): Comparison to radioimmunoassays 査読有り

    Masataka Kudo, Fumitoshi Satoh, Ryo Morimoto, Osamu Murakami, Akira Sugawara, Akira Uruno, Kouwa Yamashita, Mitsuteru Numazawa, Sadayoshi Ito

    ENDOCRINE JOURNAL 57 S634-S634 2010年3月

    出版者・発行元:JAPAN ENDOCRINE SOC

    ISSN:0918-8959

  119. FK506結合蛋白質12.6ノックアウトマウスではブドウ糖刺激インスリン分泌が低下する

    吉川雄朗, 野口直哉, 高柳詩織, 宇留野晃, 菅原明, 谷内一彦

    日本薬理学雑誌 135 (1) 7P-7P 2010年1月

  120. Genetic engineering with endothelial nitric oxide synthase improves functional properties of endothelial progenitor cells from patients with coronary artery disease: an in vitro study 査読有り

    Savneet Kaur, T. R. Santhosh Kumar, Akira Uruno, Akira Sugawara, Karunakaran Jayakumar, Chandrasekharan Cheranellore Kartha

    BASIC RESEARCH IN CARDIOLOGY 104 (6) 739-749 2009年11月

    出版者・発行元:DR DIETRICH STEINKOPFF VERLAG

    DOI: 10.1007/s00395-009-0039-x  

    ISSN:0300-8428

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    Recent studies have reported a marked impairment in the number and functions of endothelial progenitor cells (EPCs) in patients with coronary artery disease (CAD). In view of an important role of eNOS in angiogenesis, in the present study, we evaluated the effects of eNOS gene transfer in ex vivo expanded EPCs isolated from patients with CAD. The expanded EPCs were transfected with mammalian expression vector pcDNA3.1-eNOS containing the full-length human eNOS gene using lipofectamine. About 35-40% of the eNOS-EPCs had higher expression of eNOS as compared to untransfected EPCs. EPCs transfected with pcDNA3.0-EGFP, the plasmid vector expressing green fluorescent protein (GFP) were used as control. The untransfected, GFP-transfected and eNOS-transfected EPCs were compared in terms of important functional attributes of angiogenesis such as proliferation, migration, differentiation and adhesion/integration into tube-like structures in vitro. Functional studies revealed that in the presence of defined growth conditions, compared to the untransfected and GFP-transfected cells, eNOS-EPCs from patients with CAD have a significant increase in [(3)H] thymidine-labeled DNA (P &lt; 0.01), migration (14.6 +/- A 1.8 and 16.5 +/- A 1.9 vs. 23.5 +/- A 3.4 cells/field, P &lt; 0.01), ability to differentiate into endothelial-like spindle-shaped cells (46 +/- A 4.5 and 56.5 +/- A 2.1 vs. 93.2 +/- A 6.6 cells/field, P &lt; 0.001) and also incorporation into tube-like structures on the matrigel (GFP-EPCs: 21.25 +/- A 2.9 vs. GFP-eNOS-EPCs: 34.5 +/- A 5.5 cells/field, P &lt; 0.05). We conclude that eNOS gene transfection is a valuable approach to augment angiogenic properties of ex vivo expanded EPCs and eNOS-modified EPCs may offer significant advantages than EPCs alone in terms of their clinical use in patients with myocardial ischemia.

  121. Important role of heparan sulfate in postnatal islet growth and insulin secretion 査読有り

    Iwao Takahashi, Naoya Noguchi, Koji Nata, Shuhei Yamada, Tomoyuki Kaneiwa, Shuji Mizumoto, Takayuki Ikeda, Kazushi Sugihara, Masahide Asano, Takeo Yoshikawa, Akiyo Yamauchi, Nausheen Jamal Shervani, Akira Uruno, Ichiro Kato, Michiaki Unno, Kazuyuki Sugahara, Shin Takasawa, Hiroshi Okamoto, Akira Sugawara

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 383 (1) 113-118 2009年5月

    出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI: 10.1016/j.bbrc.2009.03.140  

    ISSN:0006-291X

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    Heparan sulfate (HS) binds with several signaling molecules and regulates ligand-receptor interactions, playing an essential role in embryonic development. Here we showed that HS was intensively expressed in pancreatic islet beta-cells after I week of age in mice. The enzymatic removal of HS in isolated islets resulted in attenuated glucose-induced insulin secretion with a concomitant reduction in gene expression of several key components in the insulin secretion machinery. We further depleted islet HS by inactivating the exostosin tumor-like 3 gene specifically in beta-cells. These truce exhibited abnormal islet morphology with reduced beta-cell proliferation after 1 week of age and glucose intolerance due to defective insulin secretion. These results demonstrate that islet HS is involved in the regulation of postnatal islet maturation and required to ensure normal insulin secretion. (C) 2009 Elsevier Inc. All rights reserved.

  122. Predominant role of REG R#945; among the REG gene family in the proliferation of human colorectal adenocarcinoma 査読有り

    Takeo Yoshikawa, Takayuki Ikeda, Kazuko Sakai, Naoya Noguchi, Iwao Takahashi, Nausheen Shervani, Akira Uruno, Akiyo Yamauchi, Eiichi Sakai, Tohru Onogawa, Mitsunori Okabe, Toshinori Ando, Makoto Kinouchi, Koh Miura, Michiaki Unno, Tomohiro Emura, Masahiko Fujiwara, Shin Takasawa, Hiroshi Okamoto, Akira Sugawara

    CANCER RESEARCH 69 2009年5月

    出版者・発行元:AMER ASSOC CANCER RESEARCH

    DOI: 10.1369/jhc.2010.956961  

    ISSN:0008-5472

    eISSN:1538-7445

  123. マウス膵β細胞におけるヘパラン硫酸の発現とインスリン分泌の維持 査読有り

    野口直哉, 高橋巌, 吉川雄朗, ShervaniNausheen Jamal, 宇留野晃, 海野倫明, 岡本宏, 菅原明

    糖尿病 52 (Suppl.1) S-216 2009年4月

  124. アルドステロン産生腫瘍の診断の進歩 MDCT副腎静脈造影マップ法副腎静脈サンプリングの成功率と診断精度 アルドステロン産生腺腫の局在診断の精度と判定基準の検討

    佐藤文俊, 森本玲, 工藤正孝, 松田謙, 宇留野晃, 高瀬圭, 石橋忠司, 荒井陽一, 鈴木貴, 笹野公伸, 村上治, 伊藤貞嘉

    日本内分泌学会雑誌 85 (1) 190-190 2009年4月

  125. Thiazolidinediones inhibit REG I alpha gene transcription in gastrointestinal cancer cells 査読有り

    Akiyo Yamauchi, Iwao Takahashi, Shin Takasawa, Koji Nata, Naoya Noguchi, Takayuki Ikeda, Takeo Yoshikawa, Nausheen J. Shervani, Iwao Suzuki, Akira Uruno, Michiaki Unno, Hiroshi Okamoto, Akira Sugawara

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 379 (3) 743-748 2009年2月

    出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI: 10.1016/j.bbrc.2008.12.113  

    ISSN:0006-291X

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    REG (Regenerating gene) lot protein functions as a growth factor for gastrointestinal cancer cells, and its mRNA expression is strongly associated with a poor prognosis in gastrointestinal cancer patients. We here demonstrated that PPAR gamma-agonist thiazolidinediones (TZDs) inhibited cell proliferation and REG I alpha protein/mRNA expression in gastrointestinal cancer cells. TZDs inhibited the REG]a gene promoter activity, via its cis-acting element which lacked PPAR response element and could not bind to PPAR,1, in PPAR gamma-expressing gastrointestinal cancer cells. The inhibition was reversed by co-treatment with a specific PPAR gamma-antagonist GW9662. Although TZDs did not inhibit the REG la gene promoter activity in PPAR gamma-non-expressing cells, PPAR gamma overexpression in the cells recovered their inhibitory effect. Taken together, TZDs inhibit REG la gene transcription through a PPAR gamma-dependent pathway. The TZD-induced REG lot mRNA reduction was abolished by cycloheximide, indicating the necessity of novel protein(s) synthesis. TZDs may therefore be a candidate for novel anti-cancer drugs for patients with gastrointestinal cancer expressing both REG I alpha and PPAR gamma. (C) 2008 Elsevier Inc. All rights reserved.

  126. PROSTACYCLIN ANALOGS RAPIDLY INDUCE NITRIC OXIDE PRODUCTION THROUGH ENDOTHELIAL NITRIC OXIDE SYNTHASE PHOSPHORYLATION IN VASCULAR ENDOTHELIAL CELLS 査読有り

    Masataka Kudo, Akira Sugawara, Akiko Saito, Fumitoshi Satoh, Akira Uruno, Sadayoshi Ito

    JOURNAL OF VASCULAR RESEARCH 46 157-157 2009年

    出版者・発行元:KARGER

    ISSN:1018-1172

  127. ヘパラン硫酸はマウス膵ランゲルハンス島の形態形成やβ細胞増殖、インスリン分泌機能に重要な役割を果たしている 査読有り

    高橋巌, 野口直哉, 那谷耕司, 山田修平, 金岩知之, 水本秀二, 池田崇之, 杉原一司, 浅野雅秀, 吉川雄朗, ShervaniNausheen J, 宇留野晃, 海野倫明, 菅原一幸, 高澤伸, 岡本宏, 菅原明

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 81回・31回 1T22-3 2008年11月

    出版者・発行元:(公社)日本生化学会

  128. Stimulatory Effects of Low-Dose 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor Fluvastatin on Hepatocyte Growth Factor-Induced Angiogenesis: Involvement of p38 Mitogen-Activated Protein Kinase 査読有り

    Akira Uruno, Akira Sugawara, Masataka Kudo, Fumitoshi Satoh, Akiko Saito, Sadayoshi Ito

    HYPERTENSION RESEARCH 31 (11) 2085-2096 2008年11月

    出版者・発行元:NATURE PUBLISHING GROUP

    DOI: 10.1291/hypres.31.2085  

    ISSN:0916-9636

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    Therapeutic angiogenesis has received much attention for its potential benefits in Ischemic vascular disorders. Recently, the clinical application of hepatocyte growth factor (HGF) for therapeutic angiogenesis has become well known. Statins have also been reported to promote angiogenesis and ameliorate Ischemic conditions. In the present study, we examined the effects of fluvastatin on HGF-induced angiogenesis using a human umbilical vein endothelial cell (HUVEC)/normal human dermal fibroblast (NHDF) co-culture system. The HGF-induced angiogenesis was augmented by fluvastatin at low dose, but It was decreased at high dose. Although fluvastatin Increased vascular endothelial growth factor expression in NHDFs, it was observed only at a high dose. Low-dose fluvastatin decreased the HGF-Induced p38 mitogen-activated protein kinase (MAPK) phosphorylation (Thr-180/Tyr-182) and HUVEC apoptosis In the presence of HGF. SB203580, a p38 MAPK inhibitor, ameliorated anisomycin (a p38 MAPK activator)-induced angiogenesis suppression In the presence of HGF. Moreover, the augmentation of the HGF-Induced angiogenesis by fluvastatin was abrogated by the p38 MAPK inhibitors, SB203580, SB202190, and FR167653. High-dose fluvestatin decreased Akt phosphorylation (Ser-473) and HUVEC proliferation, and it increased p27(kIP1) In HUVECs. Interestingly, fluvastatin decreased the mRNA expression of integrins and tissue Inhibitor of metalloproteinases (TIMPs) in HUVECs. Our data therefore Indicate that the stimulatory effects of low-dose fluvastatin on the HGF-induced angiogenesis are mediated by Its inhibitory effects on p38 MAPK phosphorylation Induced by HGF, which may result in the suppression of EC apoptosis. High-dose fluvastatin inhibits Akt phosphorylation and HUVEC proliferation, and it increases p27(kIP1), which may result In Its inhibitory effects on angiogenesis. In addition, integrins and TIMPs are candidates for angiogenesis regulation by fluvastatin. (Hypertens Res 2008; 31: 2085-2096)

  129. FKBP12.6 disruption impairs glucose-induced insulin secretion 査読有り

    Naoya Noguchi, Takeo Yoshikawa, Takayuki Ikeda, Iwao Takahashi, Nausheen Jamal Shervani, Akira Uruno, Akiyo Yamauchi, Koji Nata, Shin Takasawa, Hiroshi Okamoto, Akira Sugawara

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 371 (4) 735-740 2008年7月

    出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE

    DOI: 10.1016/j.bbrc.2008.04.142  

    ISSN:0006-291X

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    Cyclic ADP-ribose (cADPR), accumulated in pancreatic P-cells in response to elevated ATP levels after glucose stimulation, mobilizes Ca2+ from the endoplasmic reticulum through the ryanodine receptor (RyR) and thereby induces insulin secretion. We have recently demonstrated in an in vitro study that cADPR activates RyR through binding to FK506-binding protein 12.6 (FKBP12.6), an accessory protein of RyR. Here we generated FKBP12.6-deficient (FKBP12.6(-/-)) mice by homologous recombination. FKBP12.6(-/-) mice showed glucose intolerance coupled to insufficient insulin secretion upon a glucose challenge. Insulin secretion in response to glucose was markedly impaired in FKP12.6(-/-) islets, while sulfonylurea- or KCl-incluced insulin secretion was unaffected. No difference was found in the glucose oxidation rate between FKBP12.6(-/-) and wild-type islets. These results indicate that FKBP12.6 plays a role in glucose-induced insulin secretion downstream of ATP production, independently of ATP-sensitive K+ channels, in pancreatic beta-cells. (c) 2008 Elsevier Inc. All rights reserved.

