Prevention of diabetes mellitus and Alzheimer dementia via improvement of low interstitial pH by food constituent

2019 Fiscal Year Annual Research Report

• Project/Area Number: 18H03182
• Research Institution: Ritsumeikan University
• Principal Investigator: 丸中 良典 立命館大学, 総合科学技術研究機構, 教授 (00127036)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 糖尿病 / アルツハイマー型認知症 / 間質液 / pH / 食品

Outline of Annual Research Achievements

糖尿病患者でのアルツハイマー型認知症発症リスクが高いことが知られているが、その原因は不明である。我々は糖尿病で間質液pHが低下し、この間質液pH低下がインスリン抵抗性発症の成因であることを発見し、間質液pH低下によりアルツハイマー型認知症の原因物質と考えられているアミロイドベータ生成が促進され、一方アミロイドベータ分解が低下し、その結果アミロイドベータ蓄積が促進される可能性を見出した。 しかしながらこれらの分子機構は未だ明らかとはなっていない。本研究アミロイドベータ、以下の研究仮説を立て、この研究仮説を正しいことを証明する。

研究仮説：以下の大きく分けて２つの研究仮説を立てた。A) 糖尿病での脳を含む間質液pH低下によりアミロイドベータ生成酵素であるβ ・γセクレターゼの活性および発現量の増大が起こり、一方でアミロイドベータ分解酵素であるネプリライシンの活性および発現量が低下し、その結果糖尿病での脳における線維化アミロイドベータ蓄積が増大する 。　B) ウメ食品を代表とした弱酸カルボン酸含有食品摂取で間質液pHが正常に保持されることにより、血糖値上昇・インスリン抵抗性発症・アミロイドベータ蓄積の予防をもたらすことが可能となる。

研究目的：1)上記仮説A)およびB)を動物およびヒトにおいて証明する。　2)間質液pHを正常に制御し得る食品選定の選定を行なう。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

糖尿病での脳を含む間質液pH低下によりアミロイドベータ生成酵素であるβ ・γセクレターゼの活性および発現量の増大が起こり得ること、一方でアミロイドベータ分解酵素であるネプリライシンの活性および発現量が低下し得ること、これらの結果、糖尿病での脳における線維化アミロイドベータ蓄積が増大する可能性を見出した。
ウメ食品を代表とした弱酸カルボン酸含有食品摂取で間質液pHが正常に保持されることを見出した。その結果、血糖値上昇を抑制し得ること、インスリン抵抗性の発症も抑制されうること、またアミロイドベータ蓄積の予防をもたら得ることも明らかとなった。

以上の結果より、ウメ関連食品での間質液pH低下改善をもたらす食品の選定に目処がたち、またその食品摂取にて血糖値改善をもたらし得る可能性も見出したことによる。これらの結果を実際の食生活の中に取り入れる試みも行う。

Strategy for Future Research Activity

ウメ関連食品での間質液pH低下改善をもたらす食品の選定に目処がたち、このことを確固たることにするための実験を実施する。
またその食品摂取にて血糖値改善をもたらし得ることを確固たることにするための実験を実施する。

