Study on the platform development for therapeutics of liver disease

• Main Authors: Yi-Jhen Li, 李宜真
• Other Authors: Rong-Tsun Wu
• Format: Others
• Language: zh-TW
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/79276429669110068574

碩士 === 國立陽明大學 === 生物藥學研究所 === 101 === Blood that enters the liver from the intestines is rich in microorganism. Liver cells all have the capacity to present antigem to T cells， along with immunosuppressive cytokines and inhibitory cell surface ligands that result in tolerance. By bacteria or viruses infection， hepatic cell populations lead to express pro-inflammatory cytokines and trigger the development of liver disease. If the hepatic injury persists， failure to regenerate parenchymal cells and hepatocytes are substituted with abundant fibrotic matrix result in liver cirrhosis. In addition， mitochondrial dysfunction is a common characteristic of liver disease. The aim of this study was to investigate a small molecule EH-201 as a potent EPO inducer for evaluating its potential medical use in mitochondria biogenesis, and to identify its potential role in liver resolution. We used ex vivo liver slices， primary hepatocyte and Raw cell to show that EH-201 could inhibite 10μg/ml LPS induced inflammataoy response. After EH-201 treatment， liver slices and raw cells demonstrated a dose-dependent inhibition in TNF-α and IL-1β mRNA expression. The acetaminophen overdose can cause mitochondria dysfunction and further and oncotic necrosis of hepatocytes. We prepared primary hepatocytes and treated them with 2.5 mM APAP. Our results showed that EH-201 2 μg/ml can promote hepatocytes proliferation and enhance mitochondrial activity after hepatotoxicity damage. Treatment of mice with acetaminophen ( 400 mg/kg， ip) and sacrificed to prepare liver slices. EH-201 2 μg / ml reduces the expression of IL-β and RAGE and enhanced IL-10 levels. Furthermore, EH-201 cans up-regulate EPO and PGC1α expression to reach its protective effect. To determine if EH-201 was hepatoprotective， C57BL/6J were pretreated with EH-201 (10， 30 and 90 mg/kg， ip). Following EH-201 90 mg/kg treatment， we observed that prevent acetaminophen-induced hepatotoxicity， as measured histologically and biochemically by decreased serum transaminase levels. Induction of EPO and PGC-1α mRNA and protein production and reduction KC and RAGE mRNA expression. Activation of autophagy protected against hepatotoxicity. Using DMN-induced liver cirrhosis model， EH-201 2 mg/kg( per day) was increased around 10% survival rate. In conclusion， EH-201 might be a preventive or therapeutic agent during acute liver failure and chronic liver disease.