One of these proteins, HMGB1, has been identified as a late-acting mediator of lipopolysaccharide induced or sepsis-induced lethality in mice. In addition to the role of a non-histone nuclear protein, HMGB1 also functions as an inflammatory cytokine when passively released from necrotic cells or actively secreted from stress-received cells such as monocytes/macrophages in response to endotoxin, tumor necrosis factor -a, or interleukin -1b. Once released into the intravascular space, HMGB1 can potentially amplify local inflammatory responses by enhancing the release of cytokines and chemokines from stressed cells and interact with endothelial cells by up-regulating surface receptors and causing the secretion of soluble pro-inflammatory mediators. Extracellular HMGB1 functions as a damage-associated molecular patterns molecule and activates pro-inflammatory signaling pathways by enhancing pattern recognition receptors including toll-like receptor 4 and the receptor for advanced glycation endproducts. Mounting evidence suggests that HMGB1 may also function to facilitate the recognition of other immune coactivators such as LPS, DNA, and IL-1 through greedy binding to these molecules. To examine hepatic protection of some compound, acute hepatic injury induced by an intravenous injection of combination with a small dose of NOD-IN-1 lipopolysaccharide and D-galactosamine has been widely used as an animal model since the hepatic lesion in this model resembles that of human hepatitis. We have reported that upon stimulation by LPS activated macrophages secrete various pro-inflammatory cytokines including IL-6, IL-10, IL-12 and TNF-a. Among them, TNF-a is a key mediator causing hepatic apoptosis and necrosis in LPS/ GalN-induced liver failure. The number of apoptotic cells and the levels in serum concentration of TNF-a, IL-6, IL-10 and IL-12 as well as alanine aminotransferase significantly increase after administration of LPS/GalN. GL is a biological active substance extracted from the licorice root, which has been used for a folk medicine, and consists of one molecule of glycyrrhetinic acid and two glucuronic acids. Various pharmacological effects of GL are well known, such as anti-inflammatory, anti-viral, anti-allergic activities, hepatocyte proliferation and hepatoprotection. Intravenous administration of GL improves ALT level of patients with chronic hepatitis. Especially in Japan, Stronger Neo Minophagen C has been used to remedy patients with hepatitis C, and GL is main compound of SNMC. The effects and safety of SNMC have been assessed in Europe, too. In addition, the research using nuclear magnetic resonance and fluorescence methods reported the additional mechanism of GL that bound directly to HMGB1 and inhibited HMGB1 chemoattractant and mitogenic activities. According to recent studies,A-1331852 furthermore, GL inhibits the cell proliferation and migration stimulated by HMGB1 as well as HMGB1-induced formation of blood vessels, and reduces inflammatory infiltrates. Previous findings demonstrate that oxidative stress in hepatocytes leads to early shuttling of HMGB1 from the nucleus to cytoplasm, attended with its subsequent release in the absence of cell death, although it can be passively released following necrosis. The pathways governing HMGB1 release from hepatocytes are known to involve TLR4 activation and calcium signaling through calcium/calmodulin-dependent protein kinases.