The Protective Effect of Glycyrrhetinic Acid on Carbon Tetrachloride-Induced Chronic Liver Fibrosis in Mice via Upregulation of Nrf2

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.

Jian carp ( Cyprinus carpio var. Jian) intestinal immune responses, antioxidant status and tight junction protein mRNA expression are modulated via Nrf2 and PKC in response to dietary arginine deficiency

“…Several studies indicated that up-regulation of Nrf2 expression can elevate SOD and CAT mRNA levels in mouse liver [64] and GR mRNA levels in rat lung [65]. Interestingly, the present study showed that arginine deficiency and excess caused an upregulation of Nrf2 mRNA expression level in juvenile Jian carp intestine, which exhibited an opposite pattern with SOD1, CAT and GR mRNA levels.…”

Dietary riboflavin deficiency decreases immunity and antioxidant capacity, and changes tight junction proteins and related signaling molecules mRNA expression in the gills of young grass carp (Ctenopharyngodon idella)

“…The correlation analysis showed that CuZnSOD and GR mRNA levels were positively related to Nrf2 mRNA level (r CuZnSOD ¼ þ0.831, P CuZnSOD < 0.05; r GR ¼ þ0.953, P GR < 0.01) in the gills of young grass carp, indicating that riboflavin deficiency decreased CuZnSOD and GR mRNA levels may be partly by decreasing Nrf2 mRNA level in the gills of fish. It was reported that Nrf2 was sequestered by its suppressor Keap1 in the cytoplasm which prevented Nrf2 nuclear translocation in mice [29]. Devling et al [85] reported that the down-regulation of Keap1 gene expression could promote the nuclear translocation of Nrf2, and subsequent increased antioxidant enzymes gene expression in HaCaT cells.…”

“…To our knowledge, antioxidant enzyme activities partly rely on antioxidant enzyme mRNA expression [28]. Meanwhile, antioxidant enzymes genes expression has proven to be regulated by Nrf2 signaling pathway in mice [29]. Therefore, we next investigated the effects of riboflavin on antioxidant enzymes mRNA expression and Nrf2 signaling pathway in the gills of fish.…”

“…Lambertucci et al [28] reported that antioxidant enzyme activities partly dependent on antioxidant enzyme genes transcription in rat muscle. Furthermore, antioxidant enzymes genes expression has proven to be regulated by NF-E2-related factor 2 (Nrf2), the key transcription factor in mice [29]. Recently, our laboratory was the first to clone the cDNA of Nrf2 (GenBank accession no.…”

Modulation of hepatotoxicity, DNA fragmentation and gene expression of Solanum nigrum leaves extract in rats treated with silver nanoparticles

“…On the other hand, CCl 4 is well known to degrade DNA in liver tissue of rats by generating free radicals and increase DNA fragmentation (Alkreathy et al, 2014). Regarding the gene expression level, the current findings indicated that, CCl 4 induced down-regulation of the examined antioxidant enzymes (SOD and GPx) gene expression and liver fibrosis in mice (Chen et al, 2013). The genotoxic effects of AgNPs were represented by the increase in DNA fragmentation and the disturbance of gene expression which may be attributed to oxidative stress created by AgNPs exposure.…”