The Protective Effects Of ADP355 And Embelin On Liver Injury

1.ADP355 peptide as an alternative of adiponectin protects liver from acute injury and chronic fibrosis by suppression of hepatic stellate cells and macrophage.Background:Adiponectin is an adipocyte-derived circulating protein with beneficial effects on liver injury.Mice lacking of adiponectin develops an enhanced liver fibrosis,suggest adiponectin could be a therapeutic target for liver injury.Aim:In present study,we investigate the protective role of ADP355,an adiponectin-based active short peptide,in thioacetamide-induced mice acute injury and chronic liver fibrosis.Methods:Liver injury was induced by 4%thioacetamide(TAA)dissolved in PBS.ADP355(H-Asn-Ile-Pro-Nva-Leu-Tyr-Ser-Phe-Ala-DSer-NH2)and scramble(H-Pro-IIe-Asn-Tyr-Ala-Nva-Ser-Phe-Leu-Ser-NH2)were synthesized and also dissolved in PBS.Three independent experiments in vivo were performed to investigate the anti-fibrogenic effects of ADP355,the compensatory substitute of ADP355 for adiponectin-KO mice in chronic liver injury and the beneficial effects of ADP355 on acute liver injury.Analysis in vitro was performed using spleen leukocytes isolated from the splenic tissues,LX-2(human hepatic stellate cell line)and RAW264.7 cells(mouse macrophage cell line).Results:ADP355 treatment decreased liver necroinflammation and fibrogenesis(collagen I and III and alpha-smooth muscle actin)by inhibiting the activation of hepatic stellate cells(HSCs)and macrophage.ADP355 restored the mice from liver dysfunction by promoting liver regeneration,and compensated to some extent effects of adiponectin in the adiponectin deficiency mice.Furthermore,in the in vitro study,ADP355 treatment with HSCs LX-2 undermined the phosphorylation and nuclear translocation of-SMAD2,increase phosphorylation of AMPKa,and enhanced the apoptosis of LX-2 cells;In addition,ADP355 also increased the phosphorylation of STAT3 in macrophage RAW 264.7 cells.In addition,ADP355 treatment reduces the proliferation of helper T cells induced by TAA.Conclusion:ADP355 could well mimic adiponectin action and suitable for preclinical or clinical therapy of acute and chronic liver injury.2.Embelin as an inhibitor of nuclear factor-?B p65 reduces chronic and acute liver injury induced by thioacetamide.Background:Liver disease as one of the most deathful diseases still is harming people's health over the world.NF-?B transcription factors had been discovered to play an important role in chronic and acute inflammatory diseases,an increasing research has been done and doing to focus on aberrant regulation of NF-?B for intense drug discovery and development efforts.It has been reported that embelin is a potent inhibitor of nuclear factor-KB(NF-?B).Aim:The study investigated embelin as an inhibitor of NF-?B induced the apoptosis of hepatic stellate cell and protected liver from both of chronic and acute injury.Methods:Hepatic stellate cells(LX-2 cell)was cultured in DMEM treated with TAA 10ng/ml-100?g/ml and then embelin 10-50?M.Chronic liver injury was induced by TAA(100-200?g/g bw ip)and then embelin(50?g/g bw ig)treated daily after 6 times of TAA administration.Acute liver injury by a single injection of 4%TAA(300?g/g bw ip),and embelin(50?g/g bw ig)treated starting 2 days before administration of TAA and thenthroughout the study.Results:Embelin hampered TAA-induced NF-KBp65 activation in hepatic stellate cells(LX-2 cells,embelin 50?M)in vitro,in livers from chronic and acute liver injury models(mice,embelin 50?g/g bw ig)in vivo,and protected the liver from both chronic and acute injury.Conclusion:Embelin as an inhibitor of NF-KBp65 activation can be an attracting therapeutic reagent in treatment of liver disease.