  130. Impaired glucose-induced insulin secretion in FK506-binding protein 12.6-deficient mice 査読有り

    Takeo Yoshikawa, Naoya Noguchi, Takayuki Ikeda, Iwao Takahashi, Nausheen J. Shervani, Akira Uruno, Akiyo Yamauchi, Koji Nata, Shin Takasawa, Hiroshi Okamoto, Akira Sugawara

    DIABETES 57 A55-A55 2008年6月

    出版者・発行元:AMER DIABETES ASSOC

    ISSN:0012-1797

  131. Hypocalcemia in a patient with severe hypertension and surgically induced relative hypoparathyroidism 査読有り

    Masayuki Tanemoto, Akira Uruno, Takaaki Abe, Sadayoshi Ito

    JOURNAL OF BONE AND MINERAL METABOLISM 26 (3) 298-300 2008年5月

    出版者・発行元:SPRINGER TOKYO

    DOI: 10.1007/s00774-007-0817-1  

    ISSN:0914-8779

  132. Angiographic index for angioplasty-treatable atheromatous renal artery stenosis 査読有り

    Masayuki Tanemoto, Michiaki Abe, Akira Uruno, Takaaki Abe, Sadayoshi Ito

    HYPERTENSION RESEARCH 31 (5) 881-885 2008年5月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.31.881  

    ISSN:0916-9636

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    The relative reduction of the lumen diameter by an atheromatous lesion (% diameter reduction) is generally used as an angiographic index for atheromatous renal artery stenosis (ARAS), but its association with the clinical outcome of angioplasty has not been sufficiently evaluated. This study aimed to identify an angiographic index(ices) that can be used to identify angioplasty-treatable ARAS. We evaluated the clinical outcome of angioplasty in 27 patients who had unilateral ARAS without renal insufficiency by assessing the reduction in systemic arterial blood pressure (BP) after angioplasty and examined its association with various angiographic indices. In the receiver operating characteristic analysis for BP reduction, the area under the curve was larger for the absolute value of the lumen diameter at the narrowest part of its constriction (the narrowest diameter), an angiographic index introduced in this study, than for % diameter reduction (0.770 vs. 0.731). At a 3-mm maximum threshold, the narrowest diameter identified cases with BP reduction; the sensitivity/specificity was 0.89/0.75 (p &lt; 0.001). Furthermore, the narrowest diameter correlated better than % diameter reduction with hemodynamic indices of ARAS. In conclusion, the narrowest diameter is an angiographic index that can effectively identify angioplasty-treatable ARAS in patients without renal insufficiency.

  133. FK506結合蛋白質12.6ノックアウトマウスにおけるグルコース刺激インスリン分泌の低下

    吉川 雄朗, 野口 直哉, 池田 崇之, 高橋 巌, Shervani Nausheen Jamal, 宇留野 晃, 山内 晶世, 那谷 耕司, 高澤 伸, 岡本 宏, 菅原 明

    糖尿病 51 (Suppl.1) S-209 2008年4月

    出版者・発行元:(一社)日本糖尿病学会

    ISSN:0021-437X

    eISSN:1881-588X

  134. 膵β細胞特異的糖転移酵素EXTL3欠損マウスはβ細胞増殖能低下と耐糖能異常を生じる 査読有り

    高橋巌, 那谷耕司, 野口直哉, 池田崇之, 吉川雄朗, 山内晶世, ShervaniNausheen J, 宇留野晃, 杉原一司, 浅野雅秀, 海野倫明, 高澤伸, 岡本宏, 菅原明

    糖尿病 51 (Suppl.1) S-318 2008年4月

    出版者・発行元:(一社)日本糖尿病学会

    ISSN:0021-437X

    eISSN:1881-588X

  135. Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 Labeling index is a predictor for recurrence of adrenocortical carcinomas 査読有り

    Ryo Morimoto, Fumitoshi Satoh, Osamu Murakami, Takashi Suzuki, Takaaki Abe, Masayuki Tanemoto, Mlchiaki Abe, Akira Uruno, Shigeto Ishidoya, Yoichi Arai, Kazuhiro Takahashi, Hironobu Sasano, Sadayoshi Ito

    ENDOCRINE JOURNAL 55 (1) 49-55 2008年2月

    出版者・発行元:JAPAN ENDOCRINE SOC

    DOI: 10.1507/endocrj.K07-079  

    ISSN:0918-8959

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    Adrenocortical carcinoma (ACC) is a rare, highly malignant tumor. The aim of the present study is to evaluate the prognostic relevance of a proliferation marker Ki67/MIB1 by immunohistochemistry in 17 cases who underwent resections of the primary tumors and diagnosed to have ACC at Tohoku University Hospital based on the criteria of Weiss during the period from 1976 to 2005. The follow-up periods ranged from 221 days to 10659 days (about 29 years) with the median of 1895 days. The median age at diagnosis was 46 years old, and the mean size of the primary tumors was 7.1 cm with the minimal of 3.5 cm. Ki67/MIB1 labeling index (Ki67/MIB1LI) ranged from 1% to 26%. Kaplan-Meier analysis revealed that patients with Ki67/MIB1LI of 7% or more were associated with significantly shortened disease-free survival (P = 0.0037). The evaluation with Weiss criteria revealed that the median score of Weiss criteria was five, and 13 patients (76.5%) presented positive findings in the criteria of mitotic rate. The survival analysis with Weiss score showed that patients with the scores of 6 or more had both significantly shortened disease-free survival (P = 0.0001) and overall survival (P = 0.0063). The present study has suggested that Ki67/MIB1LI, as well as Weiss score, is a useful predictor for tumor recurrence after resection of the primary tumors in patients with ACC.

  136. [Case of rhabdomyolysis induced by the approved daily dose of a traditional Chinese medicine]. 査読有り

    Takafumi Toyohara, Masayuki Tanemoto, Akira Uruno, Michiaki Abe, Takaaki Abe, Sadayoshi Ito

    Nihon Jinzo Gakkai shi 50 (2) 135-9 2008年

    ISSN:0385-2385

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    We report a case of a 67-year-old woman with hypokalemic rhabdomyolysis induced by pseudohyperaldosteronism. The pseudohyperaldosteronism in this case was caused by the administration of a traditional Chinese medicine, which contained 2.0 g of licorice in the approved daily dose. She started to suffer from hypertension and general fatigue after taking the medication, but continued it for two years until admission after an episode of diarrhea and vomiting. On admission, severe hypokalemia (1.6 mEq/L) and increased serum creatinine kinase (8,778 IU/L) was noted. With the findings of a high transtubular potassium concentration gradient (TTKG) in spite of low plasma renin activity and a low plasma aldosterone concentration, we suspected licorice-induced pseudohyperaldosteronism as the cause of her hypokalemic rhabdomyolysis. The Chinese medicine was terminated, and she received appropriate hydration and potassium replacement therapy as judged by the value of TTKG with the result that her serum potassium and creatinine kinase levels were normalized without any more adverse events. Since it was only a low dose of licorice (2.0 g/day) that induced hypokalemic rhabdomyolysis in this case, serum electrolytes should be examined in all cases under the possible consumption of licorice.

  137. FK506-binding protein 12.6ノックアウトマウスにおけるブドウ糖刺激インスリン分泌の低下

    吉川 雄朗, 野口 直哉, 池田 崇之, 高橋 巌, Shervani Nausheen Jamal, 宇留野 晃, 山内 晶世, 那谷 耕司, 高澤 伸, 岡本 宏, 菅原 明

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 80回・30回 2T15-13 2007年11月

    出版者・発行元:(公社)日本生化学会

  138. 糖転移酵素EXTL3の膵β細胞特異的欠損マウスにおけるβ細胞増殖能の低下と耐糖能異常 査読有り

    高橋巌, 那谷耕司, 野口直哉, 池田崇之, 吉川雄朗, 山内晶世, ShervaniNausheen J, 杉原一司, 浅野雅秀, 宇留野晃, 海野倫明, 高澤伸, 岡本宏, 菅原明

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集 80回・30回 3T6-2 2007年11月

    出版者・発行元:(公社)日本生化学会

  139. Localization of aldosterone-producing adrenocortical adenomas: Significance of adrenal venous sampling 査読有り

    Fumitoshi Satoh, Takaaki Abe, Masayuki Tanemoto, Masahiro Nakamura, Michiaki Abe, Akira Uruno, Ryo Morimoto, Akihiro Sato, Kei Takase, Shigeto Ishidoya, Yoichi Arai, Takashi Suzuki, Hironobu Sasano, Tadashi Ishibashi, Sadayoshi Ito

    HYPERTENSION RESEARCH 30 (11) 1083-1095 2007年11月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.30.1083  

    ISSN:0916-9636

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    Accurate localization of aldosterone-producing adenoma (APA) is essential for the treatment of primary aldosteronism (PA). In order to confirm the clinical usefulness of adrenal venous sampling (AVS), we retrospectively studied 87 cases of PA in whom AVS was conducted. We collected right and left adrenal venous effluents simultaneously before and after adrenocorticotropic hormone (ACTH) stimulation for measurements of aldosterone concentration (A) and cortisol concentration (C). Based on AVS results, we judged 66 cases as having unilateral aldosterone hypersecretion and the remaining 21 cases as having no apparent laterality. Of the above 66 subjects, 61 underwent laparoscopic removal of the adrenal gland through a retroperitoneal approach. The presence of APA was histopathologically confirmed, and blood pressure decreased significantly with normalization of plasma aldosterone concentration (PAC) in all cases. The receiver operator characteristics (ROC) curve analysis between the operated and no-apparent-laterality groups revealed that the ratio of A/C on the higher side to A/C on the lower side (A/C ratio) after ACTH stimulation is a useful index, with a cutoff value of 2.6, a sensitivity of 0.98 and a specificity of 1.0. The ROC curve analysis between the APA side and contralateral side within the operated patients revealed that the cutoff value of A was 1,340 ng/dL, with a sensitivity of 0.92 and a specificity of 1.00. Our results indicate the usefulness of simultaneous AVS and ACTH stimulation for localizing APA.

  140. 術前MDCTにて副腎結節性病変を認めなかった原発性アルドステロン症の自験例に関する検討

    森本玲, 佐藤文俊, 村上治, 宇留野晃, 阿部倫明, 種本雅之, 阿部高明, 伊藤貞嘉, 高瀬圭, 山田隆之, 石橋忠司, 高橋昭喜, 石戸谷滋人, 佐藤信, 荒井陽一, 鈴木貴, 笹野公伸

    日本内分泌学会雑誌 83 (2) 460-460 2007年9月

  141. 副腎静脈サンプリングの適応と解釈 原発性アルドステロン症における副腎静脈サンプリングの手術適応の診断 左副腎静脈のカテーテル位置の重要性

    佐藤文俊, 森本玲, 宇留野晃, 阿部倫明, 種本雅之, 阿部高明, 荒井陽一, 笹野公伸, 石橋忠司, 伊藤貞嘉

    日本内分泌学会雑誌 83 (1) 77-77 2007年4月

  142. 原発性アルドステロン症はコモンディジーズか? 原発性アルドステロン症の多様性 スクリーニング、確定診断におけるレニン・アンジオテンシン系抑制とACTH反応性の意義

    佐藤文俊, 森本玲, 宇留野晃, 阿部倫明, 種本雅之, 阿部高明, 荒井陽一, 笹野公伸, 石橋忠司, 伊藤貞嘉

    日本内分泌学会雑誌 83 (1) 38-38 2007年4月

  143. All-trans retinoic acid induces in vitro angiogenesis via retinoic acid receptor: Possible involvement of paracrine effects of endogenous vascular endothelial growth factor signaling 査読有り

    Akiko Saito, Akira Sugawara, Akira Uruno, Masataka Kudo, Hiroyuki Kagechika, Yasufumi Sato, Yuji Owada, Hisatake Kondo, Mayumi Sato, Masahiko Kurabayashi, Masue Imaizumi, Shigeru Tsuchiya, Sadayoshi Ito

    ENDOCRINOLOGY 148 (3) 1412-1423 2007年3月

    出版者・発行元:ENDOCRINE SOC

    DOI: 10.1210/en.2006-0900  

    ISSN:0013-7227

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    A natural retinoid all-trans retinoic acid ( ATRA) regulates a variety of important cellular functions via retinoic acid receptor ( RAR). ATRA has therapeutically been used against various malignancies including acute promyelocytic leukemia. Recently ATRA has also been recognized to be beneficial against atherosclerotic vascular disorders. However, its effects on angiogenesis remain controversial. We therefore examined ATRA effects on in vitro angiogenesis in terms of capillary-like tube formation using human umbilical vein endothelial cells ( HUVECs)/ normal human dermal fibroblast ( NHDF) coculture. ATRA as well as RAR agonist Am80 significantly induced capillary-like tube formation. The ATRA- induced tube formation was inhibited by coincubation with RAR antagonist LE540/ LE135. HUVEC proliferation, but not its migration, was also induced by ATRA. The ATRA- induced tube formation was completely abolished by coincubation with vascular endothelial growth factor ( VEGF) neutralizing antibody or with VEGF receptor ( VEGFR)- 2 ( KDR) neutralizing antibody, but not VEGFR-1 ( Flt-1) neutralizing antibody. ATRA and Am80 induced VEGF secretion in the coculture as well as VEGF secretion/ mRNA expression in NHDFs. Transcription activity of human VEGF gene promoter in NHDFs was stimulated by ATRA, which was augmented by RAR overexpression. ATRA also induced VDGFR-2/ KDR mRNA expression in HUVECs. Moreover, ATRA- induced secretion of hepatocyte growth factor as well as angiopoietin-2 in the coculture. Taken together, ATRA may have induced angiogenesis via RAR mainly by stimulation of HUVEC proliferation and enhancement of endogenous VEGF signaling and in part by induction of hepatocyte growth factor and angiopoietin-2 production. Retinoids may therefore be potential candidates for therapeutic angiogenesis against ischemic vascular disorders.

