Establishment of new analytical method for visualizing chemical agents and xenobiotics on pathology speciments

• Project/Area Number: 15K15098
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human pathology
• Research Institution: The University of Tokushima
• Principal Investigator: TSUNEYAMA Koichi 徳島大学, 大学院医歯薬学研究部(医学系), 教授 (10293341)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 自己免疫疾患 / 化学物質 / イメージング / 質量分析 / ナノ粒子 / 原発性胆汁性胆管炎 / 原発性胆汁性肝硬変

Outline of Final Research Achievements

It is not well known how chemical agents and xenobiotics cause vital reaction.Recent several reports suggested that primary biliary cholangitis (PBC), which is characterized by immune mediated bile duct injury and autoantibody against mitochondria was induced by exposure to xenobiotics such as 2-octynoic acid(2-OA). In present study, we performed nano-particle assisted imaging mass spectrometry analysis using 2-OA skin painting mice model. 2-OA reached to the liver from the skin just after 6 hours. In long2-OA painting analysis, portal inflammation was occurred in the liver and 2-OA was deposited around the bile duct. Because 2-OA was detected in the bile, 2-OA may be metabolized in the hepatocytes and secreted to the bile. Like 2-OA, other chemical agents may reach to various organs from the skin and may cause inflammation.

Research Products

• [Int'l Joint Research] University of California, Davis(米国)
• [Int'l Joint Research] 中国科学技術大学(中国)
• [Int'l Joint Research] University of California, Davis(米国)
• [Journal Article] Prolonged activation of IL-5-producing ILC2 causes pulmonary arterial hypertrophy. (2017)
  • Author(s): Ikutani M, Tsuneyama K, Kawaguchi M, Fukuoka J, Kudo F, Nakae S, Arita M, Nagai Y, Takaki S, Takatsu K.
  • Journal Title: JCI Insight. Volume: 2 Issue: 7
  • DOI: 10.1172/jci.insight.90721
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Primary Biliary Cholangitis: Its Pathological Characteristics and Immunopathological Mechanisms (2017)
  • Author(s): Tsuneyama K, Baba H, Morimoto Y, Tsunematsu T, Ogawa H.
  • Journal Title: The Journal of Medical Investigation Volume: 64 Issue: 1.2 Pages: 7-13
  • DOI: 10.2152/jmi.64.7
  • NAID: 130005501980
  • ISSN: 1343-1420, 1349-6867
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Daily Coffee Intake Inhibits Pancreatic Beta Cell Damage and Nonalcoholic Steatohepatitis in a Mouse Model of Spontaneous Metabolic Syndrome, Tsumura-Suzuki Obese Diabetic Mice. (2017)
  • Author(s): Watanabe S, Takahashi T, Ogawa H, Uehara H, Tsunematsu T, Baba H, Morimoto Y, Tsuneyama K.
  • Journal Title: Metab Syndr Relat Disord. Volume: 15(4) Issue: 4 Pages: 170-177
  • DOI: 10.1089/met.2016.0114
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Human β-Defensin 2 in Primary Sclerosing Cholangitis. (2017)
  • Author(s): Chang C, Lleo A, Kananurak A, Grizzi F, Tsuneyama K, Invernizzi P, Bevins CL, Bowlus CL.
  • Journal Title: Clin Transl Gastroenterol. Volume: 8(3) Issue: 3 Pages: e80-e80
  • DOI: 10.1038/ctg.2017.8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Establishment of a mouse model of enalapril-induced liver injury and investigation of the pathogenesis. (2017)
  • Author(s): Shirai Y, Oda S, Makino S, Tsuneyama K, Yokoi T.
  • Journal Title: Lab Invest. Volume: in press Issue: 7 Pages: 545-553
  • DOI: 10.1038/labinvest.2017.22
  • NAID: 120006352182
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Chemokine receptor CXCR3 deficiency exacerbates murine autoimmune cholangitis by promoting pathogenic CD8(+) T cell activation. (2017)
  • Author(s): Ma HD, Ma WT, Liu QZ, Zhao ZB, Liu MZ, Tsuneyama K, Gao JM, Ridgway WM, Ansari AA, Gershwin ME, Fei YY, Lian ZX.
