Identification of novel zinc-responsive protein and clarification of significance in colorectal cancer prevention

• Project/Area Number: 16K16281
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Eating habits
• Research Institution: Ishikawa Prefectural University
• Principal Investigator: HIGASHIMURA YASUKI 石川県立大学, 生物資源環境学部, 助教 (70628924)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 亜鉛 / 大腸炎 / マクロファージ / リンパ球 / Th17 / 大腸がん / 炎症性腸疾患

Outline of Final Research Achievements

Hypozincemia regarded as a risk for colon cancer and colitis. However, the precise mechanisms involved in zinc deficiency of the intestinal inflammation remains unclear. This study demonstrates that zinc deficiency resulting from using a zinc chelator administration aggravates colonic inflammation through the activation of type 17 helper T (Th17) cells in mice. Flow cytometric analysis revealed that zinc deficiency significantly increases the proportion of pro-inflammatory (M1) macrophages in inflamed colon. A zinc chelator up-regulates IL-23p19 expression, which is deeply associated with Th17 development, in mouse bone marrow-derived macrophages (BMDMs). Furthermore, the nuclear accumulation of interferon-regulatory factor 5 is critically involved in IL-23p19 induction in zinc-deficient BMDMs. Thus, zinc deficiency aggravates colonic inflammation through activation of the IL-23/Th17 axis, and the activation is controlled by subcellular distribution of interferon-regulatory factor 5.

