Plumbagin Protects Liver From Acute And Chronic Injury

Background:The liver,as the largest solid organ in the body,plays a pivotal role in metabolism and has alexipharmic function in the body.Liver injury is a major disease which seriously threatens people’s health around the world,especially in Asian countries.Fulminant hepatic failure(FHF)is caused by a variety of factors such as virus infection,drugs damage and food poisoning.It often present with extensive necrosis of hepatocytes and severe liver functional abnormality.Fulminant hepatic failure has been concerned by people for its onset acute,progress fast and high fatality rate.The fibrosis of liver not only causes chronic hepatitis,hypohepatia,and sequelae after cure,but also is the necessary process of hepatocirrhosis.Plumbagin is a quinonoid constituent founded in the roots of the medicinal herbs Plumbago genus and then named.It has been shown to have diverse pharmacological effects include hypolipidemic,antibacterial,antimalarial,antiatherosclerotic and anticarcinogenic effects.However,the knowledge of liver damage is still very poor at present.In this study,a deeper and more extensive investigate of plumbagin on liver injury is provided.Objective:In present study,we investigate the protective role of plumbagin in TAA-induced acute and chronic injury in vivo and the cellular mechanism of plumbagin on anti-inflammatory or anti-fibrosis functions in vitro.Methods:Liver injury was induced by 4%thioacetamide(TAA)dissolved in PBS.plumbagin was prepared in dimethyl sulfoxide(DMSO)and diluted with PBS.Two independent experiments in vivo were performed to investigate the plumbagin protective effects of fibrogenic,inflammatory,liver functional abnormality and cell damage.Analysis in vitro was performed using LX-2(human hepatic stellate cell line)and RAW264.7 cells(mouse macrophage cell line).Liver sections were observed by HE staining,Picrosirius red staining,PAS staining and Immunohistochemistry staining.The effects of plumbagin on LX-2 and RAW264.7 signaling mechanisms were measured by western blot.FACS was applied to detect the effects of plumbagin on LX-2 proliferation and apoptosis.Results;Plumbagin increased survival rate and reduced liver congestion in the FHF model.Histochemistry staining showed that plumbagin not only inhibit inflammatory infiltration by preventing the recruitment of macrophages but also have the function of protecting hepatocytes from damage in acute liver injury.In liver fibrosis model,plumbagin treatment decreased liver necroinflammation and fibrogenesis(collagenⅠ/Ⅲ and alpha-smooth muscle actin)by inhibiting the activation of hepatic stellate cells(HSCs)and macrophage.Plumbagin restored the mice from liver dysfunction by promoting liver regeneration.Furthermore,in the in vitro study,plumbagin through the way of increasing AMPK phosphorylation to compete transcriptional coactivator p300 against with pSmad2.Plumbagin also attenuated NF-KB/p65,Stat3 and Akt/mTOR signaling pathways thereby regulating LX-2 apoptosis and proliferation in vitro.In addition,plumbagin also increased the phosphorylation of NF-KB/p65 in macrophage RAW 264.7 cells.Conclusion:Plumbagin appears to be a powerful drug candidate which can protect liver from acute and chronic injury by target on macrophages and HSCs.