Clarifying the molecular mechanism of the Nrf-2 activator carnosic acid in the regulation of the hepatocyte apoptosis

• Project/Area Number: 24590992
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Iwate Medical University
• Principal Investigator: WANG TING 岩手医科大学, 医学部, 助教 (70416171)
• Co-Investigator(Renkei-kenkyūsha): TAKIKAWA Yasuhiro 岩手医科大学医学部, 消化器・肝臓内科肝臓分野, 教授 (50254751)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: カルノシン酸 / シグナル / アポトーシス / 酸化ストレス / 細胞死 / Carnosic acid / Nrf2 / Oxidative stress

Outline of Final Research Achievements

Carnosic acid (CA) did not induce the activity of Nrf2 anti-oxidative system in vivo. CA at concentrations as low as 1μM significantly protected against H2O2-induced cytotoxicity and apoptosis of hepatocytes. H2O2 induced phosphorylation of extracellular-signal-regulated kinase 1 and 2 (ERK1/2) in primary hepatocytes. U0126 inhibited the decrease in cell viability induced by H2O2. Co-treatment with CA inhibited ERK1/2 activation induced by H2O2. 4. CA at 1 μM increased protein levels of SIRT1. Pretreatment with EX527 or transfection of SiRNA of SIRT1 weakened the protective effects of CA against H2O2-induced cell death. Our data indicate that CA protects against oxidative stress-induced cytotoxicity via SIRT1 by regulating subsequent downstream factors such as ERK1/2. On the other hand, CA decreased cell viability of human hepatoma Huh 7 and HepG2 cell line in a cell-dependent way. SIRT1/Nrf2 signaling is involved in its function.

Research Products

• [Journal Article] Proliferation of mouse liver stem/progenitor cells induced by plasma from (2014)
  • Author(s): Wang T, Takikawa Y, Watanabe A, Kakisaka K, Oigawa K, Miyamoto Y, Suzuki K.
  • Journal Title: J Gastroenterol. Volume: 49 Issue: 12 Pages: 1557-1566
  • DOI: 10.1007/s00535-013-0927-6
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Usefulness and accuracy of the international normalized ratio and activity percent of prothrombin time in patients with liver disease. (2014)
  • Author(s): Takikawa Y, Harada M, Wang T, Suzuki K.
  • Journal Title: Hepatol Res. Volume: 44 Issue: 1 Pages: 92-101
  • DOI: 10.1111/hepr.12093
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proliferation of mouse liver stem/progenitor cells induced by plasma from patients with acute liver failure is modulated by P2Y2 receptor-mediated JNK activation. (2013)
  • Author(s): Wang T, Takikawa Y, Watanabe A, Kakisaka K, Oikawa K, Miyamoto Y, Suzuki K.
  • Journal Title: J Gastroenterol. Volume: Epub ahead of print
  • Peer Reviewed
• [Journal Article] Evodiamine Inhibits Insulin-Stimulated mTOR-S6K Activation and IRS1 Serine Phosphorylation in Adipocytes and Improves Glucose Tolerance in Obese/Diabetic Mice. (2013)
  • Author(s): Wang T, Kusudo T, Takeuchi T, Yamashita Y, Kontani Y, Okamatsu Y, Saito M, Mori N, Yamashita H.
  • Journal Title: PLoS One. Volume: ８
  • Peer Reviewed
• [Journal Article] Carnosic acid prevents lipid accumulation in hepatocytes through EGF/MAPK pathway (2012)
  • Author(s): Wang T, Takikawa Y, Tabuchi T, Kosaka K, Satoh T, Suzuki K. .
  • Journal Title: J Gastroenterol Volume: 47 Pages: 805-13
  • Peer Reviewed
• [Journal Article] Negative regulation of human astrocytes by Interferon (IFN) α in relation to growth inhibition and impaired glucose utilization. (2012)
  • Author(s): Wang T, TakikawaY, Sawara K, YoshidaY, Suzuki K.
  • Journal Title: Neurochem Res Volume: 37 Pages: 1898-905
  • Peer Reviewed
• [Presentation] Lysosome dysfunction contributes impairment of autophagy in mouse model of liver steatosis. (2014)
  • Author(s): A. Suzuki, K. Kakisaka, A. Watanabe, T. Wang, Y. Takikawa
  • Organizer: ＡＡＳＬＤ
  • Place of Presentation: Boston
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Carnosic acid protects against oxidative stress-induced cytotoxicity in primary hepatocytes, induces tumor cell death, and inhibits TGFβ-induced migration and invasion in HepG2 cells. (2013)
  • Author(s): Takikawa Y、Wang T, Watanabe A, Kakisaka K, Onodera M, Oikawa K.
  • Organizer: AASLD
  • Place of Presentation: Washington DC.
• [Presentation] IFN-α/5-FU併用によるTGFβシグナルへの影響 (2013)
  • Author(s): 王挺、滝川康裕、葛西和博、渡辺亜沙子、鈴木一幸。
  • Organizer: 第49回肝臓学会総会
  • Place of Presentation: 東京
• [Presentation] IFN-α/5-FU併用によるTGFβの発現量および分泌量変化への影響 (2012)
  • Author(s): 王挺
  • Organizer: JDDW 2012
  • Place of Presentation: 神戸