  • Journal Title: J Autoimmun. Volume: 78 Pages: 19-28
  • DOI: 10.1016/j.jaut.2016.12.012
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Toxicological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice. (2017)
  • Author(s): Oda S, Shirai Y, Akai S, Nakajima A, Tsuneyama K, Yokoi T.
  • Journal Title: J Appl Toxicol. Volume: 37 Issue: 5 Pages: 545-553
  • DOI: 10.1002/jat.3388
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Aberrant iron metabolism might have an impact on progression of diseases in Tsumura Suzuki obese diabetes mice, a model of spontaneous metabolic syndrome. (2016)
  • Author(s): Nishida T, Tsuneyama K, Fujimoto M, Nomoto K, Hayashi S, Miwa S, Nakajima T, Nakanishi Y, Hatta H, Imura J.
  • Journal Title: Pathol Int. Volume: 66(11) Issue: 11 Pages: 622-628
  • DOI: 10.1111/pin.12466
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A diagnostic marker for superficial urothelial bladder carcinoma: lack of nuclear ATBF1 (ZFHX3) by immunohistochemistry suggests malignant progression. (2016)
  • Author(s): Kawaguchi M, Hara N, Bilim V, Koike H, Suzuki M, Kim TS, Gao N, Dong Y, Zhang S, Fujinawa Y, Yamamoto O, Ito H, Tomita Y, Naruse Y, Sakamaki A, Ishii Y, Tsuneyama K, Inoue M, Itoh J, Yasuda M, Sakata N, Jung CG, Kanazawa S, Akatsu H, Minato H, Nojima T, Asai K, Miura Y.
  • Journal Title: BMC Cancer. Volume: 16(1) Pages: 805-805
  • NAID: 120006814095
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] HIF-1α in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance. (2016)
  • Author(s): Takikawa A, Mahmood A, Nawaz A, Kado T, Okabe K, Yamamoto S, Aminuddin A, Senda S, Tsuneyama K, Ikutani M, Watanabe Y, Igarashi Y, Nagai Y, Takatsu K, Koizumi K, Imura J, Goda N, Sasahara M, Matsumoto M, Saeki K, Nakagawa T, Fujisaka S, Usui I, Tobe K.
  • Journal Title: Diabetes Volume: 65 Pages: 3649-3659
  • NAID: 40021380120
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Chronic expression of interferon-gamma leads to murine autoimmune cholangitis with a female predominance. (2016)
  • Author(s): Bae HR, Leung PS, Tsuneyama K, Valencia JC, Hodge DL, Kim S, Back T, Karwan M, Merchant AS, Baba N, Feng D, Park O, Gao B, Yang GX, Gershwin ME, Young HA.
  • Journal Title: Hepatology Volume: 64 Issue: 4 Pages: 1189-201
  • DOI: 10.1002/hep.28641
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Endogenous interleukin-22 protects against inflammatory bowel disease but not autoimmune cholangitis in dominant negative form of transforming growth factor beta receptor type II mice. (2016)
  • Author(s): Yang GX, Sun Y, Tsuneyama K, Zhang W, Leung PS, He XS, Ansari AA, Bowlus C, Ridgway WM, Gershwin ME.
  • Journal Title: Clin Exp Immunol. Volume: 185 Issue: 2 Pages: 154-64
  • DOI: 10.1111/cei.12806
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice. (2016)
  • Author(s): Iwamura A, Watanabe K, Akai S, Nishinosono T, Tsuneyama K, Oda S, Kume T, Yokoi T.
  • Journal Title: Drug Metab Dispos. Volume: 44 Issue: 7 Pages: 888-96
  • DOI: 10.1124/dmd.116.069575
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Liver disease risk of xenobiotics due to percutaneous absorption revealed by nano-PALDI imaging mass spectrometry. (2016)
  • Author(s): Taira S, Yamaguchi N, Morimoto S, Tatsuta Y, Katano H, Ichiyanagi Y, tsuneyama K, Kikuchi K.
