Abstract
This study was designed to investigate the potentially protective effects of glycyrrhetinic acid (GA) and the role of transcription factor nuclear factor-erythroid 2(NF-E2)-related factor 2 (Nrf2) signaling in the regulation of Carbon Tetrachloride (CCl4)-induced chronic liver fibrosis in mice. The potentially protective effects of GA on CCl4-induced chronic liver fibrosis in mice were depicted histologically and biochemically. Firstly, histopathological changes including regenerative nodules, inflammatory cell infiltration and fibrosis were induced by CCl4.Then, CCl4 administration caused a marked increase in the levels of serum aminotransferases (GOT, GPT), serum monoamine oxidase (MAO) and lipid peroxidation (MDA) as well as MAO in the mice liver homogenates. Also, decreased nuclear Nrf2 expression, mRNA levels of its target genes such as superoxide dismutase 3 (SOD3), catalase (CAT), glutathione peroxidase 2 (GPX2), and activity of cellular antioxidant enzymes were found after CCl4 exposure. All of these phenotypes were markedly reversed by the treatment of the mice with GA. In addition, GA exhibited the antioxidant effects in vitro by on FeCl2-ascorbate induced lipid peroxidation in mouse liver homogenates, and on DPPH scavenging activity. Taken together, these results suggested that GA can protect the liver from oxidative stress in mice, presumably through activating the nuclear translocation of Nrf2, enhancing the expression of its target genes and increasing the activity of the antioxidant enzymes. Therefore, GA may be an effective hepatoprotective agent and viable candidate for treating liver fibrosis and other oxidative stress-related diseases.
Highlights
In spite of tremendous scientific advancement in the field of hepatology in recent years, liver problems are on the rise and account for a high death rate [1]
NF-E2related factor 2 (Nrf2) is a member of the ‘‘‘cap’ ‘n’ collar’’ family of basic leucine zipper transcription factors, which is sequestered by its suppressor Kelch-like ECHassociated protein 1 (Keap1) in the cytoplasm when in an inactive state, but in an active state, translocated into the nucleus where it binds to the antioxidant responsive element (ARE) and led to expression of target genes, upon cell stimulation [14,15,16]
Severe hepatic lesions induced by CCl4 were remitted by the administration of glycyrrhetinic acid (GA) to some extent, which were in good agreement with the results of the serum aminotransferase activities, GA can reverse the increasing level of GOT/GPT in serum induced by CCl4
Summary
In spite of tremendous scientific advancement in the field of hepatology in recent years, liver problems are on the rise and account for a high death rate [1]. It has been reported that CYP450 in rat liver activates CCl4 to a trichloromethyl free radical (CCl3N and/or CCl3OON), and stimulates Kupffer cells to produce ROS, such as NO22, H2O2 and NOH, which damage the liver [9,10,11]. These ROS are eliminated by antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and CAT. Nrf is regarded as a protective role and known to act as a mediator in CCl4-induced liver fibrosis by regulated the antioxidant enzymes activity and relative genes expression, but its protective role is perhaps relative to the damage time. The mechanisms underlying the liver fibrosis elicited by GA in association with Nrf up-regulation remain poorly understood [26]
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