Research Products

• [Int'l Joint Research] Jiangsu University/University of Macau/Zhejiang University(中国)
  • Country Name: CHINA
  • Counterpart Institution: Jiangsu University/University of Macau/Zhejiang University
  • # of Other Institutions: 17
• [Int'l Joint Research] National Institute of Health/Universita Politecnica delle Marche/University of Naples Federico II(イタリア)
  • Country Name: ITALY
  • Counterpart Institution: National Institute of Health/Universita Politecnica delle Marche/University of Naples Federico II
  • # of Other Institutions: 2
• [Int'l Joint Research] H. Lee Moffitt Cancer Center Res Inst/Medical College of Wisconsin/University of Massachusetts(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: H. Lee Moffitt Cancer Center Res Inst/Medical College of Wisconsin/University of Massachusetts
  • # of Other Institutions: 1
• [Int'l Joint Research] University of New South Wales(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: University of New South Wales
• [Int'l Joint Research] Bulgarian Academy of Sciences(ブルガリア)
  • Country Name: BULGARIA
  • Counterpart Institution: Bulgarian Academy of Sciences
• [Int'l Joint Research]
  • # of Other Countries: 4
• [Journal Article] Enhancement of ciliary beat amplitude by carbocisteine in ciliated human nasal epithelial cells (2020)
  • Author(s): Inui TA, Yasuda M, Hirano S, Ikeuchi Y, Kogiso H, Inui T, MARUNAKA Y, Nakahari T
  • Journal Title: Laryngoscope Volume: 130 Pages: E289-E297
  • DOI: 10.1002/lary.28185
  • Peer Reviewed
• [Journal Article] Standard medical nutrition therapy of 25kcal/kg ideal bodyweight/day often does not reach even resting energy expenditure for patients with type 2 diabetes (2020)
  • Author(s): Fukuda T, Tanaka M, Yamazaki M, MARUNAKA Y, Fukui M
  • Journal Title: Journal of Diabetes Investigation Volume: 11 Pages: 626-632
  • DOI: 10.1111/jdi.13167
  • Peer Reviewed / Open Access
• [Journal Article] ANO9 regulated cell cycle in human esophageal Squamous cell carcinoma (2020)
  • Author(s): Katsurahara K, Shiozaki A, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, MARUNAKA Y, Otsuji E
  • Journal Title: Annals of Surgical Oncology Volume: - Pages: -
  • DOI: 10.1245/s10434-020-08368-y
  • Peer Reviewed
• [Journal Article] Refining transfer set in calibration transfer of near infrared spectra by backward refinement of samples (2020)
  • Author(s): Zheng K, Feng T, Zhang W, Huang X, Li Z, Zhang D, Shi J, MARUNAKA Y, Zou X
  • Journal Title: Analytical Methods Volume: 12 Pages: 1495-1503
  • DOI: org/10.1039/D0AY00085J
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Body fluid pH balance in metabolic health and possible benefits of dietary alkaline foods (2020)
  • Author(s): Aoi W, Zou X, Xiao J, MARUNAKA Y
  • Journal Title: eFood Volume: 1 Pages: 12-23
  • DOI: org/10.2991/efood.k.190924.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The algal polysaccharide ulvan suppresses growth of hepatoma cells (2020)
  • Author(s): Zhao C, Lin G, Wu D, Liu D, You L, Hogger P, Simal-Gandara J, Wang M, da Costa JGM, MARUNAKA Y, Daglia M, Khan H, Filosa R, Wang S, Xiao J
  • Journal Title: Food Frontiers Volume: 1 Pages: 83-101
  • DOI: org/10.1002/fft2.13
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Food intake targeting and improving acidity in diabetes and cancer (2020)
  • Author(s): MARUNAKA Y, Niisato N, Zou X, Xiao J, Nakahari T
  • Journal Title: Food Frontiers Volume: 1 Pages: 9-12
  • DOI: org/10.1002/fft2.5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Airway ciliary beating affected by the Pcp4 dose-dependent [Ca2+]i in Down syndrome mice, Ts1Rhr (2020)
  • Author(s): Kogiso H, Raveau M, Yamakawa K, Saito D, Ikeuchi Y, Okazaki T, Asano S, Inui T, MARUNAKA Y, Nakahari T
  • Journal Title: Int J Mol Sci Volume: 21 Pages: 1947
  • DOI: 10.3390/ijms21061947
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Food Frontiers: An academically sponsored new journal (2020)
  • Author(s): L Wang, J Simal‐Gandara, M Du, B Lu, JL Quiles, ZY Chen, B Hennig, M Wang, H Xiao, J Arcot, T Yue, B Zheng, X Zou, Y MAMRUNAKA, et al.
  • Journal Title: Food Frontiers Volume: 1 Pages: 3-5
  • DOI: org/10.1002/fft2.8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 細胞内 Cl-による細胞機能調節と疾患 (2020)
  • Author(s): 丸中良典
