The roles of methylxanthine derivative on prevention of several disorders

• Project/Area Number: 25282021
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Eating habits
• Research Institution: Kanazawa University
• Principal Investigator: SUGIMOTO Naotoshi 金沢大学, 医学系, 准教授 (80272954)
• Co-Investigator(Kenkyū-buntansha): 紫藤 治 島根大学, 医学部, 教授 (40175386) ; 谷内江 昭宏 金沢大学, 医学系, 教授 (40210281) ; 少作 隆子 金沢大学, 保健学系, 教授 (60179025) ; 平田 耕造 神戸女子大学, 家政学部, 教授 (70110624)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2016: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 栄養 / 嗜好食品 / がん化予防 / 老化予防 / 認知予防 / 食品 / 栄養学 / 生理学

Outline of Final Research Achievements

Theobromine, which is a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. Mice were fed a diet supplemented with 0.05% theobromine for 30 days. The theobromine-fed (TB) mice performed better on the three-lever task than the control (CN) mice did. Brain-derived neurotrophic factor (BDNF) in brain were higher in the TB mice compared with those in the CN mice. BDNF supports cell survival and neuronal functions, including learning and memory. These results strongly suggested that orally administered theobromine augmented the motor learning in mice.

Research Products

• [Journal Article] Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice. (2017)
  • Author(s): Yoneda M, Sugimoto N, Katakura M, Matsuzaki K, Tanigami H, Yachie A, Ohno-Shosaku T, Shido O.
  • Journal Title: J Nutr Biochem. Volume: 39 Pages: 110-116
  • DOI: 10.1016/j.jnutbio.2016.10.002
  • NAID: 120005895700
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Capsaicin partially mimics heat in mouse fibroblast cells in vitro. (2017)
  • Author(s): Sugimoto N, Katakura M, Matsuzaki K, Nakamura H, Yachie A, Shido O.
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol. Volume: 390 Issue: 3 Pages: 281-289
  • DOI: 10.1007/s00210-016-1331-6
  • NAID: 120005982994
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Protein kinase A and Epac activation by cAMP regulate the expression of glial fibrillary acidic protein in glial cells. (2016)
  • Author(s): Sugimoto N, Miwa S, Nakamura H, Tsuchiya H, Yachie A.
  • Journal Title: Arch Biol Sci. Volume: 68 Issue: 4 Pages: 795-801
  • DOI: 10.2298/abs160112067s
  • NAID: 120005982993
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The critical role of lipopolysaccharide in the upregulation of aquaporin 4 in glial cells treated with Shiga toxin. (2015)
  • Author(s): Sugimoto N, Leu H, Inoue N, Shimizu M, Toma T, Kuroda M, Saito T, Wada T, Yachie A.
  • Journal Title: J Biomed Sci Volume: 22 Issue: 1 Pages: 78-78
  • DOI: 10.1186/s12929-015-0184-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] β-amyloid infusion into lateral ventricle alters behavioral thermoregulation and attenuates acquired heat tolerance in rats (2015)
  • Author(s): Kentaro Matsuzaki, Masanori Katakura, Naotoshi Sugimoto, Toshiko Hara, Michio Hashimoto & Osamu Shido
  • Journal Title: Temperature Volume: 2（３） Issue: 3 Pages: 418-424
  • DOI: 10.1080/23328940.2015.1044635
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Oral intake of encapsulated dried ginger root powder hardly affects human thermoregulatory function, but appears to facilitate fat utilization. (2015)
  • Author(s): Miyamoto M, Matsuzaki K, Katakura M, Hara T, Tanabe Y, Shido O
  • Journal Title: Int J Biomet. Volume: 未定 Issue: 10 Pages: 1461-1474
  • DOI: 10.1007/s00484-015-0957-2
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Involvement of neurogenesis in the hypothalamic area in establishing long-term heat acclimation in rats (2015)
  • Author(s): Osamu Shido, Kentaro matsuzaki
  • Journal Title: Temperature Volume: 2 (3) Issue: 3 Pages: 362-367
  • DOI: 10.1080/23328940.2015.1076591
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Aging attenuates acquired heat tolerance and hypothalamic neurogenesis in rats. (2015)
  • Author(s): Matsuzaki K, Katakura M, Inoue T, Hara T, Hashimoto M, Shido O.