  144. 原発性アルドステロン症の病型鑑別と頻度

    佐藤文俊, 阿部高明, 森本玲, 宇留野晃, 阿部倫明, 種本雅之, 荒井陽一, 笹野公伸, 石橋忠司, 伊藤貞嘉

    日本内科学会雑誌 96 (Suppl.) 138-138 2007年2月

  145. Differential effects of angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker on gene expression in vascular endothelial cells revealed by DNA microarray analyses 査読有り

    Akira Sugawara, Masataka Kudo, Akiko Saito, Michio Hongo, Akira Uruno, Sadayoshi Ito

    JOURNAL OF HYPERTENSION 24 238-238 2006年12月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  146. Effects of pioglitazone, belaprost, and fluvastatin on gene expression in vascular endothelial cells revealed by DNA microarray analyses 査読有り

    Masataka Kudo, Akira Sugawara, Akiko Saito, Akira Uruno, Sadayoshi Ito

    JOURNAL OF HYPERTENSION 24 238-238 2006年12月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  147. Therapeutic intervention of morning hypertension by the angiotensin II receptor blocker olmesartan - Clinical implication of the reduction of albuminuria for the prevention of brain and heart disease 査読有り

    Fumitoshi Satoh, Ryo Morimoto, Akira Uruno, Michiaki Abe, Masayuki Tanemoto, Takaaki Abe, Sadayoshi Ito

    JOURNAL OF HYPERTENSION 24 252-253 2006年12月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  148. Effects of hepatocyte growth factor and fluvastatin co-administration on in vitro angiogenesis and endothelial cell proliferation 査読有り

    Akira Uruno, Akira Sugawara, Akiko Saito, Masataka Kudo, Sadayoshi Ito

    JOURNAL OF HYPERTENSION 24 325-325 2006年12月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  149. Effects of all-trans retinoic acid on in vitro angiogenesis 査読有り

    Akiko Saito, Akira Sugawara, Akira Uruno, Masataka Kudo, Masue Imaizumi, Shigeru Tsuchiya, Sadayoshi Ito

    JOURNAL OF HYPERTENSION 24 368-368 2006年12月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  150. Beneficial effects of pitavastatin on serum lipids and inflammatory mediators in the treatment of hypertensive, hypercholesterolemic patients 査読有り

    Fumitoshi Satoh, Ryo Morimoto, Akira Uruno, Michiaki Abe, Masayuki Tanemoto, Takaaki Abe, Sadayoshi Ito

    JOURNAL OF HYPERTENSION 24 371-371 2006年12月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  151. 原発性アルドステロン症の局在診断における副腎静脈サンプリングと最新型16列MDCTの有用性 招待有り 査読有り

    佐藤文俊, 種本雅之, 中村匡宏, 阿部倫明, 宇留野晃, 森本玲, 佐藤明弘, 高瀬圭, 石戸谷滋人, 荒井陽一, 鈴木貴, 笹野公伸, 石橋忠司, 阿部高明, 伊藤貞嘉

    日本高血圧学会総会28回プログラム・抄録集 59-59 2005年9月

  152. 多発微小腺腫による原発性アルドステロン症の一例 治療決定のための選択的副腎静脈サンプリングと病理診断における3βHSD染色の意義

    佐藤文俊, 森本玲, 杉浦章, 宇留野晃, 阿部倫明, 種本雅之, 阿部高明, 佐藤明弘, 石橋忠司, 石戸谷滋人, 荒井陽一, 鈴木貴, 笹野公伸, 伊藤貞嘉

    日本内分泌学会雑誌 81 (2) 457-457 2005年9月

  153. Upregulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway 査読有り

    A Uruno, A Sugawara, H Kanatsuka, H Kagechika, A Saito, K Sato, M Kudo, K Takeuchi, S Ito

    CIRCULATION 112 (5) 727-736 2005年8月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    DOI: 10.1161/CIRCULATIONAHA.104.500959  

    ISSN:0009-7322

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    Background - A natural retinoid all-trans retinoic acid (ATRA) contains various beneficial effects on vasculature, including suppression of neointima formation after balloon injury. However, little is known about the effects of ATRA on vascular endothelial function. We therefore studied its role in nitric oxide (NO) production of vascular endothelial cells (ECs). Methods and Results - Human dermal microvascular ECs, human umbilical vein ECs, and SV40-transformed rat lung vascular ECs were incubated with or without ATRA (1 mu mol/L) for 48 hours. Their NO production was determined with the use of a fluorescent NO indicator, diaminofluorescein-2 diacetate. ATRA significantly increased their basal as well as acetylcholine-induced NO production. Treatment with N-omega-nitro-L-arginine methyl ester or carboxy-PTIO suppressed their fluorescence. Increase of NO production was also observed by incubation with retinoic acid receptor (RAR) agonist Am580. ATRA-induced NO increase was abolished by coincubation with RAR antagonist LE540. Moreover, the NO increase was completely inhibited by the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin and LY294002. ATRA as well as Am580 enhanced endothelial NO synthase ( eNOS) phosphorylation at Ser-1177 as well as Akt phosphorylation at Ser-473 without changing their protein expression. Overexpression of dominant-negative Akt inhibited the eNOS phosphorylation. Moreover, ATRA increased PI3K activity as well as PI3K catalytic subunit p110 beta protein expression, which was completely inhibited by LE540 treatment. Real-time polymerase chain reaction analyses demonstrated that ATRA increased PI3K catalytic subunit p110 beta mRNA expression without affecting its stability. Finally, ATRA-induced NO increase was observed in COS-1 cells transfected with wild-type eNOS and RAR alpha, but not with mutated eNOS whose Ser-1177 was substituted. Conclusions - ATRA increases NO production by eNOS phosphorylation through RAR-mediated PI3K/Akt pathway activation in vascular ECs and possibly plays beneficial roles in vascular endothelium. Retinoids may therefore be candidates as novel therapeutic agents against vascular disorders with endothelial damage.

  154. 原発性アルドステロン症の局在診断における副腎静脈サンプリングの意義 査読有り

    佐藤文俊, 種本雅之, 中村匡宏, 鈴木恵綾, 茶木辰治, 森本玲, 宇留野晃, 佐藤明弘, 高瀬圭, 石戸谷滋人, 荒井洋一, 鈴木貴, 笹野公伸, 石橋忠司, 阿部高明, 伊藤貞嘉

    日本内分泌学会雑誌 81 (1) 177-177 2005年4月

  155. Hepatocyte growth factor stimulates nitric oxide production through endothelial nitric oxide synthase activation by the phosphoinositide 3-kinase/Akt pathway and possibly by mitogen-activated protein kinase kinase in vascular endothelial cells 査読有り

    A Uruno, A Sugawara, H Kanatsuka, S Arima, Y Taniyama, M Kudo, K Takeuchi, S Ito

    HYPERTENSION RESEARCH 27 (11) 887-895 2004年11月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.27.887  

    ISSN:0916-9636

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    Hepatocyte growth factor (HGF) has recently been the focus of attention due to its angiogenic effects, which are similar to those of vascular endothelial growth factor (VEGF); because of these effects, HGF is considered to be a novel therapeutic agent against vascular disorders, including atherosclerotic angiopathies. Although nitric oxide (NO), which is derived from vascular endothelial cells (ECs), is also involved in angiogenesis, little is known regarding the interactions between HGF and NO. We therefore examined the effects of HGF on NO production as well as endothelial NO synthase (eNOS) phosphorylation, and investigated their mechanisms. In bovine aortic ECs, HGF induced a rapid (5 min) increase of NO production measured by diaminofluorescein-2 diacetate. Moreover, HGF rapidly (2.5 min) stimulated eNOS phosphorylation (Ser -1179) as determined by Western immunoblot analyses. Both of these effects were almost completely suppressed by the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and were partially suppressed by the mitogen-activated protein kinase (MAPK) kinase 1/2 inhibitor U0126. HGF also stimulated Akt phosphorylation (Ser-473), which was completely suppressed by LY294002 and was partially suppressed by U0126. Moreover, HGF stimulated extracellular signal-regulated kinase 1/2 phosphorylation (Thr-202/Tyr-204), which was completely suppressed by U0126 and was partially suppressed by LY294002. Taken together, these results indicate that HGF not only phosphorylates eNOS through the PI3K/Akt pathway, but also partially through the MAPK pathway, and that these two pathways may interact. Compared with VEGF, HGF was more potent in both NO production and eNOS phosphorylation. Our study thus demonstrates a novel activity of HGF-the stimulation of NO production-which occurs via eNOS phosphorylation that may in turn be mediated by cross-talk between the PI3K/Akt and MAPK pathways.

  156. Transcription suppression of peroxisome proliferator-activated receptor gamma 2 gene expression by tumor necrosis factor alpha via an inhibition of CCAAT/enhancer-binding protein delta during the early stage of adipocyte differentiation 査読有り

    M Kudo, A Sugawara, A Uruno, K Takeuchi, S Ito

    ENDOCRINOLOGY 145 (11) 4948-4956 2004年11月

    出版者・発行元:ENDOCRINE SOC

    DOI: 10.1210/en.2004-0180  

    ISSN:0013-7227

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    TNFalpha is known to inhibit adipocyte differentiation and induce insulin resistance. Moreover, TNFalpha is known to down-regulate peroxisome proliferator-activated receptor (PPAR)gamma2, an adipocyte-specific nuclear receptor of insulin-sensitizer thiazolidinediones. To clarify molecular mechanisms of TNFalpha-mediated PPARgamma2 down-regulation, we here examined the effect of TNFalpha on transcription regulation of PPARgamma2 gene expression during the early stage of adipocyte differentiation. 3T3-L1 preadipocytes (2 d after 100% confluent) were incubated in a differentiation mixture (dexamethasone, insulin, 3-isobutyl-1-methlxanthine), with or without 50 ng/ml TNFalpha, for 24 h. TNFalpha significantly decreased PPARgamma2 expression both at mRNA and protein levels (to similar to40%), as well as aP2 mRNA expression. The mouse PPARgamma2 gene promoter region (2.2-kb) was isolated and was used for luciferase reporter assays by transient transfection. TNFalpha significantly suppressed PPARgamma2 gene transcription (to similar to50%), and deletion analyses demonstrated that the suppression was mediated via CCAAT/enhancer- binding protein (C/EBP) binding elements at the -320/-340 region of the promoter. Moreover, TNFalpha significantly decreased expression of C/EBPdelta mRNA and protein levels (to similar to40%). EMSA, using 3T3-L1 cells nuclear extracts with the -320/-340 region as a probe, demonstrated the binding of C/EBPdelta to the element, which was significantly decreased by TNFalpha treatment. Overexpression of CEBP/delta prevented the TNFalpha-mediated suppression of PPARgamma2 transactivation. Taken together, TNFalpha suppresses PPARgamma2 gene transcription by the inhibition of C/EBPdelta expression and its DNA binding during the early stage of adipocyte differentiation, which may contribute to the inhibition of adipocyte differentiation, as well as the induction of insulin resistance.

  157. Expression of peroxisome proliferator-activated receptor isoform proteins in the rat kidney 査読有り

    K Sato, A Sugawara, M Kudo, A Uruno, S Ito, K Takeuchi

    HYPERTENSION RESEARCH 27 (6) 417-425 2004年6月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.27.417  

    ISSN:0916-9636

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    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors mediating ligand-dependent transactivation. Among the 3 isoforms, PPAR-alpha is involved in lipid metabolism in the liver, while PPAR-gamma(-gamma1 and -gamma2) is involved in adipocyte differentiation. Recently, PPARs have been suggested to be involved in renal electrolyte metabolism as well as atherosclerosis. PPAR-alpha is known to regulate cytochrome P450 gene expression, and may possibly affect sodium retention in the kidney. Moreover, PPAR-gamma is involved in the transcription regulation of blood pressure regulatory genes, including thromboxane and angiotensin II type 1 receptors. In the kidney, although expression of PPARs has been reported, detailed immunohistochemical analyses have not been performed. We here generated isoform-specific anti-PPAR antibodies to localize their proteins in the kidney. Anti-PPAR antibodies were raised against synthetic peptides. Their isoform specificity was confirmed by immunoblot analyses, immunoprecipitations, and antibody supershift experiments by electrophoretic mobility shift assay. We therefore studied the protein expression of PPARs in the kidney of adult Sprague-Dawley rats using these antibodies. Immunoblot analyses demonstrated protein expression of PPAR-alpha and -gamma1, but not of -gamma2, in the kidney nuclear extracts. Immunohistochemical analyses demonstrated that both PPAR-alpha and -gamma1 proteins were widely expressed in the nuclei of mesangial and epithelial cells in glomeruli, proximal and distal tubules, the loop of Henle, medullary collecting ducts, and intima/media of renal vasculatures. PPAR-alpha and -gamma1 proteins are thus widely expressed along the nephron segments, and may affect gene expression at these segments. Further studies will be needed to identify additional target genes for PPARs along the nephron segments.

  158. Endothelium-derived nitric oxide modulates vascular action of aldosterone in renal arteriole 査読有り

    S Arima, K Kohagura, HL Xu, A Sugawara, A Uruno, F Satoh, K Takeuchi, S Ito

    HYPERTENSION 43 (2) 352-357 2004年2月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    DOI: 10.1161/01.HYP.0000111138.78714.1a  

    ISSN:0194-911X

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    We have recently demonstrated that aldosterone causes nongenomic vasoconstriction by activating phospholipase C (PLC) in the preglomerular afferent arteriole (Af-Art). In the present study, we tested the hypothesis that endothelium modulates this vasoconstrictor action by releasing nitric oxide (NO). In addition, to study the post-PLC mechanism, we examined possible contributions of phosphoinositol hydrolysis products. Rabbit Af-Arts were microperfused at 60 mm Hg in vitro, and increasing doses of aldosterone (10(-10) to 10(-8) mol/L) were added to the bath and lumen. Aldosterone caused dose-dependent vasoconstriction (within 10 minutes); significant (P&lt;0.01) constriction was observed from 5x10(-9) mol/L, and at 10(-8) mol/L, intraluminal diameter decreased by 29%&PLUSMN;3% (n=9). Disrupting the endothelium augmented vasoconstriction; significant constriction was observed from 10(-10) mol/L, and at 10(-8) mol/L, the diameter decreased by 38%&PLUSMN;2% (n=6). NO synthesis inhibition reproduced this augmentation (n=7). Pretreatment with chelerythrine (10(-6) mol/L), a protein kinase C (PKC) inhibitor, slightly attenuated the constriction; aldosterone at 10(-8) mol/L now decreased the diameter by 18%&PLUSMN;3% (n=7). However, in Af-Arts treated with thapsigargin (10-6 mol/L) or dantrolene (3x10(-5) mol/L), which blocks inositol 1,4,5-triphosphate (IP3)-induced intracellular calcium release, aldosterone at 10(-8) mol/L decreased the diameter by only 9%&PLUSMN;1% (n=6) or 9%&PLUSMN;2% (n=5), respectively. These results demonstrate that in the Af-Art endothelium-derived NO modulates vasoconstrictor actions of aldosterone that are mediated by the activation of both IP3 and PKC pathways. Such vasoconstrictor actions of aldosterone may contribute to the development or aggravation of hypertension by elevating renal vascular resistance in cardiovascular diseases associated with endothelium dysfunction.

