Hepatoprotective Mechanism Of Traditional Plant-Based Medicine

Acute hepatic injury is usually a self-limiting disease, but may cause severe liver injury leading to fulminant hepatic failure and eventually need for liver transplantation to prevent death and, with some causes, may progress to chronic hepatitis. Chronic inflammation infected by hepatitis B or C viruses is also a frequent cause of liver cancer. Furthermore, alcohol may also increase intestinal permeability to peptidoglycan which can initiate inflammatory response in liver.In recent years, plant-derived natural products have received considerable attention due to their diverse pharmacological properties. A growing interest has been observed in the analysis of these natural entities for their potential benefits to human health on hepatoprotective effects. Thus, pharmacological inhibition of hepatocyte apoptosis may potentially attenuate liver injury and fibrosis by blocking hepatocyte apoptosis. To ascertain the net effect of inhibiting liver cell apoptosis on liver injury, inflammation, and hepatic fibrogenesis, we conducted in vivo/in vitro investigation to reveal the hepatoprotective mechanism of bioactive compounds from traditional medicine, such as gentiopicroside and methanol extract from Gentiana manshurica Kitagawa (GM), sarmentosin-containing extracts of Sedum sarmentosum (SS), ginsenosides Rh2 metabolized from Panax ginseng.We apply in vivo model of D-galactosamine/lipopolysaccharide-induced feminant hepatic failure and ethanol-induced acute alcohol liver injury model using C57BL/6 mice. In addition, we used lipopolysaccharide to stimulate RAW 264.7 murine macrophage cell line to mimick the process of inflammation.(1) GM significantly reduced the increases in serum ALT and AST levels, the serum and hepatic triglyceride levels at 4 h after the last ethanol administration in mice. GM was also found to prevent ethanol-induced hepatic steatosis and necrosis, as indicated by liver histopathological studies. Additionally, GM suppressed the elevation of malondialdehyde (MDA) levels, restored the glutathione (GSH) levels and enhanced the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities. The concurrent administration of GM efficaciously abrogated the cytochrome P450 2E1 (CYP2E1) induction. Moreover, GM significantly reduced the nuclear translocation of SREBP-1 protein (nSREBP-1) in ethanol-treated mice.(2) Gentiopicroside markedly reduced the increases in serum aminotransferase activities and lipid peroxidation. The glutathione content decreased in D-GalN/LPS alone group, and this decrease was attenuated by gentiopicroside. Increases in serum tumor necrosis factor-α(TNF-α), which were observed in D-GalN/LPS alone group, were significantly reduced by gentiopicroside. Importantly, gentiopicroside attenuated D-GalN/LPS-induced apoptosis of hepatocytes, as estimated by the caspase-3 cleavage, poly(ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. D-GalN/LPS-induced caspase-8 and-9 activation were significantly suppressed by gentiopicroside. Moreover, increased cytosolic cytochrome c protein was reduced by gentiopicroside. Also, the increased ratio of Bax and Bcl-2 protein was significantly attenuated by gentiopicroside. After 6 h of D-GalN/LPS injection, phosphorylated c-jun N-terminal kinase (JNK) and extracellular signal regulated kinase (ERK) was significantly increased, whereas phosphorylation JNK and ERK were attenuated by gentiopicroside.(3) Pretreatment with SS markedly protected mice from lethal liver injury, which has known to be associated with an abrupt elevation of serum TNF-αlevel. Indeed, SS significantly blocked the elevation of TNF-αand ALT and AST as well. SS also remarkably reduced number of apoptotic hepatocytes and DNA fragmentation in the liver, which correlated with blockade of caspase-3 activation. In addition, SS suppressed the increased expression of toll-like receptor 4 (TLR4). The activation of JNK, ERK and p38 induced by D-GalN/LPS were also significantly suppressed by SS treatment. Furthermore, SS significantly inhibited the activation of nuclear factor (NF)-κB. In RAW 264.7 cells stimulated with LPS, TNF-αrelease and TLR4 expression was suppressed by SS pretreatment, which was in line with in vivo results.(4) Ginsenosides Rh2 blocked CD14 and TLR4 expression 24 h after LPS stimulation. Furthermore, ginsenosides Rh2 significantly inhibited TGF-beta activated kinase 1 (TAK1) and JNK phosphorylation 30 min after LPS stimulation. Ginsenosides Rh2 also inhibited NF-κB p65 translocation into the nucleus by suppressing IκB-αdegradation. Pretreatment of ginsenosides Rh2 successively prolonged the inhibition of HIF-1αexpression.Thus, these traditional medicine may be useful as a potential pharmacological therapy for the prevention of liver injury and represent a potential new source of drugs for hepatoprotection. But further investigation is required to determine the exact protective mechanism and to discover the active candidates.