Research Products

• [Journal Article] Lactobacillus brevis KB290 With Vitamin A Ameliorates Murine Intestinal Inflammation Associated With the Increase of CD11c+ Macrophage/CD103? Dendritic Cell Ratio (2018)
  • Author(s): Fuke Nobuo、Takagi Tomohisa、Higashimura Yasuki、Tsuji Toshifumi、Umeda Ryohei、Mizushima Katsura、Tanaka Makoto、Suganuma Hiroyuki、Aizawa Koichi、Yajima Nobuhiro、Naito Yuji
  • Journal Title: Inflammatory Bowel Diseases Volume: 24 Issue: 2 Pages: 317-331
  • DOI: 10.1093/ibd/izx003
  • Peer Reviewed
• [Journal Article] Secreted protein acidic and rich in cysteine functions in colitis via IL17A regulation in mucosal CD4(+) T cells. (2018)
  • Author(s): Tanaka M, Takagi T, Naito Y, Uchiyama K, Hotta Y, Toyokawa Y, Ushiroda C, Hirai Y, Aoi W, Higashimura Y, Mizushima K, Okayama T, Katada K, Kamada K, Ishikawa T, Handa O, Itoh Y.
  • Journal Title: J Gastroenterol Hepatol. Volume: 33 Issue: 3 Pages: 671-680
  • DOI: 10.1111/jgh.13842
  • Peer Reviewed / Open Access
• [Journal Article] Effects of molecular hydrogen-dissolved alkaline electrolyzed water on intestinal environment in mice (2018)
  • Author(s): Higashimura Yasuki、Baba Yasunori、Inoue Ryo、Takagi Tomohisa、Uchiyama Kazuhiko、Mizushima Katsura、Hirai Yasuko、Ushiroda Chihiro、Tanaka Yoshinori、Naito Yuji
  • Journal Title: Medical Gas Research Volume: 8 Issue: 1 Pages: 6-6
  • DOI: 10.4103/2045-9912.229597
  • Peer Reviewed
• [Journal Article] Partially hydrolyzed guar gum enhances colonic epithelial wound healing via activation of RhoA and ERK1/2. (2016)
  • Author(s): Horii Y, Uchiyama K, Toyokawa Y, Hotta Y, Tanaka M, Yasukawa Z, Tokunaga M, Okubo T, Mizushima K, Higashimura Y, Dohi O, Okayama T, Yoshida N, Katada K, Kamada K, Handa O, Ishikawa T, Takagi T, Konishi H, Naito Y, Itoh Y
  • Journal Title: Food Funct. Volume: 8(7) Issue: 7 Pages: 3176-3183
  • DOI: 10.1039/c6fo00177g
  • Peer Reviewed
• [Journal Article] Protective effect of agaro-oligosaccharides on gut dysbiosis and colon tumorigenesis in high-fat diet-fed mice (2016)
  • Author(s): Higashimura Y, Naito Y, Takagi T, Uchiyama K, Mizushima K, Ushiroda C, Ohnogi H, Kudo Y, Yasui M, Inui S, Hisada T, Honda A, Matsuzaki Y, Yoshikawa T
  • Journal Title: Am. J. Physiol. Gastrointest. Liver Physiol. Volume: 310 Issue: 6 Pages: G367-G375
  • DOI: 10.1152/ajpgi.00324.2015
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] pVHL-mediated degradation of HIF-2α regulates estrogen receptor α expression in normoxic breast cancer cells. (2016)
  • Author(s): Higashimura Y, Kitakaze T, Harada N, Inui H, Nakano Y, Yamaji R.
  • Journal Title: FEBS Lett. Volume: 590 Issue: 16 Pages: 2690-2699
  • DOI: 10.1002/1873-3468.12265
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prevention of colitis by controlled oral drug delivery of carbon monoxide. (2016)
  • Author(s): Steiger C, Uchiyama K, Takagi T, Mizushima K, Higashimura Y, Gutmann M, Hermann C, Botov S, Schmalz HG, Naito Y, Meinel L.
  • Journal Title: J Control Release. Volume: 239 Pages: 128-36
  • DOI: 10.1016/j.jconrel.2016.08.030
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Partially hydrolysed guar gum ameliorates murine intestinal inflammation in association with modulating luminal microbiota and SCFA. (2016)
  • Author(s): Takagi T, Naito Y, Higashimura Y, Ushiroda C, Mizushima K, Ohashi Y, Yasukawa Z, Ozeki M, Tokunaga M, Okubo T, Katada K, Kamada K, Uchiyama K, Handa O, Itoh Y, Yoshikawa
  • Journal Title: Br. J. Nutr. Volume: 116(7) Pages: 1199-1205
  • Peer Reviewed
• [Journal Article] Zinc and gastrointestinal disorders (2016)
  • Author(s): Higashimura Y, Takagi T, Naito Y.
  • Journal Title: Nihon Rinsho. Volume: 74(7) Pages: 1121-1125
  • NAID: 40020885811
  • Peer Reviewed
• [Presentation] 亜鉛欠乏と腸管炎症 (2018)
  • Author(s): 東村泰希
  • Organizer: 第16回亜鉛栄養治療研究会学術集会
  • Invited
• [Presentation] 亜鉛欠乏に伴う腸管炎症の増悪について (2017)
  • Author(s): 東村泰希，内藤裕二
  • Organizer: 第28回日本微量元素学会学術集会
  • Invited
• [Presentation] 栄養・食品成分による腸管免疫細胞の機能制御を基軸とした大腸炎予防 (2017)
  • Author(s): 東村泰希
  • Organizer: カロテノイド研究会若手の会
  • Invited
• [Presentation] 亜鉛欠乏に伴う腸管炎症増悪における分子機序の解明 (2016)
  • Author(s): 東村泰希
  • Organizer: 第9回北陸合同バイオシンポジウム
  • Place of Presentation: グランディア芳泉（福井県あわら市）
  • Year and Date: 2016-11-04
  • Invited
• [Presentation] Participation of IRF5 in the up-regulation of IL-17A production mediated by zinc deficiency (2016)
  • Author(s): 東村泰希，内藤裕二，髙木智久，水島かつら，吉川敏一
  • Organizer: 第27回日本微量元素学会学術集会
  • Place of Presentation: 芝蘭会館（京都府京都市）
  • Year and Date: 2016-07-30
• [Presentation] 亜鉛欠乏に伴うIL17A産生亢進における分子機序の解明 (2016)
  • Author(s): 東村泰希、内藤裕二、髙木智久、水島かつら、吉川敏一
  • Organizer: 日本ビタミン学会第68回大会
  • Place of Presentation: 富山国際会議場（富山県富山市）
  • Year and Date: 2016-06-17