  159. Cytochrome P-450 metabolites but not NO, PGI2, and H 2O2 contribute to ACh-induced hyperpolarization of pressurized canine coronary microvessels 査読有り

    Mitsuaki Tanaka, Hiroshi Kanatsuka, Boon-Hooi Ong, Toshinori Tanikawa, Akira Uruno, Tatsuya Komaru, Ryoji Koshida, Kunio Shirato

    American Journal of Physiology - Heart and Circulatory Physiology 285 (5) H1939-H1948 2003年11月

    ISSN:0363-6135

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    The endothelium-dependent hyperpolarization of cells has a crucial role in regulating vascular tone, especially in microvessels. Nitric oxide (NO) and prostacyclin (PGI2), in addition to endothelium-derived hyperpolarizing factor (EDHF), have been reported to hyperpolarize vascular smooth muscle in several organs. Studies have reported the hyperpolarizing effects of these factors are increased by a stretch in large coronary arteries. EDHF has not yet been identified and cytochrome P-450 metabolites and H 2O2 are candidates for EDHF. With the use of the membrane potential-sensitive fluorescent dye bis-(1,3-dibutylbarbituric acid)trimethione oxonol [DiBAC4(3)], we examined whether NO, PGI2, Cytochrome P-450 metabolites, and H2O2 contribute to ACh-induced hyperpolarization in pressurized coronary microvessels. Canine coronary arterial microvessels (60-356 μm internal diameter) were cannulated and pressurized at 60 cmH2O in a vessel chamber perfused with physiological salt solution containing DiBAC4(3). Fluorescence intensity and diameter were measured on a computer. There was a linear correlation between changes in the fluorescence intensity and membrane potential. ACh significantly decreased the fluorescence intensity (hyperpolarization) of the microvessels without any inhibitors. Endothelial damage caused by air perfusion abolished the ACh-induced decrease in fluorescence intensity. The inhibitors of NO synthase and cyclooxygenase did not affect the ACh-induced decreases in the fluorescence intensity. The addition of 17-octadecynoic acid, a cytochrome P-450 monooxygenase inhibitor, to those inhibitors significantly attenuated the ACh-induced decreases in fluorescence intensity, whereas catalase, an enzyme that dismutates H 2O2 to form water and oxygen, did not. Furthermore, catalase did not affect the vasodilation produced by ACh. These results indicate that NO and PGI2 do not contribute to the ACh-induced hyperpolarization and that the cytochrome P-450 metabolites but not H 2O2 are involved in EDHF-mediated hyperpolarization in canine coronary arterial microvessels.

  160. Transcription suppression of thromboxane receptor gene expression by retinoids in vascular smooth muscle cells 査読有り

    A Uruno, A Sugawara, M Kudo, M Sato, K Sato, S Ito, K Takeuchi

    HYPERTENSION RESEARCH 26 (10) 815-821 2003年10月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.26.815  

    ISSN:0916-9636

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    Thromboxane (TX) A(2) induces contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. Retinoids, derivatives of vitamin A, have recently been shown to be anti-atherosclerotic in VSMCs. We therefore examined the effects of retinoids on TX-induced cell growth and TXR expression in VSMCs. TX-induced VSMC proliferation assessed by H-3-thymidine incorporation was completely abrogated by all-trans retinoic acid (ATRA) treatment. The expression of TXR mRNA was significantly decreased by treatment either with ATRA or its stereoisomer 9-cis retinoic acid (RA). Transcription activity of the TXR gene promoter was suppressed by treatment with these retinoids, and a study using retinoid receptor-selective agonists demonstrated that retinoic acid receptors (RARs), rather than retinoid X receptors (RXRs), were mainly involved in the transcription suppression. Deletion analyses demonstrated that the suppression was mediated via the -22/-7 GC-box related sequence. Electrophoretic mobility shift assays showed that Sp1, but not RAR and/or RXR, could bind to the element. The formation of the Sp1-DNA complex was inhibited by co-incubation with RAR, but not by RXR. Taken together, these findings suggest that TXR gene transcription suppression may be mediated by the inhibition of Sp1 binding to the -22/-7 GC-box related sequence by activated RAR, which may result in the inhibition of TX-incluced VSMC proliferation. Our study indicates a novel anti-atherosclerotic action of retinoids in VSMCs.

  161. Effects of mitogen-activated protein kinase pathway and co-activator CREP-binding protein on peroxisome proliferator-activated receptor-gamma-mediated transcription suppression of angiotensin II type 1 receptor gene 査読有り

    A Sugawara, K Takeuchi, A Uruno, M Kudo, K Sato, S Ito

    HYPERTENSION RESEARCH 26 (8) 623-628 2003年8月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.26.623  

    ISSN:0916-9636

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    Peroxisome proliferator-activated receptor (PPAR)-gamma and its ligands suppress several genes related to atherogenesis. We previously reported that ligand-activated PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the -58/-34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction. It has been reported that the mitogen-activated protein (MAP) kinase pathway inhibits PPAR-gamma function through its phosphorylation, and co-activator CREB-binding protein (CBP)/p300 interacts with PPAR-gamma and modulates its activity. Since both the MAP kinase pathway and CBP have recently been reported to be atherogenic, we examined their effects on PPAR-gamma-mediated AT1R gene transcription suppression. We observed that 1) PPAR-gamma-mediated AT1R gene transcription suppression was augmented by treatment with the MAP kinase kinase inhibitor PD98059, while treatment with the p38 kinase inhibitor SB203580 showed no effect; 2) the PPAR-gamma-mediated AT1R mRNA decrease was also augmented by PD98059 treatment; 3) CBP overexpression partially, but significantly, abrogated PPAR-gamma-mediated AT1R gene transcription suppression; and 4) the CBP effect was eliminated when the -58/-34 GC-box related element was disrupted. It is therefore speculated that: 1) PPAR-gamma phosphorylation by the MAP kinase pathway may attenuate PPAR-gamma-mediated AT1R gene transcription suppression through the inhibition of PPAR-gamma activity; and 2) CBP may enhance the activity of the remaining Sp1 on the -58/-34 GC-box related element, resulting in a reduction in PPAR-gamma-mediated AT1R gene transcription suppression. The MAP kinase pathway and CBP may thus antagonize against PPAR-gamma in AT1R gene transcription, probably leading to the progression of atherosclerosis.

  162. マウスPPARγ2遺伝子転写調節領域の単離およびTNFαによる転写抑制メカニズム

    工藤正孝, 菅原明, 宇留野晃, 佐藤和則, 竹内和久, 伊藤貞嘉

    血圧 10 (3) 256-259 2003年

  163. Peroxisome Proliferators-Activated Receptor(PPAR)-γによるトロンボキサン受容体遺伝子転写発現抑制

    竹内和久, 菅原明, 佐藤和則, 工藤正孝, 宇留野晃, 伊藤貞嘉

    代謝異常治療研究基金研究業績集 30 12-15 2003年1月

  164. 家族性高アルドステロン症(II型)の一家系 査読有り

    工藤正孝, 菅原明, 宇留野晃, 佐藤和則, 佐藤文俊, 村上治, 鈴木貴, 笹野公伸, 竹内和久, 伊藤貞嘉

    日本内分泌学会雑誌 78 (Suppl.) 101-103 2002年10月

  165. Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Sp1 in vascular smooth muscle cells 査読有り

    A Sugawara, A Uruno, M Kudo, Y Ikeda, K Sato, Y Taniyama, S Ito, K Takeuchi

    JOURNAL OF BIOLOGICAL CHEMISTRY 277 (12) 9676-9683 2002年3月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M104560200  

    ISSN:0021-9258

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    Thromboxane (TX) A(2) exerts contraction and proliferation of vascular smooth muscle cells (VSMCs) via its specific membrane TX receptor (TXR), possibly leading to the progression of atherosclerosis. A nuclear hormone receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, has recently been reported to be expressed in VSMCs. Here we examined a role of PPAR-gamma in TXR gene expression in VSMCs. PPAR-gamma ligands 15-deoxy-Delta(12,14)-prostaglandin J(2) and troglitazone reduced TXR mRNA expression levels as well as cell growth as assessed by [H-3]thymidine incorporation. Transcriptional activity of the TXR gene promoter was suppressed with PPAR-gamma ligands, and the suppression was augmented further by PPAR-gamma overexpression. By deletion and mutation analyses, the transcription suppression was shown to be the result of a -22/-7 GC box-related sequence (upstream of transcription start site). Electrophoretic mobility shift assays also showed that the sequence was bound by Sp1 but not by PPAR-gamma, and the formation of a Sp1.DNA complex was inhibited either by coincubation with PPAR-gamma or PPAR-gamma ligand treatment of VSMCs. Moreover, glutathione S-transferase pull-down assays demonstrated a direct interaction between PPAR-gamma and Sp1. In conclusion, PPAR-gamma suppresses TXR gene transcription via an interaction with Sp1. PPAR-gamma may possibly have an antiatherosclerotic action by inhibiting TXR gene expression in VSMCs.

  166. 家族性高アルドステロン症(2型)の一家系 査読有り

    工藤正孝, 竹内和久, 菅原明, 宇留野晃, 佐藤和則, 佐藤文俊, 村上治, 伊藤貞嘉, 鈴木貴, 笹野公伸

    日本内分泌学会雑誌 78 133-133 2002年2月

  167. 2型家族性高アルドステロン症の一家系 査読有り

    工藤正孝, 竹内和久, 菅原明, 宇留野晃, 佐藤和則, 佐藤文俊, 村上治, 伊藤貞嘉, 鈴木貴, 笹野公伸

    日本内分泌学会雑誌 77 (2) 446-446 2001年9月

  168. Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells 査読有り

    A Sugawara, K Takeuchi, A Uruno, Y Ikeda, S Arima, M Kudo, K Sato, Y Taniyama, S Ito

    ENDOCRINOLOGY 142 (7) 3125-3134 2001年7月

    出版者・発行元:ENDOCRINE SOC

    DOI: 10.1210/en.142.7.3125  

    ISSN:0013-7227

    詳細を見る 詳細を閉じる

    Angiotensin (A) II plays a critical role in vascular remodeling, and its action is mediated by type 1 AII receptor (AT1R). Recently, 15deoxy-(Delta 12,14)-prostaglandin J(2) and thiazolidinediones have been shown to be ligands for peroxisome proliferator-activated receptor (PPAR)-gamma and activate PPAR-gamma. In the present work, we have studied the effect of PPAR-gamma on AT1R expression in rat vascular smooth muscle cells (VSMCs). We observed that: 1) endogenous AT1R expression was significantly decreased by PPAR-gamma ligands both at messenger RNA and protein levels, whereas AT1R messenger RNA stability was not affected; 2) AII-induced increase of H-3-thymidine incorporation into VSMCs was inhibited by PPAR-gamma ligands; 3) rat AT1R gene promoter activity was significantly suppressed by PPAR-gamma ligands, and PPAR-gamma overexpression further suppressed the promoter activity; 4) transcriptional analyses using AT1R gene promoter mutants revealed that a GC-box-related sequence within the -58/-34 region of the AT1R gene promoter was responsible for the suppression; 5) Spl overexpression stimulated AT1R gene transcription via the GC-box-related sequence, which was inhibited by additional PPAR-gamma overexpression; 6) electrophoretic mobility shift assay suggested that Spl could bind to the GC-box-related sequence whereas PPAR-gamma could not; 7) antibody supershift experiments using VSMC nuclear extracts revealed that protein-DNA complexes formed on the GC-box-related sequence, which were decreased by PPAR-gamma coincubation, were mostly composed of Spl; and 8) glutathione S-transferase pull-down assay revealed a direct interaction between PPAR-gamma and Spl. Taken together, it is suggested that activated PPAR-gamma suppresses AT1R gene at a transcriptional level by inhibiting Spl via a protein-protein interaction. PPAR-gamma ligands, thus, may inhibit AII-induced cell growth and hypertrophy in VSMCs by AT1R expression suppression and possibly be beneficial for treatment of diabetic patients with hypertension and atherosclerosis.

  169. Renal tubule-specific transcription and chromosomal localization of rat thiazide-sensitive Na-Cl cotransporter gene 査読有り

    Y Taniyama, K Sato, A Sugawara, A Uruno, Y Ikeda, M Kudo, S Ito, K Takeuchi

    JOURNAL OF BIOLOGICAL CHEMISTRY 276 (28) 26260-26268 2001年7月

    出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

    DOI: 10.1074/jbc.M101614200  

    ISSN:0021-9258

    詳細を見る 詳細を閉じる

    The molecular mechanism underlying the renal expression localization of the thiazide-sensitive Na-CI cotransporter (TSC) gene was studied, The TSC gene was localized to chromosome 19p12-14, In cultured cells, tissue-specific transcription activity of the 5 ' -flanking region of the rat rTSC gene (5 ' FL/rTSC) was demonstrated, and the major promoter region was located between position -580 and -141. To further examine the tissue-specific transcription, transgenic rats harboring the 5 ' FL/rTSC fused upstream of the LacZ gene were generated. Immunohistochemical analysis clearly showed that LacZ gene expression was co-localized to distal convoluted tubules (DCT) with TSC, indicating that the 5 ' FL/rTSC regulates the renal tubule-specific TSC expression. Because a transcription factor, HFH-3 (hepatocyte nuclear factor-3/folk head homologue-3), had also been localized to DCT, a possible role of the putative cia-acting element (HPH-3/rTSC, -400/-387 position) for HFH-3 binding in the tissue-specific transcription was examined. Deletion and mutation analyses suggested that transcription of the HFH-3/rTSC was actually responsive to HFH-3, and electrophoretic mobility shift assay showed a direct binding of in vitro synthesized HFH-3 to the HFH-3/rTSC. In conclusion, the rTSC gene is localized to rat chromosome 19p12-24. The transcription regulatory region of the TSC gene confers DCT-specific gene expression, DCT-specific transcription factor HFH-3 may be involved in the renal tubule-specific transcription of TSC gene.

