| Acute liver failure is a devastating liver disease with a progressive course, which is associated with cell death, inflammation, and could happen in acute and chronic liver disease and other system organ failure process. Acute liver failure define as healthy people with normal liver function deteriorate suddenly in short period, resulting in the syndromes of progressive sensorium change, even coma or coagulation disorders. Major etiology is drug-induced liver damage, viral hepatitis, autoimmune liver disease, shock or hypoperfusion. In addition, 20 percent of acute liver failure couldn't find out etiology. Most young people happen to occurring acute liver failure with a high mortality. Therefore, it has been an important subject to find out effective drug and therapy target for many researchers.Acanthoic acid (AA), (-)-primara-9(11), 15-dien-19-oic acid, is a pimaradiene diterpene isolated from the root bark of Acanthopanax koreanum Nakai, which has been used as a tonic and sedative as well as a remedy for the treatment of rheumatism and diabetes. It was found that AA suppressed the production of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), and interleukin-8 (IL-8), which are major pro-inflammatory cytokines inducing the synthesis and release of many inflammatory mediators. Salidroside, (SDS, (4-hydroxy-phenethyl)-β-D-glucopyranoside) isolated from Rhodiola sachalinensis A. Bor. (Gao-shan-hong-jing-tian in Chinese) is one of the most popular traditional Chinese medicines. Rhodiola sachalinensis has a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, resisting anoxia, preventing high altitude sickness, and is especially famous in the treatment of mountain malhypoxia in China. In this study, acetaminophen (APAP) and D-galactosamine/lipopolysaccharide (D-GalN/LPS) were used to induce acute liver failure in mice, and the protective effect and molecular mechanism of AA and SDS on these animal models were discussed. The protective mechanism was investigated through, apoptosis path, nitric oxide (NO), hypoxia inducible factor-1α, respectively. NO was firstly recognized in 1980s possessing bioactive molecule. Recent decade, researches have confirmed that nitric oxide played an important effect in multiple pathophysiological processes. Hypoxia-inducible factor-1α(HIF-1α) is a key transcriptional control factor of progressive adaptation reaction mediated cell hypoxia microenvironment. Current studies have found that organism increase HIF-1αto regulate EPO and VEGF expression with the happen of hypoxia and tumorigenesis, thus tolerate hypoxia and affect the generation and transformation of tumor. However, whether HIF-1αparticipate acute inflammatory reaction and its mechanism were unrevealed. Our results demonstrated that HIF-1αexpression increased during APAP or D-GalN/LPS induced acute liver failure. Simultaneously, we discuss the dependablity of HIF-1αwith TNF-α, NO, and inducible nitric oxide synthase (iNOS). HIF-1αexpression increased while serum TNF-αlevel, NO and iNOS activities elevated in the mice model of acute liver failure, which indicated there must be a certain dependability among these factors that should also further approach. HIF-1αis intimately correlated with generation and development of acute liver failure, and inhibition of HIF-1αexpression might be a benefit therapy.The liver injury was assessed biochemically and histologically. AA and SDS attenuated the D-GalN/LPS-induced acute increase in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) activites, TNF-αlevels and serum NO levels , replenished the depleted hepatic glutathione (GSH), superoxide dismutase (SOD), Catalase (CAT), glutathione peroxidase (GSH-Px) activities, decreased malondialdehyde (MDA) level and considerably reduced the histopathological alterations. Histopathological, immunohistochemical, western blot and apoptotic cells analyses also demonstrated that AA and SDS could reduce the appearance of necrosis regions as well as caspase-3 and hypoxia inducible factor-1α (HIF-1α) expression in liver tissue. Our results indicated that AA and SDS protected liver tissue from the oxidative stress elicited by APAP or D-GalN/LPS-induced liver damage and suggested that the hepatic protection mechanism of AA and SDS would relate to antioxidation and hypoxia factor on D-GalN/LPS-induced hepatotoxicity. Intervention mechanism of AA and SDS supplied rationale for clinical acute liver failure therapy to develop new durg.
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