  • Journal Title: J Comp Neurol. Volume: 523(8) Issue: 8 Pages: 1190-201
  • DOI: 10.1002/cne.23732
  • NAID: 120006938647
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Long-term Heat Exposure Prevents Hypoxia-Induced Apoptosis in Mouse Fibroblast Cells (2014)
  • Author(s): Sugimoto N, Shido O, Matsuzaki K, Katakura M, Hitomi Y, Tanaka M, Sawaki T, Fujita Y, Kawanami T, Masaki Y, Okazaki T, Nakamura H, Koizumi S, Yachie A and Umehara H
  • Journal Title: Cell biochemistry and biophysics Volume: (in press) Issue: 1 Pages: 301-7
  • DOI: 10.1007/s12013-014-9912-9
  • Peer Reviewed
• [Journal Article] Shiga toxin-2 enhances heat-shock-induced cell death in cultured and primary glial cells. (2014)
  • Author(s): Sugimoto N, Toma T, Shimizu M, Kuroda M, Wada T, Yachie A.
  • Journal Title: Cell Biol Toxicol Volume: 30 Issue: 5 Pages: 289-299
  • DOI: 10.1007/s10565-014-9286-1
  • Peer Reviewed / Open Access
• [Journal Article] Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt/mammalian target of rapamycin kinase, and nuclear factor-kappa B (2014)
  • Author(s): Sugimoto N, Miwa S, Hitomi Y, Nakamura H, Tsuchiya H, Yachie A
  • Journal Title: Nutr Cancer Volume: 66(3) Issue: 3 Pages: 419-23
  • DOI: 10.1080/01635581.2013.877497
  • Peer Reviewed
• [Journal Article] Rotavirus gastroenteritis-associated urinary ammonium acid urate crystals (2014)
  • Author(s): Yokoyama T, Sugimoto N, Kato E, Ohta K, Ishikawa S, Ueno K, Shimizu M, Yachie, A
  • Journal Title: Pediatrics International Volume: 57 Issue: 1 Pages: 158-160
  • DOI: 10.1111/ped.12405
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Upregulation of aquaporin expression in the salivary glands of heat-acclimated rats (2013)
  • Author(s): Sugimoto N, Matsuzaki K, Ishibashi H, Tanaka M, Sawaki T, Fujita Y, Kawanami T, Masaki Y, Okazaki T, Sekine J, Koizumi S, Yachie A, Umehara H and Shido O
  • Journal Title: Scientific Reports Volume: 3 Issue: 1 Pages: 1763-1763
  • DOI: 10.1038/srep01763
  • Peer Reviewed
• [Journal Article] Lactobacillus casei cell wall extract directly stimulates the expression of COX2 independent of Toll-like receptor 2 in rat glial cells (2013)
  • Author(s): Sugimoto N, Ohta K, Saito T, Nakayama Y, Nakamura T, Maeda A, Yachie A.
  • Journal Title: J Microbiol Immunol Infect. Volume: 46 Issue: 5 Pages: 389-92
  • DOI: 10.1016/j.jmii.2012.03.004
  • NAID: 120004161555
  • Peer Reviewed
• [Journal Article] Dynamic color-coded fluorescence imaging of the cell-cycle phase, mitosis, and apoptosis demonstrates how caffeine modulates cisplatinum efficacy (2013)
  • Author(s): Miwa S, Yano S, Tome Y, Sugimoto N, Hiroshima Y, Uehara F, Mii S, Kimura H, Hayashi K, Efimova EV, Fujiwara T, Tsuchiya H, Hoffman RM
  • Journal Title: J Cell Biochem Volume: 114(11) Issue: 11 Pages: 2454-60
  • DOI: 10.1002/jcb.24593
  • Peer Reviewed
• [Journal Article] Real-time Imaging of αv Integrin Molecular Dynamics in Osteosarcoma Cells In Vitro and In Vivo. (2013)
  • Author(s): Tome Y, Sugimoto N, Yano S, Momiyama M, Mii S, Maehara H, Bouvet M, Tsuchiya H, Kanaya F, Hoffman RM.
  • Journal Title: Anticancer Res. Volume: 33 Pages: 3021-3025
  • Peer Reviewed
• [Journal Article] High Lung-metastatic Variant of Human Osteosarcoma Cells, Selected by Passage of Lung Metastasis in Nude Mice, Is Associated with Increased Expression of αvβ3 Integrin. (2013)
  • Author(s): Tome Y, Kimura H, Maehara H, Sugimoto N, Bouvet M, Tsuchiya H, Kanaya F, Hoffman RM.