  170. Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes 査読有り

    A Sugawara, K Takeuchi, A Uruno, Y Ikeda, S Arima, K Sato, M Kudo, Y Taniyama, S Ito

    HYPERTENSION RESEARCH 24 (3) 229-233 2001年5月

    出版者・発行元:JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

    DOI: 10.1291/hypres.24.229  

    ISSN:0916-9636

    詳細を見る 詳細を閉じる

    Peroxisome proliferator-activated receptor (PPAR)-gamma ligands thiazolidinediones (TZDs) have recently been reported to be anti-hypertensive and anti-atherosclerotic. We have previously shown that one of the TZDs troglitazone significantly suppressed the transcription of both thromboxane receptor (TXR) and angiotensin II type 1 receptor(AT1R) genes in vascular smooth muscle cells (VSMCs) by activating PPAR-gamma, In the present study, we compared the effects of troglitazone and other TZDs on the transcription of these genes. TXR and AT1R mRNAs in rat VSMCs were determined by semi-quantitative RT-PCR, Luciferase chimeric constructs containing either the 989-bp rat TXR gene promoter or the 1,969-bp rat AT1R gene promoter were transiently transfected into VSMCs, The cells were incubated with troglitazone, RS-1455 Ia derivative of troglitazone which does not contain the hindered phenol resembling alpha -tocopherol), pioglitazone, or rosiglitazone for 12 h before harvesting. mRNA expression levels of TXR and AT1R were significantly decreased by troglitazone in contrast to rosiglitazone, TXR gene and AT1R gene transcription was significantly suppressed by troglitazone in a dose-dependent manner, while RS-1455 was less potent. Pioglitazone and rosiglitazone weakly suppressed the transcription of both genes in a manner almost similar to F18-1455. We have shown that troglitazone suppresses transcription of both the TXR and AT1R genes more potently than other TZDs. The structure of troglitazone and RS-1455 is identical except the hindered phenol, which is recently recognized to function as an antioxidant, Moreover, we have shown that the potency for activating PPAR-gamma is almost identical between troglitazone and RS-1455, We therefore speculate that the strong transcriptional suppression of the TXR and AT1R genes by troglitazone may be mediated in part by its antioxidant effect.

  171. ラットサイアザイド感受性NaCl共輸送体遺伝子の腎尿細管組織特異的遺伝子転写機構:トランスジェニックラットによる解析 査読有り

    佐藤和則, 谷山 佳弘, 竹内和久, 池田勧夫, 宇留野晃, 工藤正孝, 菅原晃, 伊藤貞嘉

    血圧 8 (3) 251-254 2001年

  172. 下垂体におけるレチノイドX受容体(RXR):その発現、調節および機能に関する検討

    菅原明, 竹内和久, 宇留野晃, Poul M.Yen、Ronald, M.Lechan, 山王なほ子, 長村義之, 永田年, William W.Chin, 伊藤貞嘉

    ホルモンと臨床 49 143-151 2001年

  173. Suppression of rat thromboxane synthase gene transcription by peroxisome proliferator-activated receptor γ in macrophages via an interaction with NRF2 査読有り

    Y. Ikeda, A. Sugawara, Y. Taniyama, A. Uruno, K. Igarashi, S. Arima, S. Ito, K. Takeuchi

    Journal of Biological Chemistry 275 (42) 33142-33150 2000年10月20日

    出版者・発行元:American Society for Biochemistry and Molecular Biology Inc.

    DOI: 10.1074/jbc.M002319200  

    ISSN:0021-9258

    詳細を見る 詳細を閉じる

    We have studied the transcription regulation of the rat thromboxane synthase (TXS) gene by peroxisome proliferator-activated receptor γ (PPARγ) in macrophages. The transcription activity of a cloned 5'-flanking region (1.6 kilobases) of the rat TXS gene (5'FL-TXS) was examined by luciferase reporter gene assay. TXS mRNA expression and the transcription activity of 5'FL-TXS were inhibited by PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2), and the thiazolidinedione troglitazone (TRO) in a dose-dependent manner. Overexpression of PPARy also significantly suppressed transcription, and further addition of PGJ2 or TRO augmerited the suppression. Deletion analysis showed that the element responsible for the PPARγ effect is located in a region containing the nuclear factor E2 (NF-E2)/AP-1 site (-98/-88), which was indicated to be the major promoter of the TXS gene. By electrophoretic mobility shift assay using the NF-E2/AP-1 site and nuclear extracts from macrophages, we observed a specific protein-DNA complex formation, which was inhibited by a specific antibody against the transcription factor NRF2 (NF-E2-related factor 2). Moreover, the complex was decreased with PGJ2, TRO, or in vitro translated PPARγ. The transcription suppression by PPARy was confirmed using this truncated NRF2-binding element (-98/-88) by the reporter gene assay. Finally, a direct interaction between PPARγ and NRF2 was confirmed by glutathione S-transferase pull-down assay. In conclusion, the NRF2-binding site (-98/-88) is the major promoter of 5'FL-TXS which can be suppressed by activated PPARγ via a protein-protein interaction with NRF2 in macrophages.

  174. ラットサイアザイド感受性Na-Cl共輸送体の部位特異的発現調節機構についての検討

    谷山佳弘, 竹内和久, 菅原明, 池田勧夫, 佐藤和則, 宇留野晃, 工藤正孝, 近藤泰輝, 伊藤貞嘉

    Therapeutic Research 21 (5) 1055-1058 2000年5月

    出版者・発行元:ライフサイエンス出版(株)

    ISSN:0289-8020

    詳細を見る 詳細を閉じる

    クローニングしたラットTSC遺伝子5'隣接領域には,TSCの組織特異的遺伝子発現を規定する部位が含まれており,またその部位特異的発現調節機構にHFH-3が関与している可能性が示唆された

  175. サイアザイド感受性Na-Cl共輸送体の部位特異的発現機構

    谷山 佳弘, 竹内 和久, 菅原 明, 池田 勧夫, 佐藤 和則, 宇留野 晃, 工藤 正孝, 近藤 泰輝, 有馬 秀二, 伊藤 貞嘉

    日本腎臓学会誌 42 (3) 278-278 2000年4月

    出版者・発行元:(一社)日本腎臓学会

    ISSN:0385-2385

    eISSN:1884-0728

  176. ステロイドによるサイアザイド感受性Na-Cl共輸送体遺伝子の転写調節

    谷山 佳弘, 竹内 和久, 菅原 明, 池田 勧夫, 佐藤 和則, 宇留野 晃, 工藤 正孝, 近藤 泰輝, 伊藤 貞嘉

    日本内分泌学会雑誌 76 (1) 158-158 2000年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

    eISSN:2186-506X

  177. 【分子高血圧 最新の進歩】血管内皮細胞における15-deoxy-Δ12,14-プロスタグランジンJ2によるラット-トロンボキサン合成酵素遺伝子の転写性発現調節

    池田 勧夫, 竹内 和久, 菅原 明, 宇留野 晃, 谷山 佳弘, 有馬 秀二, 佐藤 和則, 工藤 正孝, 近藤 泰輝, 伊藤 貞嘉

    血圧 7 (3) 285-287 2000年3月

    出版者・発行元:(株)先端医学社

    ISSN:1340-4598

    詳細を見る 詳細を閉じる

    15-deoxy-Δ12,14-プロスタグランジンJ2(PGJ2)によるトロンボキサン合成酵素(TXS)遺伝子の転写性発現調節に及ぼす影響を検討した.PGJ2はTXS mRNAの発現を増強し,またTXS遺伝子プロモーターを活性化させたことから,PGJ2はTXS遺伝子の発現を転写レベルで増強することが示唆された.トロンボキサン(TX)はTXSによって産生されるプロスタグランジン系生成物の一つで,endothelium-derived contracting factor(EDCF)である.PGJ2はTXS遺伝子の発現をうながし,血管のホメオスタシスに影響を与えている可能性が示唆された

  178. Gene transcription of thiazide-sensitive Na-Cl cotransporter: effect of steroid hormones 査読有り

    Y Taniyama, K Takeuchi, A Sugawara, Y Ikeda, K Sato, A Uruno, M Kudo, Y Kondo, S Ito

    CONTROL AND DISEASES OF SODIUM DEPENDENT TRANSPORT PROTEINS AND ION CHANNELS 1208 53-54 2000年

    出版者・発行元:ELSEVIER SCIENCE BV

    ISSN:0531-5131

  179. Effect of steroid hormones on gene transcription of thiazide-sensitive Na-Cl cotransporter: Taniyama Y, Hitomi H, Shah H, Alexander RW, Griendling KK

    Taniyama Y, Takeuchi K, Sugawara A, Ikeda Y, Sato K, Kondo Y, Kudo A, Uruno A, Ito S

    Control and Disease of Sodium Dependent Transporter Proteins and Ion Channels. ed. by E. Calafoli, M 53-54 2000年

  180. Characterization of mouse retinoid X receptor (RXR)-beta gene promoter: negative regulation by tumor necrosis factor (TNF)-alpha 査読有り

    A Sugawara, A Uruno, T Nagata, MM Taketo, K Takeuchi, S Ito

    ENDOCRINOLOGY 139 (6) 3030-3033 1998年6月

    出版者・発行元:ENDOCRINE SOC

    DOI: 10.1210/en.139.6.3030  

    ISSN:0013-7227

    eISSN:1945-7170

    詳細を見る 詳細を閉じる

    A genomic clone of mouse retinoid X receptor (RXR)-beta (Rxrb) has recently been isolated and mapped within the H2-K region of the mouse major histocompatibility complex. A putative 250-bp promoter, which is located between Rxrb and H2-Ke4, and may possibly be their common promoter, has also been identified Zn order to study the gene regulation of Rxrb, we analyzed the transcriptional function of the Rxrb promoter with chimeric constructs containing the Rxrb promoter fragments fused upstream of a firefly luciferase cDNA, which were transiently transfected into rat GH, cells. We found that 1) a part of the H2-Ke4 genomic region (1.9-kb), as well as the 250-bp promoter, was transcriptionally active as an RxrB promoter; 2) tumor necrosis factor (TNF)-alpha significantly repressed the activity of the 250-bp promoter although thyroid hormone, 9-cis retinoic acid, interleukin (IL)-1 beta, and IL-6 did not affect the activity; 3) either the change in orientation or point mutations of a consensus NF-kappa B site located in the 250-bp promoter did not affect the repression; 4) SE 203580, a highly specific inhibitor of p38 mitogen-activated protein NAP) kinase, completely abolished the repression by TNF-alpha. These data suggest that TNF-alpha represses the promoter activity of the 250-bp region, and the repression is mediated by p38 MAP kinase independent of NF-kappa B. We thus have first shown a relation between the retinoic acid receptor and a cytokine TNF-alpha.

︎全件表示 ︎最初の5件までを表示

MISC 68

  1. 東北メディカル・メガバンク計画・地域住民コホート調査詳細三次調査(宮城)の進捗

    中谷 直樹, 小暮 真奈, 畑中 里衣子, 中谷 久美, 千葉 一平, 菅野 郁美, 小原 拓, 中村 智洋, 宇留野 晃, 布施 昇男, 泉 陽子, 丹野 高三, 辻 一郎, 栗山 進一, 寳澤 篤

    東北公衆衛生学会誌 (71) 28-28 2022年7月

    出版者・発行元:東北公衆衛生学会

    ISSN:0915-549X

  2. 炭素質コンドライトの高分解能イメージング質量分析: CHN化合物の分布が示す初期太陽系での有機物生成

    古川 善博, 三枝 大輔, 可野 邦行, 宇留野 晃, 齋藤 律水, 伊藤 元雄, 松本 恵, 青木 淳賢, 山本 雅之, 中村 智樹

    日本地球化学会年会要旨集 69 190 2022年

    出版者・発行元:一般社団法人日本地球化学会

    DOI: 10.14862/geochemproc.69.0_190  

    詳細を見る 詳細を閉じる

    炭素質コンドライトに含まれる低分子量の可溶性有機物は、初期太陽系の環境を推定するための指標となる可能性がある。このような有機分子の研究は、ほとんどの場合が抽出液の分析によって行われてきた。本研究では表面支援レーザー脱離イオン化質量分析(SALDI)法により高空間分解能で炭素質コンドライト中の多種の有機物の空間分布を測定した。検出された多様なCHN化合物は同族体であり、類似した不均質な分布を示した。このことは、逐次反応が隕石構成微粒子ごとに起こっていること示しており、CHN化合物の生成が母天体集積前に起こったことを示唆している。

  3. 東北メディカル・メガバンク計画・地域住民コホート調査詳細三次調査(宮城)の概要

    中谷 直樹, 小暮 真奈, 畑中 里衣子, 菅野 郁美, 中谷 久美, 小原 拓, 中村 智洋, 宇留野 晃, 布施 昇男, 泉 陽子, 丹野 高三, 辻 一郎, 栗山 進一, 呉 繁夫, 寳澤 篤

