Protective Effects And Mechanism Of Bisdemethoxycurcumin On CCL₄-induced Acute Liver Injury And TAA-induced Liver Fibrosis

Bisdemethoxycurcumin(BDMC,C19H16O4)is a natural polyphenolic compound,which is a diarylheptane skeleton extracted from the Zingiberaceae.BDMC has various pharmacological activities such as anti-tumor,anti-inflammatory,anti-oxidation,anti-allergyand neuroprotection.In this paper,we studied the protective effect of BDMC and its related mechanism on carbon tetrachloride-induced liver injury in mice and thioacetamide-induced liver fibrosis in mice.Method:1.To explore the protective effect and related mechanism of BDMC on carbon tetrachloride-induced liver injury in mice.Male ICR mice were randomly divided into normal control group,model group and positive drug control group(silymarin 30 mg/kg),BDMC high,medium and low dose groups(200 mg/kg,100 mg/kg,50 mg/ kg).The mice were orally administration for 8 consecutive days.After administration on day 7,except for the normal control group,the other groups were intraperitoneally injected with 0.1% CCl4 solution to establish acute liver injury model in mice.After the experiment,the contents of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in serum were measured by biochemical analysis;Pathological changes of liver tissue were observed by HE staining;The content of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),malondialdehyde(MDA)and nitric oxide(NO)in liver tissue were determined;Determination of tumor necrosis factor-α(TNF-α),interleukin(IL-6,IL-1β)in liver tissue by enzyme-linked immunosorbent assay(ELISA);The proteins expression levels of p-NF-κBp65 in liver tissue was detected by Western blot.2.To explore the protective effect and related mechanism of BDMC on thioacetamide-induced liver fibrosis in mice.Male ICR mice were randomly divided into normal control group,model group and positive drug control group(silymarin 30 mg/kg),BDMC high,medium and low dose groups(200 mg/kg,100 mg/kg,50 mg/ kg).The drug administration group was orally administered for 7 weeks.Except the normal control group,the other groups were intraperitoneally injected with thioacetamide solution(200 mg/kg)every other day to induce the liver fibrosis model in mice.At the end of the experiment,ALT,AST,total bilirubin(TBIL)in serum and hydroxyproline(HYP)in liver tissue were measuresd by biochemical analysis;The content of hyaluronic acid(HA),layer adhesion Protein(LN),PC-III and IV-C were determined by ELISA;HE and Masson staining method to observe the pathological changes of liver tissue in mice;The levels of interleukin(IL-6,IL-1β,IL-10)were measured by ELISA;The proteins expression levels of p-PI3 K,p-Akt,TGF-β1,α-SMA in liver tissue was detected by Western blot.Result:1.The protective effect and related mechanism of BDMC on carbon tetrachloride-induced liver injury in mice.Compared with the normal control group,the levels of ALT and AST in the model group were significantly increased in serum(P<0.01),HE staining showed significant damage in liver tissue;The contents of SOD and GSH-Px in liver tissue was markedly decreased(P<0.01),the levels of MDA and NO were significantly increased(P<0.01);The levels of proinflammatory factors TNF-α,IL-6 and IL-1β in liver tissues were significantly increased(P<0.01);The proteins expression of p-NF-κBp65 were significantly increased(P<0.01).Compared with the model group,the levels of ALT and AST were significantly lower in the high-dose BDMC group in serum(P<0.01),and liver tissue damage was significantly improved.The contents of SOD and GSH-Px in liver tissue were significantly increased(P<0.01),while the contents of MDA,NO was significantly decreased(P<0.01);The levels of pro-inflammatory factors TNF-α,IL-6 and IL-1β in liver tissues were significantly decreased(P<0.01);The protein expression of p-NF-κBp65 in liver tissues were significantly reduced(P < 0.01).3.The protective effect and related mechanism of BDMC on thioacetamide-induced liver fibrosis in mice.Compared with the normal control group,the levels of ALT,AST,TBIL,HA,LN,PC-III,IV-C and HYP in the model group were significantly increased(P<0.01);HE and Masson staining showed that collagen was significant deposition in liver tissue;IL-6 and IL-1β levels in liver tissue were significantly increased(P<0.01),while IL-10 levels were significantly decreased(P<0.01);The proteins expression of p-PI3 K,p-Akt,TGF-β1,α-SMA in liver tissues were significantly decreased(P<0.01).Compared with the model group,the levels of ALT,AST,TBIL,HA,LN,PC-III,IV-C and HYP in the high-dose group of BDMC mice were significantly lower(P<0.01);HE and Masson results showed that it significantly improved liver tissue damage and liver fibrosis;IL-6 and IL-1β levels in liver tissue were significantly decreased(P<0.01),while IL-10 levels were significantly increased(P<0.01);The proteins expression of p-PI3 K,p-Akt,TGF-β1,α-SMA were significantly decreased(P<0.01).Conclusion:1.BDMC has protective effect on carbon tetrachloride-induced liver injury in mice,and its mechanism might be related to enhance antioxidant capacity,inhibit the expression of inflammatory factors and NF-κB protein.2.BDMC has a therapeutic effect on thioacetamide-induced liver fibrosis in mice,and its mechanism might be related to regulate inflammatory factors and inhibit the expression of TGF-β1,α-SMA and PI3K/Akt protein.