  • Journal Title: Anticancer Res. Volume: 33 Pages: 3623-3628
  • Peer Reviewed
• [Journal Article] Targeted activation of PKA and Epac promotes glioblastoma regression in vitro (2013)
  • Author(s): Sugimoto N, Miwa S, Tsuchiya H, Hitomi Y, Nakamura H, Yachie A, Koizumi S
  • Journal Title: Mol Clin Oncol Volume: 1(2) Issue: 2 Pages: 281-285
  • DOI: 10.3892/mco.2013.65
  • Peer Reviewed
• [Journal Article] Soluble ST2 as a marker of disease activity in systemic juvenile idiopathic arthritis. (2013)
  • Author(s): Ishikawa S, Shimizu M, Ueno K, Sugimoto N, Yachie A.
  • Journal Title: Cytokine Volume: 62 Issue: 2 Pages: 272-277
  • DOI: 10.1016/j.cyto.2013.03.007
  • NAID: 130007956852
  • Peer Reviewed
• [Journal Article] Uncultured adipose-derived regenerative cells promote peripheral nerve regeneration (2012)
  • Author(s): Suganuma S, Tada K, Hayashi K, Takeuchi A, Sugimoto N, Ikeda K, Tsuchiya H
  • Journal Title: J Orthop Sci Volume: 18 Issue: 1 Pages: 145-51
  • DOI: 10.1007/s00776-012-0306-9
  • Peer Reviewed
• [Presentation] Theobromine crosses the blood brain barrier resulting in increased phosphorylation of vasodilator-stimulated phosphoprotein and cAMP-response element-binding protein in the mouse brain (2017)
  • Author(s): Sugimoto N, Katakura M, Matsuzaki K, Yoneda M, Sumiyoshi E, Ohno-Shosaku T, Yachie A, Shido O.
  • Organizer: FFC’s 21st International Conference “Functional Foods and Bioactive Compounds in Health and Gisease: Science and Practice”
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2017-03-25
  • Int'l Joint Research
• [Presentation] 高齢者から子供まで親しまれる嗜好食品の可能性 (2016)
  • Author(s): 杉本直俊
  • Organizer: 第四回「食と環境、そして高齢化を考える研究会」
  • Place of Presentation: 三重県志摩市
  • Year and Date: 2016-10-21
  • Invited
• [Presentation] Theobromine crosses the blood brain barrier in vivo resulting in increased phosphorylation of vasodilator-stimulated phosphoprotein in the mouse brain (2016)
  • Author(s): Sugimoto N, Katakura M, Matsuzaki K, Ohno-Shosaku T, Yachie A, Shido O.
  • Organizer: Physiology 2016
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2016-07-29
  • Int'l Joint Research
• [Presentation] Theobromine, the primary methylxanthine found in Theobroma cacao, can pass through the blood-brain barrier in mice (2016)
  • Author(s): Sugimoto N, Katakura M, Matsuzaki K, Ohno-Shosaku T, Yachie A, Shido O.
  • Organizer: Experimental Biology 2016 (EB2016)
  • Place of Presentation: San Diego, CA, USA.
  • Year and Date: 2016-04-02
  • Int'l Joint Research
• [Presentation] Examination of the effects of theobromine feeding on motor learning and adaptive behavior of mice by using three-lever operant task (2016)
  • Author(s): Tanigami H, Yoneda M, Tabata Y, Sugimoto N, Ohno-Shosaku T
  • Organizer: The 93rd Annual Meeting of the Physiological Society of Japan
  • Place of Presentation: 北海道札幌市
  • Year and Date: 2016-03-22
• [Presentation] 東アジア諸国の高齢者対策－生活と労働－ (2016)
  • Author(s): 杉本直俊
  • Organizer: 第三回 「食と環境、そして高齢化を考える研究会」
  • Place of Presentation: 石川県金沢市
  • Year and Date: 2016-03-04
  • Invited
• [Presentation] Review of Long-term Care Insurance in Japan (2015)
  • Author(s): Sugimoto N
  • Organizer: The 2015 Conference of Long-term Care and Social Care
  • Place of Presentation: 台湾台中市
  • Year and Date: 2015-10-16
  • Int'l Joint Research / Invited
• [Presentation] The effect of exposure to mild heat stress on culture cells. (2015)
  • Author(s): Sugimoto N, Matsuzaki K, Katakura M, Yachie A, Shido O.