    日本公衆衛生学会総会抄録集 80回 219-219 2021年11月

    出版者・発行元:日本公衆衛生学会

    ISSN:1347-8060

  4. MALDI-MSI分析における導電性粘着フィルムで作製した生体組織切片の有用性について

    三枝 大輔, 齋藤 律水, 川本 孔明, 宇留野 晃, 可野 邦行, 青木 淳賢, 山本 雅之, 川本 忠文

    JSBMS Letters 44 (Suppl.) 122-122 2019年8月

    出版者・発行元:(一社)日本医用マススペクトル学会

    ISSN:1881-5464

  5. 新規リスク因子(尿ナトカリ比高値・睡眠効率不良)の高血圧への集団寄与危険割合の検討

    平田 匠, 中村 智洋, 小暮 真奈, 宮川 健, 小原 拓, 中谷 直樹, 宇留野 晃, 菅原 準一, 栗山 進一, 寳澤 篤

    日本循環器病予防学会誌 54 (2) 121-121 2019年4月

    出版者・発行元:(一社)日本循環器病予防学会

    ISSN:1346-6267

  6. MSイメージングによる疾患モデル動物解析と創薬への応用性について

    三枝大輔, 三枝大輔, 三枝大輔, 齋藤律水, 齋藤律水, 宇留野晃, 宇留野晃

    バイオメディカル分析科学シンポジウム講演要旨集 32nd 2019年

    ISSN:1347-2364

  7. KEAP1‐NRF2制御系の活性化はアルツハイマー病様病態を改善する

    松丸大輔, 領家梨恵, 齋藤律水, 三枝大輔, 齊藤貴志, 西道隆臣, 川島隆太, 山本雅之, 山本雅之, 宇留野晃, 宇留野晃, 本橋ほづみ

    日本生化学会大会(Web) 91st ROMBUNNO.3P‐285 (WEB ONLY)-285] 2018年

    出版者・発行元:(公社)日本生化学会

  8. マウス一過性中大脳動脈閉塞モデルにおけるimaging mass spectrometryによるメタボローム解析

    阿部考貢, 新妻邦泰, 鹿毛淳史, 藤村幹, 三枝大輔, 宇留野晃, 山本雅之, 冨永悌二

    日本分子脳神経外科学会プログラム・抄録集 18th 2017年

  9. 質量分析計を用いるスフィンゴ脂質分子測定手法の開発

    三枝 大輔, 王 嬌, 可野 邦行, 齋藤 律水, 宇留野 晃, 青木 淳賢

    日本生化学会大会プログラム・講演要旨集 89回 [3P-076] 2016年9月

    出版者・発行元:(公社)日本生化学会

  10. レチノイド受容体と内分泌・代謝疾患

    菅原明, 宇留野晃, 横山敦, 箱田明子, 影近弘之

    日本応用酵素協会誌 (50) 21-24 2016年6月1日

    ISSN:0913-3348

  11. レチノイン酸/レチノイドの抗動脈硬化作用

    菅原明, 宇留野晃, 箱田明子, 清水恭子, 佐藤郁子, 松田謙, 壱岐裕子, 吉川雄朗, 工藤正孝, 伊藤貴子, 伊藤貞嘉

    東北大学医学部保健学科紀要 21 (2) 61-63 2012年7月

    出版者・発行元:東北大学医学部保健学科

    ISSN:1348-8899

  12. PPARγと高血圧・動脈硬化

    菅原明, 宇留野晃, 工藤正孝, 松田謙, 清水恭子, 吉川雄朗, 伊藤貴子, 箱田明子, 伊藤貞嘉

    東北大学医学部保健学科紀要 21 (1) 1-5 2012年1月

  13. レチノイドX受容体(RXR)によるACTH分泌・POMC遺伝子発現抑制作用の検討

    宇留野晃, 箱田明子, 松田謙, 工藤正孝, 岩崎泰正, 伊藤貞嘉, 菅原明

    ACTH RELATED PEPTIDES 2011年9月

  14. ACE阻害薬およびアンジオテンシンⅡ受容体拮抗薬の血管内皮細胞における遺伝子発現に及ぼす影響 マイクロアレイを用いた検討

    菅原明, 宇留野晃, 松田謙, 箱田明子, 工藤正孝, 伊藤貞嘉

    感性福祉研究所年報 2011年7月

  15. ACE阻害薬およびアンジオテンシン2受容体拮抗薬の血管内皮細胞における遺伝子発現に及ぼす影響--マイクロアレイを用いた検討

    菅原 明, 宇留野 晃, 松田 謙

    感性福祉研究所年報 (12) 175-177 2011年3月

    出版者・発行元:東北福祉大学感性福祉研究所

    ISSN:1344-9966

  16. Measurements of Aldosterone and Cortisol in Human Plasma by Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry (LC-ESI-MS/MS): Comparison to Radioimmunoassays or Immunoassays.

    M. Kudo, F. Satoh, R. Morimoto, O. Murakami, A. Sugawara, A. Uruno, K. Yamashita, M. Numazawa, S. Ito

    ENDOCRINE REVIEWS 31 (3) 2010年6月

    出版者・発行元:ENDOCRINE SOC

    ISSN:0163-769X

  17. SLEに合併した自己免疫性下垂体円の2例

    田島結実, 工藤正孝, 村上治, 森本玲, 石井智徳, 宇留野晃, 菅原明, 佐藤文俊, 伊藤貞嘉

    ACTH RELATED PEPTIDES 21 113-116 2010年3月

  18. 【核内受容体と内分泌疾患UPDATE】 PPARγと生活習慣病 (ホルモンと臨床)

    菅原明, 宇留野晃, 松田謙, 工藤正孝, 伊藤貞嘉

    ホルモンと臨床 58 (2) 143-148 2010年2月

    出版者・発行元:医学の世界社

    ISSN:0045-7167

  19. 【ストレスと糖尿病】ストレスと生体反応 Nrf2-Keap1システムによるストレス応答の制御

    宇留野 晃, 森口 尚, 山本 雅之

    Diabetes Frontier 21 (4) 412-417 2010年

    出版者・発行元:(株)メディカルレビュー社

    ISSN:0915-6593

  20. Autoantibodies to REG family proteins in Japanese diabetes patients

    N. J. Shervani, N. Noguchi, T. Ikeda, I. Takahashi, T. Yoshikawa, A. Yamauchi, A. Uruno, K. Nata, S. Takasawa, H. Okamoto, A. Sugawara

    DIABETOLOGIA 52 S114-S114 2009年9月

    出版者・発行元:SPRINGER

    ISSN:0012-186X

  21. チアゾリン誘導体はPPARγおよびCa2+/カルモジュリン依存症キナーゼ(CaMK)を介して副腎皮質癌H295R細胞におけるアルドステロン分泌を抑制する

    宇留野晃, 松田謙, 野口直哉, 吉川雄朗, 工藤正孝, 佐藤文俊, 伊藤貞嘉, 岡本宏, 菅原明

    ACTH RELATED PEPTIDES 20 36-37 2009年3月

  22. 過去八年間の当科におけるCushing病・Cushing症候群の治療成績の検討

    工藤正孝, 佐藤文俊, 森本玲, 松田謙, 宇留野晃, 菅原明, 村上治, 伊藤貞嘉

    日本内分泌学会雑誌 85 (1) 315-315 2009年

  23. サブクリニカル・クッシング症候群の診断基準の改訂 デキサメサゾン抑制試験でのサブクリニカルクッシング症候群診断基準 ms/msデータ100症例で本邦の汎用測定キットの低濃度コルチゾール測定の信頼性を検証する

    佐藤文俊, 森本玲, 工藤正孝, 宇留野晃, 菅原明, 村上治, 伊藤貞嘉

    日本内分泌学会雑誌 85 (1) 229-229 2009年

  24. 2型リアノジン受容体遺伝子にはGG-AG配列で切断されるイントロンが存在する

    池田崇之, 野口直哉, 吉川雄朗, 宇留野 晃, 那谷耕司, 高沢 伸, 岡本 宏, 米倉秀人, 菅原 明

    第82回日本生化学会大会プログラム・要旨集 82回 3T18a-6-6 2009年

    出版者・発行元:(公社)日本生化学会

  25. Sera from Japanese diabetes patients show autoimmunity to REG family protein.

    Shervani, N. J, Nata, K, Noguchi, N, Takahashi, I, Ikeda, T, Ohashi, K, Yoshikawa, T, Uruno, A, Takasawa, S, Okamoto, H, Sugawara, A

    第82回日本生化学会大会プログラム・要旨集 3P-733 2009年

  26. Reduced beta cell proliferation and impaired glucose tolerance in pancreatic beta cell specific Extl3 knockout mice

    I. Takahashi, K. Nata, N. Noguchi, T. Ikeda, K. Sugihara, M. Asano, T. Yoshikawa, A. Yamauchi, N. J. Shervani, A. Uruno, M. Unno, S. Takasawa, H. Okamoto, A. Sugawara

    DIABETOLOGIA 51 S307-S307 2008年9月

    出版者・発行元:SPRINGER

    ISSN:0012-186X

  27. 常用量の漢方薬内服中に横紋筋融解症を呈した1症例. 査読有り

    豊原敬文, 種本雅之, 宇留野晃, 阿部倫明, 阿部高明, 伊藤貞嘉

    日本腎臓学会誌 50 135-139 2008年

  28. Embryonic lethality and impaired beta cell replication by disruption of Reg receptor gene

    S. Takasawa, K. Nata, I. Takahashi, T. Ikeda, N. Noguchi, M. Asano, K. Sugihara, A. Yamauchi, T. Yoshikawa, N. J. Shervani, A. Uruno, M. Unno, A. Sugawara, H. Okamoto

    DIABETOLOGIA 50 (Suppl. 1) S206-S206 2007年9月

    出版者・発行元:SPRINGER

    ISSN:0012-186X

  29. 狭窄部最小径の腎動脈狭窄の治療指標としての有用性

    種本 雅之, 宇留野 晃, 阿部 倫明, 佐藤 文俊, 阿部 高明, 伊藤 貞嘉

    日本腎臓学会誌 49 (3) 321-321 2007年4月

    出版者・発行元:(一社)日本腎臓学会

    ISSN:0385-2385

  30. 腎血管性高血圧の画像診断における狭窄部最小径の有用性

    種本 雅之, 阿部 倫明, 宇留野 晃, 佐藤 文俊, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌 83 (1) 206-206 2007年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

  31. レチノイン酸とAm80による血管新生促進作用の検討

    斉藤明子, 菅原明, 宇留野晃, 工藤正孝, 今泉益栄, 土屋滋, 伊藤貞嘉

    日本内分泌学会雑誌 83 (1) 132-132 2007年

  32. 抗動脈硬化作用を有する心血管作動物質としてのレチノイン酸:その血管内皮機能および血管新生に及ぼす影響の検討 (脈管学)

    菅原 明, 宇留野晃, 斉藤明子, 工藤正孝, 伊藤貞嘉

    脈管学 46 365-368 2006年8月18日

  33. 腎動脈エコーが腎血管性高血圧の診断に有用であった3症例

    豊原 敬文, 宇留野 晃, 阿部 倫明, 種本 雅之, 佐藤 文俊, 阿部 高明, 竹内 和久, 伊藤 貞嘉

    日本腎臓学会誌 48 (6) 597-597 2006年8月

    出版者・発行元:(一社)日本腎臓学会

    ISSN:0385-2385

  34. アルドステロンと生活習慣病における臓器障害 原発性アルドステロン症からみたアルドステロンの臓器障害作用

    佐藤 文俊, 中村 匡宏, 森本 玲, 種本 雅之, 阿部 倫明, 宇留野 晃, 荒井 陽一, 笹野 公伸, 石橋 忠司, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌 82 (1) 36-36 2006年4月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

  35. レチノイン酸による血管新生促進作用の検討

    斉藤明子, 菅原明, 宇留野晃, 工藤正孝, 今泉益栄, 土屋滋, 伊藤貞嘉

    日本内分泌学会雑誌 82 (2) 512-512 2006年

  36. 全トランス型レチノイン酸および合成レチノイドAm80の血管内皮細胞における遺伝子発現に及ぼす影響-マイクロアレイを用いた検討- 招待有り

    菅原明, 斉藤明子, 宇留野晃, 今泉益栄, 工藤正孝, 影近弘之, 本郷道夫, 伊藤貞嘉

    血圧 13 (3) 18-20 2006年

  37. 早朝高血圧に対する新規ARBオルメサルタンによる介入 尿中アルブミン減少効果について

    佐藤 文俊, 森本 玲, 宇留野 晃, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌 81 (2) 558-558 2005年9月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

  38. Pitavastatinによる血清脂質改善・抗動脈硬化作用の臨床的検討

    森本 玲, 佐藤 文俊, 宇留野 晃, 阿部 倫明, 種本 雅之, 阿部 高明, 伊藤 貞嘉

    日本内分泌学会雑誌 81 (2) 563-563 2005年9月

    出版者・発行元:(一社)日本内分泌学会

    ISSN:0029-0661

  39. 腎動脈狭窄症における血管内超音波エコーによる診断および治療法の検討

    宇留野 晃, 阿部 倫明, 種本 雅之, 佐藤 文俊, 竹内 和久, 伊藤 貞嘉

    日本高血圧学会総会プログラム・抄録集 28回 149-149 2005年9月

    出版者・発行元:(NPO)日本高血圧学会

  40. 腎動脈狭窄の原因診断と治療法の選択における血管内超音波検査(IVUS)の有効性

    宇留野 晃, 種本 雅之, 阿部 倫明, 佐藤 文俊, 阿部 高明, 竹内 和久, 伊藤 貞嘉

    日本腎臓学会誌 47 (6) 712-712 2005年8月

    出版者・発行元:(一社)日本腎臓学会

    ISSN:0385-2385

  41. 抗動脈硬化作用を有する心脈管作動性物質としてのレチノイン酸とプロスタサイクリン : それらの血管内皮機能および血管新生に及ぼす影響

    菅原 明, 宇留野 晃, 斉藤 明子, 工藤 正孝, 伊藤 貞嘉

    臨床化学 34 71-71 2005年6月10日

    ISSN:0370-5633

  42. OO11-1 レチノイン酸の血管新生に対する作用(口演 神経芽腫(TR),第21回日本小児がん学会 第47回日本小児血液学会 同時期開催)

    斉藤 明子, 菅原 明, 今泉 益栄, 工藤 正孝, 宇留野 晃, 伊藤 貞嘉

    小児がん : 小児悪性腫瘍研究会記録 42 (3) 569-569 2005年

    出版者・発行元:がんの子供を守る会

    ISSN:0389-4525

  43. プロスタサイクリンによる血管内皮細胞でのNO産生亢進作用および血管新生促進作用 招待有り

    工藤正孝, 菅原明, 斎藤明子, 宇留野晃, 伊藤貞嘉

    血圧 12 (3) 343-345 2005年

  44. 【分子甲状腺学の進歩2004】 レチノイン酸の血管系に及ぼす影響 (ホルモンと臨床)

