Roles Of Curcumin On Liver Fibrosis

BackgroundHepatic fibrosis represents the consequences of injury-recovery response to various chronic liver diseases, which leads to the over-produced extracellular matrix (ECM) accumulate in the liver. It is accepted the procedure is reversible though the origin and mechanisms of each liver fibrogenesis are difference without effective therapy, Hepatic fibrosis can progress into cirrhosis even liver cancer. Because the mechanisms of LF are too complicated, the knowledge of Hepatic fibrosis is poor by now which limit the progress of its therapy. Accroding to the achievement of research of liver diseases, two theraputic strategies are developed. One is to remove the etiological factors and another is to treat fibrosis. The later refers to vious anti-fibrosis medicine currently. How to avoid hepatic fibrosis is rather important since no effective anti-fibrosis treatment is established.Curcumin is the product obtained by solvent extraction of turmeric i.e., the ground rhizomes of Curcuma longa L. (Curcuma domestica Valeton) and purification of the extract by crystallization. Multiple studies indicated that curcumin is a potential tool to protect liver from fibrosis. The mechanisms of this effect need further investigation. Furthermore, how to make curcumin clinical available is another task since it is difficult to solve in water and relatively unstable.MethodsRat liver fibrostic model induced with CCl4 was used in this study. Meantime,culturative HSC was also utilized in the study together to explore the preventive effect of curcumin and the possible mechanism on liver fibrosis, trying to elucidate the theraputic value of curcumin. Various volume of curcumin was administrated to SD rat. Liver functions and immunohistochemistry images were analyzed before and after administration. The level of liver fibrosis was evaluated and compared within different groups. Furthermore, the proliferation and apoptosis of CFSC-2G cell were determined before and after co-incubated with various concentration of curcumin. Meanwhile, the mRNA expression of several cytokines, including TGF-βand CTGF, was detected at the indicated time.Result(1)in vivo study: A Comparing with control group, the hepatic index was significantly higher in curcumin treated(P<0.05) groups; B Compare with normal SD rat, AST and ALT of liver fibrostic rat is much higher (P<0.01)but decreased dramatically after treatment with curcumin (P<0.05); C In CCl4 induced liver fibrosis rat, as shown in the result, accompanied with the injection of ccl4, hepatocyes necrosis, inflammatory infiltration as well as fiber septa formation occurred, implying the progression of liver fibrosis; in contrast with model group, liver tissue kept relatively normal structure in curcumin treated groups though mild fibrosis was identified; D Masson stain also confirmed that liver fibrosis is milder in curcumin treated group than in model group. Moreover, quantitative determination of Masson stain showed that fiber synthesis is much more than normal group(P<0.01)but less than that of model group(P<0.05); E As shown in the figures, type I collagen synthesis was identified in model group(P<0.01) but this effect was diminished in curcumin treated groups( P<0.05); Meantime, synthesis of type III collagen also showed the same pattern with that of type I collagen and curcumin inhibited both types of collagen; F 1.6 mRNA expression of TGF-β1 and CTGF elevated in model group than normal group(P<0.01) but curcumin inhibited the expression of TGF-β1 mRNA significantly (P<0.01); however, though CTGF mRNA was inhibited by curcumin, it is not statistically dramatic; G Expression of Erk, JNK, p38 and Akt are higher than normal group(P<0.01); But after treatment of low concentration of curcumin, the expression of Erk was dramatically decreased than that of model rat group(P<0.01); However, in the groups of medium or high concentration of curcuma ; Erk expression increased significantly than normal rat group(P<0.01); no significant difference with model rat group; H Meanwhile, JNK expression was decreased in all three curcumin groups(P<0.05 in low con. group, P<0.01 in medium and high con. group)than in model rat group; I As for the p38 expression, only high con. group show decreased p38 expression dramatically(P<0.05) than model rat group, medium con. group also showed such tendency but not statistic significantly; J Akt expression was decreased in all three curcumin treated group dramatically(P<0.01)than model rat group; K As shown in the result, EGF expression of model rat was higher than normal rat(P<0.01), but curcumin treatment suppressed the expression of EGF significantly(P<0.01)than that of model group. (2) In vitro study: A MTT assay showed that HSC proliferation was suppressed 12h after being co-incuated with various con. of curcumin(5,10,15,20,40μmol/L)and 48h after con-incubation, this effect was greater than negative control group(colchicines); the suppression effect showed concentration dependent pattern; B After 24h treated with curcumin, type III and type I collagen was decreased in supernatant than control group (P < 0.05); C After 48 h of co-incubation with 20μmol/Lcurcumin, apoptosis was dramatically increased(P < 0.01) than control group but lower than colchicines treated group(P < 0.05); D the synthesis of type I Collagen and type III Col lagen was suppressed in curcumin treated group(P < 0.01); E the expression of TGF-β1,CTGF and EGF was increased together with the HSC culture but declined significantly after the treatment of curcumin; F Compare with normal control group, Akt, ERK and JNK expression were decreased in curcumin and colchicines treated groups (P<0.01), p38 expression was decreased significantly in colchicines group, though the similar pattern was also seen in curcumin, the decrease was not statistic significantly.ConclusionThe result of this study indicated that:⑴Curcumin protects rat from liver damage and facilitates keeping the normal tissue structure and normal liver function;⑵in vivo as well as in vitro study showed that curcumin inhibits the synthesis of ECM in liver thus maintain the liver function and normal tissue structure;⑶curcumin inhibit the mRNA expression of TGF-βand CTGF, which are considered the important pro-fibrosis factor, implying TGF-βand CTGF are two potential targets for anti-fibrosis therapy;⑷curcumin inhibits expression of EGF in HSC of rats with liver fibrosis thus inhibits the proliferation and enhances appoptosis of HSC;⑸MAPK signaling pathway was involved in liver fibrogenesis. Curcumin inhibited liver fibrogenesis through suppressing the expression of multiple cytokines which participate in MAPK signaling. In a word, curcumin aids to protect liver from damages and slow down the progress of liver fibrosis through mataining the liver function, and this effect is achieved via regulating multiple targets including MAPK signaling.