  • Journal Title: International Journal of recent Scientific Research Volume: 7(7) Pages: 12589-12592
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Histopaythologival characteristics of glutamine syntheses-positive hepatic tumor lesions in a mouse model of spontaneous metabolic syndrome (TSOD mouse) (2016)
  • Author(s): Takahashi T, Nishida T, Baba H, Hatta H, Imura J, Sutoh M, Toyohara S, Hokao R, Watanabe S, Ogawa H, Uehara H, Tsuneyama K
  • Journal Title: Molecular and Clinical Oncology Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ORAL ADMINISTRATION OF a-LIPOIC ACID INCREASES SERUM LEVELS OF ASCORBIC ACID AND TOCOPHEROL: A PILOT HEMATOLOGICAL STUDY (2016)
  • Author(s): Takahashi T, Baba H, Hatta H, Ogawa H, Uehara H, Nishida Y, Kataguchi I, Tsuneyama K
  • Journal Title: CURRENT TOPICS IN NUTRACEUTICAL RESEARCH Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathogenetic analyses of carbamazepine-induced liver injury in F344 rats focused on morphology and immune- and inflammation-related factors. (2016)
  • Author(s): Eita Sasaki, Azumi Iida, Shingo Oda, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakaima, and Tsuyoshi Yokoi
  • Journal Title: Exp. Toxicol. Pathol. Volume: 68 Issue: 1 Pages: 27-38
  • DOI: 10.1016/j.etp.2015.09.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Kupffer cell-mediated exacerbation of methimazole-induced acute liver injury in rats. (2016)
  • Author(s): Akai S, Uematsu Y, Tsuneyama K, Oda S, Yokoi T.
  • Journal Title: J Appl Toxicol. Volume: 36 Issue: 5 Pages: 702-715
  • DOI: 10.1002/jat.3202
  • NAID: 130005483633
  • Peer Reviewed
• [Journal Article] Establishment of a mouse model for amiodarone-induced liver injury and analyses of its hepatotoxic mechanism. (2016)
  • Author(s): Shohei Takai, Shingo Oda, Koichi Tsuneyama, Tatsuki Fukami, Miki Nakajima and Tsuyoshi Yokoi.
  • Journal Title: J. Appl. Toxicol. Volume: 36 Issue: 1 Pages: 35-37
  • DOI: 10.1002/jat.3141
  • Peer Reviewed
• [Journal Article] Accumulated myeloid-derived suppressor cells demonstrate distinct phenotypes and functions in two non-alcoholic steatohepatitis mouse models. (2015)
  • Author(s): Tsunashima H, Tsuneyama K, Moritoki Y, Hara M, Kikuchi K.
  • Journal Title: Hepatobiliary Surg Nutr. Volume: 4 Pages: 313-319
  • Peer Reviewed
• [Journal Article] Successful treatment of murine autoimmune cholangitis by parabiosis: Implications for hematopoietic therapy. (2015)
  • Author(s): Yang JB, Wang YH, Yang W, Lu FT, Ma HD, Zhao ZB, Jia YJ, Tang W, Tsuneyama K, Ridgway WM, Gershwin ME, Lian ZX.
  • Journal Title: J Autoimmun. Volume: 66 Pages: 108-117
  • DOI: 10.1016/j.jaut.2015.09.002
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Insight into the molecular mechanism of heme oxygenase-1 induction by docosahexaenoic acid in U937 cells. (2015)
  • Author(s): Cui ZG, Ogawa R, Tsuneyama K, Yan G, Tao L, Shimomura A, Inadera H.
  • Journal Title: Chem Biol Interact. Volume: 238 Pages: 180-188
  • DOI: 10.1016/j.cbi.2015.07.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Gastrointestinal Immune Response to the Shrimp Allergen Tropomyosin: Histological and Immunological Analysis in an Animal Model of Shrimp Tropomyosin Hypersensitivity. (2015)
  • Author(s): Lam YF, Tong KK, Kwan KM, Tsuneyama K, Shu SA, Leung PS, Chu KH.