    宇留野晃, 菅原明, 工藤正孝, 伊藤貞嘉

    ホルモンと臨床 52 (3) 207-211 2004年3月

    ISSN:0045-7167

  45. 血管内皮細胞における肝細胞増殖因子(HGF)によるNO産生亢進機序の解明

    宇留野晃, 菅原明, 金塚完, 工藤正孝, 竹内和久, 伊藤貞嘉

    血管 27 (1) 9-9 2004年

  46. 血管内皮細胞におけるHGFによるNO産生亢進・eNOSリン酸化機構の解明およびVEGFとの差異の検討

    宇留野晃, 菅原明, 金塚完, 工藤正孝, 竹内和久, 伊藤貞嘉

    日本高血圧学会総会プログラム・抄録集 27回 110-110 2004年

  47. 血管内皮細胞における肝細胞増殖因子(HGF)によるNO産生亢進機序の解明

    宇留野晃, 菅原明, 金塚完, 工藤正孝, 谷山佳弘, 竹内和久, 伊藤貞嘉

    日本内分泌学会雑誌 80 (1) 137-137 2004年

  48. 家族発症例のMEN2Aの診断・治療と当施設経験例のまとめ

    石山勝也, 阿部高明, 森本玲, 沖津庸子, 宇留野晃, 鈴木恵綾, 村上治, 種本雅之, 佐藤文俊, 伊藤貞嘉

    日本内分泌学会雑誌 80 (2) 492-492 2004年

  49. ラット甲状腺におけるレチノイドX受容体(RXR)の発現および機能 招待有り

    宇留野晃, 菅原明, 工藤正孝, 飯高誠, 山王なほ子, 伊藤貞嘉

    診断と治療 41 (11) 3-6 2004年

  50. 血管内皮細胞での肝細胞増殖因子(HGF)によるNo産生亢進機序の解明:P13キナーゼとMAPキナーゼによるeNOSリン酸化の関与 招待有り

    宇留野晃, 菅原明, 工藤正孝, 伊藤貞嘉, 竹内和久, 伊藤貞嘉

    血圧 11 (3) 29-31 2004年

  51. 血管内皮細胞での肝細胞増殖因子(HGF)によるNO産生亢進機序の解明 PI3キナーゼとMAPキナーゼによるeNOSリン酸化の関与

    宇留野晃, 菅原明, 金塚完, 工藤正孝, 竹内和久, 伊藤貞嘉

    日本内分泌学会雑誌 79 (2) 526-526 2003年

  52. All-trans retinoic acid(ATRA)による血管内皮細胞nitric oxide(NO)産生調節機構の検討

    宇留野晃, 菅原明, 金塚完, 竹内和久, 伊藤貞嘉

    血管 26 (1) 10-10 2003年

  53. レチノイン酸による血管内皮細胞におけるNO産生亢進及びeNOS活性化メカニズムの解明

    宇留野晃, 菅原明, 金塚完, 竹内和久, 伊藤貞嘉

    日本内分泌学会雑誌 79 (1) 219-219 2003年

  54. レチノイン酸による血管内皮細胞でのeNOS活性化及びNO産生亢進機構の解明 血管内皮機能障害に対する意義

    宇留野晃, 菅原明, 金塚完, 工藤正孝, 竹内和久, 伊藤貞嘉

    日本内分泌学会雑誌 79 (2) 526-526 2003年

  55. レチノイン酸による血管内皮細胞でのeNOS活性化およびNO産生亢進:そのメカニズムの解明および血管内皮機能障害に対する意義

    宇留野晃, 菅原明, 金塚完, 竹内和久, 伊藤貞嘉

    日本高血圧学会総会プログラム・抄録集 26回 104-104 2003年

  56. Transcriptional suppression of mPPAR-gamma 2 of gene expression by TNF-alpha via inhibition of C/EBP delta during 3T3L1 adipocyte differention

    M Kudo, A Sugawara, J Sakai, K Sato, A Uruno, K Takeuchi, S Ito

    JOURNAL OF HYPERTENSION 20 S63-S63 2002年6月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  57. Transgenic rat model for renal tubule-specific transcription of thiazide-sensitive Na-Cl cotransporter gene

    K Takeuchi, Y Taniyama, K Sato, A Sugawara, A Uruno, M Kudo, S Ito

    JOURNAL OF HYPERTENSION 20 S97-S97 2002年6月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  58. Transcription suppression of thromboxane receptor gene expression by retinoic acid in vascular smooth muscle cells

    A Sugawara, K Takeuchi, A Uruno, M Kudo, K Sato, S Ito

    JOURNAL OF HYPERTENSION 20 S173-S173 2002年6月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  59. Transcriptional regulation of rat heme oxygenase-1 gene by retinoblastoma zinc finger protein

    A Uruno, K Tekeuchi, A Sugawara, M Kudo, K Sato, S Shibahara, S Ito

    JOURNAL OF HYPERTENSION 20 S106-S106 2002年6月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  60. All-trans Retinoic Acidによる血管内皮細胞内Nitric Oxideの調節

    宇留野晃, 菅原明, 金塚完, 竹内和久, 伊藤貞嘉

    日本内分泌学会雑誌 78 (2) 455-455 2002年

  61. アンジオテンシン(AⅡ)タイプ1(AT1)受容体遺伝子のチアゾリジン系薬剤による負の転写調節:薬剤間における差異の検討 招待有り

    菅原明, 竹内和久, 宇留野晃, 工藤正孝, 池田勧夫, 佐藤和則, 伊藤貞嘉

    血圧 3月号 57-59 2002年

  62. DATA Analysis ホルモンであるレジスチンは肥満と糖尿病を関連づける (臨床高血圧)

    宇留野晃, 竹内和久, 伊藤貞嘉

    臨床高血圧 7 (3) 200-201 2001年6月

  63. 下垂体におけるレチノイドX受容体(RXR) : その発現, 調節および機能に関する検討

    菅原 明, 竹内 和久, 宇留野 晃, YEN Paul M., LECHAN Ronald M., 山王 なほ子, 長村 義之, 永田 年, CHIN William W., 伊藤 貞嘉

    ホルモンと臨牀 49 (2) 35-43 2001年2月1日

    ISSN:0045-7167

  64. Differential effects among thiazolidinediones on the transcription of thromboxane receptor and angiotensin II type 1 receptor genes

    A Sugawara, K Takeuchi, A Uruno, Y Ikeda, S Arima, K Sato, M Kudo, Y Taniyama, S Ito

    JOURNAL OF HYPERTENSION 18 S6-S6 2000年

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  65. Differential transcription regulation of rat thromboxane synthase gene by 15-deoxy-Delta(12,14) prostaglandin J(2) between macrophages and endothelial cells

    Y Ikeda, K Takeuchi, A Sugawara, Y Taniyama, K Sato, A Uruno, M Kudo, S Arima, S Ito

    JOURNAL OF HYPERTENSION 18 S182-S182 2000年

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0263-6352

  66. フォ−ラム 高血圧と臓器障害 組織特異的 招待有り

    谷山佳弘, 竹内和久, 菅原明, 池田勧夫, 佐藤和則, 工藤佳孝, 宇留野晃, 伊藤貞嘉

    血圧 7 (7) 8-11 2000年

  67. Negative regulation of angiotensin II type 1 receptor (ATIR) gene expression by peroxisome proliferator-activated receptor (PPAR)-gamma in vascular smooth muscle cells

    A Sugawara, K Takeuchi, Y Ikeda, A Uruno, M Kudo, Y Taniyama, S Ito

    HYPERTENSION 34 (2) 363-363 1999年8月

    出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS

    ISSN:0194-911X

  68. 【分子高血圧 最新の進歩】15-deoxy-Δ12,14-プロスタグランジンJ2及びトログリタゾンによるトロンボキサン受容体遺伝子の負の転写調節

    菅原 明, 竹内 和久, 宇留野 晃, 池田 勧夫, 工藤 正孝, 谷山 佳弘, 高橋 信行, 阿部 倫明, 伊藤 貞嘉

    血圧 6 (3) 213-215 1999年3月

    出版者・発行元:(株)先端医学社

    ISSN:1340-4598

    詳細を見る 詳細を閉じる

    15-deoxy-Δ12,14-PGJ2はTXR mRNAの発現を抑制し,トログリタゾンと同様TXR遺伝子プロモーター活性を低下させたことから,これらがTXR遺伝子を転写レベルで抑制しているものと考えられた.TXRの発現抑制は,高血圧や動脈硬化の進展抑制に関与している可能性が推定された

︎全件表示 ︎最初の5件までを表示

書籍等出版物 3

  1. Molecular Nutrition and Diabetes, 1st Edition.

    Yagishita Y, Uruno A, Yamamoto M

    Elsevier Science B.V. 2015年

  2. クッシング症候群診療マニュアル

    菅原明, 村上治, 佐藤文俊, 宇留野晃, 森本玲, 工藤正孝, 伊藤貞嘉

    診断と治療社 2009年

  3. Control and Diseases of Sodium Dependent Transporter Proteins and Ion Channels.

    Taniyama Y, Takeuchi K, Sugawara A, Ikeda Y, Sato K, Kondo Y, Kudo M, Uruno A, Ito S

    Elsevier Science B.V. 2000年

講演・口頭発表等 7

  1. Nrf2を標的としたアルツハイマー病の治療戦略 招待有り

    宇留野晃

    第4回 医薬品開発研究センターシンポジウム 「脳と創薬」 2021年8月6日

  2. The multiple functions of Nrf2 in diabetes mellitus and obesity 国際会議 招待有り

    宇留野 晃

    The Environmental Response V 2019年9月13日

  3. The Keap1-Nrf2 system and oxidative damage in diabetes mellitus 招待有り

    宇留野 晃

    第61回日本糖尿病学会年次学術集会 2018年

  4. Nrf2による代謝恒常性維持機構の解明 招待有り

    宇留野 晃

    第396回東北医学会例会

  5. 糖尿病におけるKeap1-Nrf2系の役割 招待有り

    宇留野 晃

    第89回日本生化学会大会

  6. Nrf2によるグルコース代謝恒常性維持機構の解明 招待有り

    宇留野 晃

    第83回例会・シンポジウム

  7. 視床下部の酸化ストレスによる肥満および糖尿病発症機序の解明 招待有り

    宇留野 晃

    第14回レドックス・ライフイノベーションシンポジウム

︎全件表示 ︎最初の5件までを表示

共同研究・競争的資金等の研究課題 19

  1. アルツハイマー病におけるグルタチオン代謝異常の機序の解明

    宇留野 晃

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Tohoku University

    2020年4月1日 ~ 2023年3月31日

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    アルツハイマーの脳におけるグルタチオン代謝異常の機序を解明するため、Nrf2活性化アルツハイマー病モデルマウスを作出し、脳内グルタチオン関連代謝物の測定を行った。アルツハイマー病モデルマウスであるAPPV717I::TAUP301LおよびAppNLGF/NLGFマウスを使用し、これらのマウスに対して、Nrf2活性化剤投与によるNrf2活性化モデルと、Keap1遺伝子改変によるNrf2活性化モデルを導入し、それぞれの脳における還元型グルタチオン、および還元型グルタチオン合成に関連するアミノ酸およびTCA回路の代謝物を解析し、比較検討を行った。アミノ酸の解析は1,5-DANをマトリックスとして用いたMALDI-質量分析イメージング法による代謝物分布と、とGC-MS法による定量的解析を組み合わせて行った。MALDI-質量分析イメージング法では、AppNLGF/NLGFマウスにおけるKeap1遺伝子改変によるNrf2活性化モデルの脳では、アミノ酸およびTCA回路代謝物の低下を認めたが、AppNLGF/NLGFマウスでのNrf2活性化剤投与によるNrf2活性化モデルの脳では還元型グルタチオンは増加したものの、これらの代謝物の低下は認めなかった。以上から、薬剤によるNrf2活性化は還元型グルタチオンは増加させるものの、アミノ酸やTCA回路代謝物は低下させないことが明らかとなった。この結果は、Nrf2活性化剤が、より安全にNrf2を活性化して、グルタチオン代謝へ介入できることを示すものであった。

  2. 脳内広範囲薬剤送達技術を用いたChemicalSurgery確立に向けた基礎研究

    齋藤 竜太, 冨永 悌二, 宇留野 晃

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Scientific Research (B)

    研究機関:Tohoku University

    2017年4月1日 ~ 2020年3月31日

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    1. 投与薬剤の代謝経路解明 昨年度の研究で脳内局所へ投与された薬剤は、投与部位には次第に代謝されながら96時間程度留まること、またそれ以外は体内へ分布した後に速やかに尿中,消化管中へ排泄されることが判明した。引き続いて、本年度は局所での薬剤分布に関して解析した。ラット脳内への局所投与に際して、薬剤ACNUと色素evans blueを混合投与し、その直後にラットを安楽死させ、脳切片を作成した。質量分析法を用いて、作成した脳切片上でのACNUの分布を可視化する条件を検討、同定し、可視化に成功した。実際の薬剤分布は、混合投与したevans blue色素の分布とほぼ一致していることが確認できた。 2. 生体内での薬物動態の可視化 昨年度までの研究で、薬剤局所投与後、MRIにてT2mapを撮影し、投与前後で比較することで薬剤分布が可視化できる可能性を確認した。本年度は、当科で実施している脳幹部神経膠腫症例に対する薬剤局所投与の臨床研究症例において、薬剤投与前後のT2map画像を撮影した。現時点まで2症例での解析を終了したが、いずれの症例においても本法により薬剤分布を可視化できる可能性が示された。腫瘍を有する実際の症例においても本法により薬剤分布を可視化できる可能性が示されたことになり、さらに症例数を重ねてproof of conceptを得る方針である。 3.新規超音波送達システムを用いる際の超音波が脳に与える影響の解明 新規超音波システムの音場特性評価として水中における超音波の伝搬を測定しデータの集積を行った。

  3. Nrf2を標的とした糖尿病に合併する認知症発症予防法の開発

    宇留野 晃

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Tohoku University

    2017年4月1日 ~ 2020年3月31日

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    アルツハイマー病モデルマウスであるApp NL-G-F/NL-G-Fマウスと恒常性Nrf2誘導変異であるKeap1floxA/floxAマウスを交配して、Nrf2活性化アルツハイマー病モデルApp NL-G-F/NL-G-F::Keap1floxA/floxAマウスを作出し、脳の生化学的解析を実施した。 Nrf2の標的遺伝子であるグルタチオン合成系酵素の影響を評価するために、脳内の還元型グルタチオンの分布を質量分析イメージング技術を用いて解析を行った。その結果、App NL-G-F/NL-G-Fマウスでは記憶に重要な海馬領域を中心とした還元型グルタチオンの低下を認めたが、App NL-G-F/NL-G-F::Keap1floxA/floxA複合変異マウスではApp NL-G-F/NL-G-Fマウスで認めた還元型グルタチオンの低下を認られなかったことから、アルツハイマー病の病態では重要な抗酸化分子であるグルタチオンが低下するものの、Nrf2誘導によりその低下を予防できることが明らかとなった。 さらに、抗酸化作用のあるプラズマローゲン型ホスファチジルエタノールアミン分布を質量分析イメージングで調べたところ、App NL-G-F/NL-G-Fマウスでは多価不飽和脂肪酸を含むプラズマローゲン型ホスファチジルエタノールアミンが海馬で低下していたが、App NL-G-F/NL-G-F::Keap1floxA/floxA複合変異マウスではその変異を認めなかった。 これらの結果から、Nrf2誘導は、認知症病態モデルの海馬における還元型グルタチオンや多価不飽和脂肪酸を含むプラズマローゲン型ホスファチジルエタノールアミンなどの抗酸化物質を保持しすることが明らかになった。