  • Journal Title: 腎と透析：特集 Cl-：電解質クイーン Volume: 88 Pages: 419-422
• [Journal Article] Ciliary beating amplitude controlled by intracellular Cl- and a high rate of CO2 production in ciliated human nasal epithelial cells (2019)
  • Author(s): Inui TA, Murakami K, Yasuda M, Hirano S, Ikeuchi Y, Kogiso H, Hosogi S, Inui T, MARUNAKA Y, Nakahari T
  • Journal Title: Pflugers Archiv - European Journal of Physiology Volume: 471 Pages: 1127-1142
  • DOI: 10.1007/s00424-019-02280-5
  • Peer Reviewed
• [Journal Article] Effect of low temperature on the regulation of cell volume after hypotonic shock in gastric cancer cells (2019)
  • Author(s): Shiozaki A, Yamazato Y, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, MARUNAKA Y, Otsuji E
  • Journal Title: Int J Oncol Volume: 55 Pages: 905-914
  • DOI: 10.3892/ijo.2019.4853
  • Peer Reviewed
• [Journal Article] LRRC8A expression influences growth of esophageal squamous cell carcinoma (2019)
  • Author(s): Konishi T, Shiozaki A, Kosuga T, Kudou M, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, MARUNAKA Y, Otsuji E
  • Journal Title: Am J Pathol Volume: 189 Pages: 1973-1985
  • DOI: 10.1016/j.ajpath.2019.06.006
  • Peer Reviewed
• [Journal Article] pH balance and lactic acid increase in the vitreous body of diabetes mellitus patients (2019)
  • Author(s): Mieno H, MARUNAKA Y, Inaba T, Kojima K, Yoneda K, Nagata K, Sotozono C
  • Journal Title: Experimental Eye Research Volume: 188 Pages: 107789
  • DOI: 10.1016/j.exer.2019.107789
  • Peer Reviewed
• [Journal Article] The expression and role of TRPV2 in esophageal squamous cell carcinoma (2019)
  • Author(s): Kudou M, Shiozaki A, Yamazato Y, Katsurahara K, Kosuga T, Shoda K, Arita T, Konishi H, Komatsu S, Kubota T, Fujiwara H, Okamoto K, Kishimoto M, Konishi E, MARUNAKA Y, Otsuji E
  • Journal Title: Scientific Reports Volume: 9 Pages: 16055
  • DOI: 10.1038/s41598-019-52227-0
  • Peer Reviewed / Open Access
• [Presentation] Building-up the primary culture system for ependymal ciliary cells from newborn mice (2020)
  • Author(s): Namoto Y, Ishii Y, Okazaki T, Asano S, MARUNAKA Y, Nakahari T
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Activation of airway ciliary beating by an [Ca2+]i increased via nifedipine-sensitive Ca2+ channels stimulated by amboxol (2020)
  • Author(s): Saito D, Kawaguchi K, Asano S, MARUNAKA Y, Nakahari T
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Secretory reflex pathway of short chain fatty acids in the rat distal colon (2020)
  • Author(s): Harata D, Asano S, Kuwahara A, Kuwahara Y, Kato I, Inui T, MARUNAKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
• [Presentation] Surface enhanced Raman spectroscopy probe for nanometer-scale measurement of pH and hydrogen peroxides on the outer membrane of cells (2020)
  • Author(s): Puppulin L, Hosogi S, Tanaka H, Kumamoto Y, Ashihara E, MARUANKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
  • Invited
• [Presentation] Non-invasive sample measurement derived from live tissue by Raman spectroscopic microscopy (2020)
  • Author(s): Akaji S, MARUNAKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
  • Invited
• [Presentation] Regulation of body fluid and electrolytes: Physiological significance of interstitial fluid (2020)
  • Author(s): MARUANKA Y
  • Organizer: The 97th Annual Meeting of the Physiological Society of Japan
  • Invited
• [Presentation] Improving action of Ninji’yoeito on the syndrome of diabetes mellitus (2019)
  • Author(s): MARUNAKA Y
  • Organizer: 62th Annual Meeting of the Japan Diabetes Society
  • Invited
• [Presentation] Improving actions of natural foods and Ninjin’yoeito (a herbal medicine) on diabetes mellitus symptoms via improvement of interstitial fluid pH (2019)
  • Author(s): MARUNAKA Y
  • Organizer: International Conference on Natural Toxicology and Pharmacology
  • Int'l Joint Research / Invited
• [Presentation] Actions of flavonoids and natural compounds on ion environments: Its physiological roles (2019)
  • Author(s): MARUNAKA Y
  • Organizer: International Workshop on Intelligent Detection of Food and Safety
  • Int'l Joint Research / Invited
• [Book] Encyclopedia of Respiratory Medicine (2020)
  • Author(s): Niisato N, MARUNAKA Y
  • Total Pages: -
  • Publisher: Elsevier
  • ISBN: 978-0-12-370879-3
• [Remarks] 丸中良典 研究室
  • URL: https://marunaka-y.com/