Hepatic Protective Effects of <i>S</i>-Allyl-L-Cysteine (SAC) in Rats with Carbon Tetrachloride (CCl₄) Induced Liver Injury

S-allyl-L-cysteine (SAC) is an organosulfur compound derived from aged garlic extract (AGE). Studies have reported that AGE possesses bioprotective capacity, including antidiabetic, antimicrobial, antioxidant, and antitumor effects. The present study examined the protective effects of SAC against carbon tetrachloride (CCl4) induced hepatotoxicity in rats. Ten male Wistar rats aged 11 - 12 weeks were randomly divided into two groups (five rats/group) as control and SAC groups. All rats had ad libitum access to water, and the SAC group received water containing SAC intragastrically (200 mg/kg) once daily for five consecutive weeks. In the fifth experimental week, 50% CCl4 in olive oil (1 mL/kg) was administered intraperitoneally three times a week to induce liver injury in both groups. Rats were sacrificed at 24 hours after the last CCl4 injection, and liver tissues were excised for histopathological, immunohistochemical and antioxidant analyses. The rats in the SAC group did not show abnormal behavior, such as decreased water intake or food consumption, during the experimental period. Body weights in all groups did not change significantly over the experimental period. Histopathological analysis showed that the percentage of hepatic steatosis was lower in the SAC group at 12.75% ± 3.74% compared to 24.64% ± 5.29% in the control group (p < 0.05). The percentage of cytochrome P4502E1 (CYP2E1) distribution area in the SAC group was also lower at 19.61% ± 6.18% compared with 25.22% ± 6.21% in the control group (p < 0.05). These results suggest that SAC can alleviate CCl4-induced liver damage by decreasing hepatic steatosis and reducing CYP2E1 expression in rats.

Role of Nrf2 in chronic liver disease

Nuclear erythroid 2-related factor 2(Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.

In vitro and in vivo protective effects of proteoglycan isolated from mycelia of Ganoderma lucidum on carbon tetrachlorideinduced liver injury

AIM： To investigate the possible mechanism of the protective effects of a bioactive fraction, Ganoderma lucidum proteoglycan （GLPG）isolated from Ganoderma luddum mycelia, against carbon tetrachloride-induced liver injury. METHODS： A liver injury model was induced by carbon tetrachloride. Cytotoxicity was measured by MTY assay. The activities of alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were determined with an automatic multifunction-biochemical analyzer and the levels of superoxide dismutase （SOD） and TNF-α were determined following the instructions of SOD kit and TNF radioimmunoassay kit. Uver sections were stained with hematoxylin and eosin （H＆E） for histological evaluation and examined under light microscope. RESULTS： We found that GLPG can alleviate the L-02 liver cells injury induced by carbon tetrachloride （CCh） through the measurements of ALT and AST activities and the administration of GLPG to L-02 cells did not display any toxicity. Furthermore, histological analysis of mice liver injury induced by CCh with or without GLPG pretreatment indicated that GLPG can significantly suppress the toxicity induced by CCh in mice liver. We also found that GLPG reduced TNF-α level induced by CCh in the plasma of mice, whereas increased SOD activity in the rat serum. CONCLUSION： GLPG has hepatic protective activity against CCl4 induced injury both in vitro and in vivo. The possible antihepatotoxic mechanisms may be related to the suppression of TNF-α level and the free radical scavenging activity.

Liver-specific glucocorticoid action in alcoholic liver disease:Study of glucocorticoid receptor knockout and knockin mice

Background and aim:Glucocorticoids are the only first-line drugs for severe alcoholic hepatitis(AH),with limited efficacy and various side effects on extrahepatic tissues.Liver-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for AH.The aim of this study was to determine the role of hepatocellular glucocorticoid receptor(GR)in alcohol-associated steatosis(AS)and AH.Materials and methods:AS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout(LKO)and heterozygote of GR.AH was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of GR.Changes in hepatic mRNA and protein expression were determined by quantitative real-time polymerase chain reaction and Western blot.Results:GR-LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS mice.Marked steatosis in GR-LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic genes.Hepatic protein levels of GR,hepatocyte nuclear factor 4 alpha,and phosphorylated signal transducer and activator of transcription 3 were gene-dosage-dependently decreased,whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO mice.Interestingly,hepatic expression of estrogen receptor alpha(ERα)was induced,and the essential estrogen-inactivating enzyme sulfotransferase 1e1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice,which was associated with induction of ERα-target genes.Liver-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice.Conclusions:Hepatic GR deficiency plays a crucial role in the pathogenesis of AS induced by high-fat diet plus binge,and liver-specific overexpression/activation of GR protects against chronic-plus-binge-induced AH in middle-aged mice.Hepatocellular GR is important for protection against AS and AH.