  4. 酸化ストレス増加が引き起こすインスリン抵抗性の病態解明とNrf2の役割(国際共同研究強化) 競争的資金

    宇留野 晃

    2017年4月 ~ 2020年3月

  5. Nrf2を標的にした糖尿病に合併する認知症発症予防法の開発 競争的資金

    宇留野 晃

    2017年4月 ~ 2020年3月

  6. 炭素質隕石の有機分子分布イメージングへの挑戦

    古川 善博, 中村 智樹, 宇留野 晃, 三枝 大輔, 齋藤 律水

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)

    研究種目:Grant-in-Aid for Challenging Research (Exploratory)

    研究機関:Tohoku University

    2017年6月30日 ~ 2019年3月31日

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    本研究では隕石中に含まれる有機分子の分布をマイクロメーターの空間分解能で明らかにすることに挑戦した。有機分子の空間分布を明らかにするために、隕石を成形し、MALDIベースのイオン化によるイメージング質量分析計で隕石を測定を行なった。その結果、いくつかの有機物を示す質量についての分布図を得ることができた。数マイクロメートルスケールの有機物分布はこれまでの隕石研究では明らかになっておらず、隕石中の有機物が太陽系のどこでいつできたのかを明らかにするために役立つはずである。現在は得られた質量情報から分子の特定に向けて分析を継続している。

  7. 代謝制御における酸化ストレスの役割の解明(国際共同研究強化)

    宇留野 晃

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Fund for the Promotion of Joint International Research (Fostering Joint International Research)

    研究種目:Fund for the Promotion of Joint International Research (Fostering Joint International Research)

    研究機関:Tohoku University

    2017年 ~ 2019年

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    糖尿病は重篤な合併症を引き起こす疾患であるが、酸化ストレスとの関連が強い。酸化ストレスの制御に関わる転写因子としてCNC因子のNrf2およびNrf1が知られているが、これらの転写因子は抗酸化酵素、解毒代謝酵素、プロテアソームサブユニットなどに加えて、代謝系酵素の遺伝子発現も制御している。線虫のCNC因子であるskn-1は同一遺伝子からスプライスバリアントとしてNrf2やNrf1のオルソログを発現する。線虫におけるRNAiによるskn-1ノックダウンおよびskn-1欠損モデルの代謝解析を実施したところ、脂質の組成や運動能の変化を認めた。

  8. 酸化ストレス増加が引き起こすインスリン抵抗性の病態解明とNrf2の役割 競争的資金

    宇留野 晃, 山本 雅之, 柳下 陽子

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Tohoku University

    2014年4月1日 ~ 2017年3月31日

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    糖尿病は生活パターンの変化から患者数は増加しており、その病態の解明は重要な課題である。糖尿病は酸化ストレスの発生と関連が強い疾患と考えられていることから、その解明を目指した。 ラットインスリンプロモーターCreによる条件付きセレノシステイン転移RNA(Trsp)欠失による(TrpsRIPKO)マウスでは、脳視床下部領域で酸化ストレスが増加しインスリンおよびレプチン抵抗性を認め、高脂肪食負荷時に糖尿病および肥満が発症した。さらに、これらの表現型はNrf2活性化により抑制された。以上から脳視床下部の酸化ストレスは肥満・糖尿病を発症させ、Nrf2により病態が制御可能であることが明らかとなった。

  9. 新たな組織特異的遺伝子改変マウスの樹立による膵β細胞におけるNrf2の機能解明

    柳下 陽子, 宇留野 晃, 山本 雅之, 長沼 絵里子, 伊達 文子

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up

    研究種目:Grant-in-Aid for Research Activity Start-up

    研究機関:Tohoku University

    2014年8月29日 ~ 2016年3月31日

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    転写因子Nrf2は、酸化ストレス応答性の生体防御因子である。ラットインスリンプロモータ(RIP)によるCre発現マウスは、Cre-loxpシステムによるβ細胞遺伝子改変に用いられるが、実験系の問題点からβ細胞解析が困難となる局面があった。本研究では、マウスIns1遺伝子を含む大腸菌人工染色体(BAC)によるCre発現を利用した新規膵β細胞Nrf2活性化マウスを作出し、β細胞におけるNrf2の機能解明を目指した。本マウスは優れた膵β細胞組織特異的な遺伝子改変を示し、ストレプトゾトシン投与によるβ細胞障害に対してNrf2が強い抑制作用を示すことが初めて明らかとなった。

  10. ストレス応答性転写因子による代謝・病態制御

    山本 雅之, 勝岡 史城, 宇留野 晃, 鈴木 教郎

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)

    研究種目:Grant-in-Aid for Scientific Research (A)

    研究機関:Tohoku University

    2012年4月1日 ~ 2015年3月31日

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    Nrf2を中心とした環境応答転写制御システムは、ストレス時に各種生命活動を結ぶハブとしての機能を活用し、基礎的な細胞機能制御ネットワーク形成にも大きく寄与しているという新しい仮説を提唱し、その検証と全容解明を目指して本研究を開始した。その結果、Keap1の反応性システイン残基が各種ストレスに対して選択的に利用されていることを解明した。また、内因性のシグナルがオートファジーを介してNrf2の活性を制御することを示した。さらに、Nrf2が臓器形成に重要な役割を果たす一方、これらの臓器における腫瘍や炎症などの病態進展においても鍵因子として機能していることを見いだした。

  11. 肥満が引き起こす膵β細胞障害におけるKeap1-Nrf2システムの役割 競争的資金

    宇留野 晃

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)

    研究種目:Grant-in-Aid for Young Scientists (B)

    研究機関:Tohoku University

    2012年4月1日 ~ 2014年3月31日

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    Keap1-Nrf2システムは、酸化ストレスなどの環境ストレスを処理するために重要な生体防御機構の一つである。糖尿病は重篤な合併症を引き起こす社会的にも重要な代謝疾患であるが、その発症や進行において膵β細胞の保護は重要である。Keap1-Nrf2システムを活性化したモデルマウスは、肥満型糖尿病モデルマウスにおける膵β細胞障害をほぼ完全に抑制した。また、肥満型糖尿病モデルマウスから単離した膵ランゲルハンス島でNrf2を活性化すると抗酸化酵素が誘導された。以上よりKeap1-Nrf2システムの活性化は肥満による膵β細胞障害のよい治療標的になりうることが明らかとなった。

  12. 膵β細胞におけるKeap1-Nrf2システムによる酸化ストレス応答機構の解明 競争的資金

    宇留野 晃

    2010年4月 ~ 2012年3月

  13. 膵β細胞におけるKeap1-Nrf2システムによる酸化ストレス応答機構の解明

    宇留野 晃, 山本 雅之

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up

    研究種目:Grant-in-Aid for Research Activity Start-up

    研究機関:Tohoku University

    2010年 ~ 2011年

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    転写因子であるNrf2は酸化ストレスなどにより活性化され、数多くの抗酸化酵素を増加させることで、ストレス防御に重要な役割を果たしている。Keap1はストレスセンサーを感知してNrf2の機能を制御しており、Keap1-Nrf2システムとして生体の環境維持に重要な役割を果たしている。本研究では、Keap1-Nrf2システムの膵β細胞における役割について解析を行った。膵ランゲルハンス島において、Nrf2標的遺伝子群は、酸化ストレス等によって誘導され、Nrf2遺伝子ノックアウトマウスの膵ランゲルハンス島ではNrf2標的遺伝子の発現は低下していた。さらに、膵β細胞障害モデルマウスにおけるNrf2遺伝子ヘテロノックアウトは、膵ランゲルハンス島の障害を悪化させ、血糖値を上昇させた。以上より、Keap1-Nrf2システムは膵β細胞におけるストレスに対する防御機構に重要な役割を果たしており、その破綻は糖尿病発症に結びつくことが明らかとなった。

  14. p38 MAPKを標的にした動脈硬化性疾患に対する新規治療法の開発 競争的資金

    宇留野 晃

    2007年4月 ~ 2010年3月

  15. p38MAPKを標的にした動脈硬化性疾患に対する新規治療法の開発

    宇留野 晃

    2007年 ~ 2009年

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    p38MAPKは虚血や炎症で活性化されアポトーシスや細胞増殖に関与するが、血管新生を強力な調節因子であることから、これを直接の標的とした血管新生治療の可能性を検討した。p38MAPK活性化作用のあるアニソマイシンの血管新生への作用を検討したところ、低濃度よりin vitro管腔形成を強力に抑制したが、p38MAPK阻害剤はアニソマイシンによる管腔形成抑制作用を強力に阻害した。p38MAPK阻害剤はアニソマイシン非刺激時にも管腔形成を強力に促進したことから、in vitro管腔形成系においては定常状態から若干p38MAPKが活性化されているが、さらに虚血や炎症などのp38MAPKが活性化された状態では、p38MAPK阻害剤はより管腔形成を促進しやすいと考えられた。さらに、スタチン系製剤は低濃度でp38MAPKの活性化を抑制する作用があることから、血管内皮前駆細胞の誘導作用以外に管腔形成自体も促進する可能性が示唆された。

  16. 腎微小循環における肝細胞増殖因子の病態生理学的意義の解明 競争的資金

    宇留野 晃

    2005年4月 ~ 2007年3月

  17. レチノイン酸による血管内皮におけるPI3キナーゼ調節機構の解明

    宇留野 晃

    2007年 ~ 2007年

  18. レチノイン酸受容体の活性化を利用した抗動脈硬化療法および血管新生療法の開発

    菅原 明, 伊藤 貞嘉, 佐藤 靖史, 影近 弘之, 佐藤 成, 宇留野 晃

    提供機関:Japan Society for the Promotion of Science

    制度名:Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    研究種目:Grant-in-Aid for Scientific Research (C)

    研究機関:Tohoku University

    2006年 ~ 2007年

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    【目的】近年の動脈硬化性病変患者の増加に伴い、治療的血菅再生療法の重要性が高まっている。今回我々は、ピタミンAの天然誘導体である全トランス型レチノイン酸(ATRA)及び合成レチノイドAm80を用いて、それらの血管新生に対する効果を検討した。【方法】1)ヒト臍帯静脈血管内皮細胞(HUVEC)とヒト皮膚線維芽細胞(NHDF)の共培養下で、ATRAまたはAm80の投与下で9日間培養した後、形成された管腔の面積と長さを解析した。2)ATRA及びAm80によるHUVECの増殖能と遊走能を評価した。3)内因性VEGF分泌およびmRNA発現の変化をELISA法ならびに定量PCRを用いて評価した。4)HUVEC上の2型VEGF受容体(KDR)のmRNA発現の変化を、定量PCRを用いて評価した。5)1)で用いた共培養系において、VEGF中和抗体またはKDR中和抗体の添加が管腔の面積・長さに及ぼす影響を解析した。【成績】1)ATRA及びAm80により管腔形成が促進された。2)ATRA及びAm80によりHUVEC増殖能の亢進が認められたが、遊走能の変化は認められなかった。3)NHDFとHUVECの共培養下およびNHDF単独培養下において、ATRA及びAm80による内因性VEGF分泌およびmRNA発現の亢進が認められた。4)HUVECにおいてATRAによるKDR mRNA発現の亢進が認められた。5)ATRAによる管腔形成は、VEGF中和抗体またはKDR中和抗体の添加により抑制された。【結論】本研究により、ATRA及び、Am80が管腔形成を促進することが明らかとなった。その機序として、HUVECの増殖促進作用、NHDFにおけVEGF分泌・発現の促進作用、およびHUVECにおけるKDRの発現亢進が考えられた。以上の結果から、ATRA及びAm80は虚血性疾患における治療的血管再生療法に有効である可能性が示唆された。

  19. 腎微小循環における肝細胞増殖因子の病態生理学的意義の解明

    宇留野 晃

    2005年 ~ 2006年

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    1.目的および方法:一般的に腎臓は血管新生が引き起こりにくい臓器であるが、腎傷害モデル動物の残存腎の微小血管維持に血管新生因子が関与することが知られる。一方、粥状動脈硬化で新生血管がその不安定化に強く関与することも知られ、腎の血流維持に関して、血管新生因子の重要度は増している。肝細胞増殖因子(HGF)は血管新生促進因子としてよく知られるが、その一方でスタチン系製剤は低濃度で血管新生促進因子として作用し、高濃度で血管新生抑制因子として作用することが知られる。ことから、その協調作の機序について検討した。皮膚線維芽細胞と臍帯静脈血管内皮細胞(HUVEC)を共培養し、HGFおよびフルバスタチン(Flu)を単独または併用下に11日間培養し、形成された管腔を解析した。HUVECをHGFおよびFluで刺激し、Aktおよびp38MAPKのリン酸化をウエスタンブロット法で、アポトーシスをTUNEL染色で細胞増殖能をBrdUの取り込みにより検討した。 2結果:低濃度FluはHGFと相加的な管腔形成の亢進を認めたが、高濃度FluはHGFによる管腔形成を完全に抑制した。低濃度FluはHUVECのアポトーシスを抑制し、高濃度Aktは細胞増殖能を完全に抑制した。低濃度FluはHGF刺激によるHUVECのp38MAPKリン酸化を抑制し、高濃度FluはAktリン酸化を抑制した。 3.結論:低濃度FluはHUVECのHGF刺激によるp38MAPKリン酸化を低下することアポトーシスを抑制し、高濃度FluはHGF刺激によるAktリン酸化を抑制することにより細胞増殖を抑制し、結果としてHGFによる血管新生を強力に調節していた。

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