  • Journal Title: Int Arch Allergy Immunol. Volume: 167 Issue: 1 Pages: 29-40
  • DOI: 10.1159/000431228
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mammary tissue microenvironment determines T cell-dependent breast cancer-associated inflammation. (2015)
  • Author(s): Takahashi K, Nagai N, Ogura K, Tsuneyama K, Saiki I, Irimura T, Hayakawa Y.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 7 Pages: 867-874
  • DOI: 10.1111/cas.12685
  • NAID: 120006389612
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] New animal models of metabolic syndrome-associated liver cancer (2016)
  • Author(s): Koichi Tsuneyama
  • Organizer: Kanazawa Univ. Chozen Project
  • Place of Presentation: 金沢大学角間キャンパス（石川県金沢市）
  • Year and Date: 2016-02-12
  • Invited
• [Presentation] 異なるメカニズムに起因する新しい肝細胞癌発症モデル動物の開発と病態解析、及び治療法解明への応用 (2016)
  • Author(s): 常山幸一
  • Organizer: 日本病理学会秋季特別総会
  • Place of Presentation: 金沢市文化ホール「石川県・金沢市」
  • Invited
• [Presentation] 新生児期ストレプトゾトシン投与４CS系マウスは通常食飼育によって持続高血糖なし に肝腫瘍を発症する (2016)
  • Author(s): 常山幸一、小川博久、常松貴明、上原久典
  • Organizer: 日本病理学会総会
  • Place of Presentation: 仙台国際センター「宮城県・仙台市」
• [Presentation] メタボリックシンドローム関連肝疾患に出現するautoimmune featuresの臨床病理学的特徴 (2016)
  • Author(s): 常山幸一
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張「千葉県・千葉市」
• [Presentation] Hyperinsulinemia, not hyperglycemia accelerates the progression of hepatocellular carcinoma in neonatal STZ induced mouse model (2015)
  • Author(s): Ryosuke Bessho, Masahiro Miki, Hayato Baba, Koichi Tsuneyama
  • Organizer: American Association for the study of Liver Diseases, Annual Meeting
  • Place of Presentation: San Francisco (USA)
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] Mass spectrometric imaging of mouse livers using functional γ-Fe2O3 nanoparticles (2015)
  • Author(s): Morimoto S, Ishikawa T, Hyodo K, Yamazaki T, Taira S, Tsuneyama K, ichiyanagi Y.
  • Organizer: Atomic Level Characterizations'2015
  • Place of Presentation: Kunibiki Messe, Matsue, Shimane, JAPAN
  • Year and Date: 2015-10-25
  • Int'l Joint Research
• [Presentation] メタボリックシンドローム関連肝疾患モデル動物の開発と応用 (2015)
  • Author(s): 常山幸一
  • Organizer: 徳島医学会総会
  • Place of Presentation: 徳島大学医学部（徳島県徳島市）
  • Year and Date: 2015-08-02
  • Invited
• [Presentation] Nano-PALDI MSイメージングを用いた 経皮吸収の薬物動態解析 (2015)
  • Author(s): 山口菜月、菊池健太郎、常山幸一、森本翔大、一柳優子、片野肇、平修
  • Organizer: 第８１回北陸質量分析談話会
  • Place of Presentation: 福井県立大学（福井県吉田郡永平寺町）
  • Year and Date: 2015-06-06
• [Presentation] 機能化した磁性ナノ微粒子を用いたマウス肝臓質量分析イメージング (2015)
  • Author(s): 森本翔大、兵藤公美典、山崎貴大、石川智也、平修、常山幸一、一柳優子
  • Organizer: ナノ学会第13回大会
  • Place of Presentation: 東北大学片平キャンパス／片平さくらホール(宮城県仙台市）
  • Year and Date: 2015-05-11