  • Organizer: EB2015
  • Place of Presentation: Boston Convention Center, Boston, MA, USA
  • Year and Date: 2015-03-27 – 2015-04-01
• [Presentation] 細胞レベルでの暑熱暴露、暑熱順化を考える (2015)
  • Author(s): 杉本直俊、松崎健太郎、片倉賢紀、紫藤治
  • Organizer: 第10回環境生理学プレコングス
  • Place of Presentation: ホテル北野プラザ六甲荘（神戸市）
  • Year and Date: 2015-03-20
• [Presentation] 高齢者骨格筋の必要性‐熱中症予防への戦略‐ (2014)
  • Author(s): 杉本直俊
  • Organizer: 第二回 「食と環境、そして高齢化を考える研究会」
  • Place of Presentation: 一般財団法人アジア太平洋研究所（大阪市）
  • Year and Date: 2014-11-28
  • Invited
• [Presentation] 低酸素環境が細胞に与える影響 (2014)
  • Author(s): 杉本直俊、松崎健太郎、片倉賢紀、紫藤治
  • Organizer: 第53回日本生気象学会大会
  • Place of Presentation: 桐蔭横浜大学（神奈川県横浜市）
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] アミロイドβ脳室投与はラット暑熱順化形成を減弱させる (2014)
  • Author(s): 松崎健太郎、片倉賢紀、杉本直俊、宮本まゆみ、原節子、紫藤治
  • Organizer: 第53回日本生気象学会大会
  • Place of Presentation: 桐蔭横浜大学（神奈川県横浜市）
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] 温度と骨格筋分化 (2014)
  • Author(s): 杉本直俊
  • Organizer: 第22回日本発汗学会総会・第28回運動と体温の研究会合同大会
  • Place of Presentation: 長崎大学文教キャンパス（長崎市）
  • Year and Date: 2014-09-17 – 2014-09-18
• [Presentation] 志賀毒素のグリア細胞への作用、2011年に発生した焼肉屋チェーン店食中毒の事例から予測されること（第2報） (2014)
  • Author(s): 杉本直俊、東馬智子、清水正樹、黒田文人、和田泰三、谷内江昭宏
  • Organizer: 第9回スフィンゴテラピィ研究会
  • Place of Presentation: 山中温泉河鹿荘ロイヤルホテル（石川県加賀市）
  • Year and Date: 2014-07-18 – 2014-07-19
• [Presentation] Theobromine, the primary methylxanthine found in Theobroma cacao, inhibits malignant glioblastoma cell growth by negatively regulating Akt/mammalian target of rapamycin kinase. (2014)
  • Author(s): Sugimoto N, Miwa S, Katakura M, Matsuzaki K, Shido O, Tsuchiya H, Yachie A.
  • Organizer: EB2014
  • Place of Presentation: San Diego Convention Center, San Diego, CA, USA
  • Year and Date: 2014-04-26 – 2014-04-30
• [Presentation] 細胞から熱中症予防を考える
  • Author(s): 杉本直俊
  • Organizer: 第27回 運動と体温の研究会
  • Place of Presentation: 立教大学池袋キャンパス（東京）
• [Presentation] 高齢者の骨格筋の役割―体温調節と水分代謝の視点からの考察―
  • Author(s): 杉本直俊
  • Organizer: 第68回日本体力医学会大会
  • Place of Presentation: 日本教育会館・学術総合センター（東京）
  • Invited
• [Presentation] アミロイド-β脳室内投与によるラット行動性体温調節機能の変化
  • Author(s): 松崎健太郎、片倉賢紀、杉本直俊、宮本まゆみ、原俊子、紫藤治
  • Organizer: 第52回日本生気象学会大会
  • Place of Presentation: 米子市文化ホール（米子市）
• [Presentation] 熱耐性能獲得細胞からの熱中症予防関連分子の同定
  • Author(s): 杉本直俊、松崎健太郎、片倉賢紀、紫藤 治
  • Organizer: 第52回日本生気象学会大会
  • Place of Presentation: 米子市文化ホール（米子市）
• [Presentation] 食と若返り
  • Author(s): 杉本直俊
  • Organizer: 第一回「食と環境、そして高齢化を考える研究会」
  • Place of Presentation: ホテル日航金沢（金沢市）
  • Invited
• [Presentation] 低酸素環境下でのがん細胞の動向
  • Author(s): 杉本直俊ほか
  • Organizer: 第 9回環境生理学プレコングス
  • Place of Presentation: 国民宿舎 レインボー桜島（鹿児島市）
• [Book] 北東アジア少子高齢化研究会報告書 東アジアにおける持続可能性のある高齢化社会構築のための方策 (2015)
  • Author(s): 木村幹・杉本直俊・金成垣・陳永峰・杉村豪一
  • Total Pages: 58
  • Publisher: 一般財団法人アジア太平洋研究所