Hepatic protection by glycyrrhizin and inhibition of iNOS expression in concanavalin A-induced liver injury in mice.
ABSTRACT In this study, the possible protective effect of glycyrrhizin (GL), an active compound derived from licorice root, was examined on T cell-mediated liver injury in mice.
Mice were subjected to liver injury by intravenous injection of concanavalin A (Con A). They had been treated with GL (i.p.) 30 min before the injection. Liver injury was estimated by measuring serum levels of alanine aminotransaminase (ALT) and aspartate aminotransaminase (AST), and by examining liver sections with hematoxylin-eosin staining. Expression of inducible nitric oxide synthase (iNOS) mRNA and protein in the liver was determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting.
Serum transaminases and hepatic iNOS levels increased with time after Con A treatment. Expression of iNOS mRNA in the liver was elevated for up to 8 h, and at 8 h, GL (ED(50): 10.5 mg/kg) suppressed the increases in AST and ALT in response to Con A. An increase in iNOS mRNA expression and protein was inhibited by treatment with GL. Furthermore, GL inhibited cell infiltration and the degeneration of hepatocytes in the liver of Con A-treated mice.
The present study suggests that the prevention by GL of Con A-induced hepatitis is due partly to the modulation of hepatic iNOS induction and of degeneration of hepatocytes.
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ABSTRACT: In this study, a novel liver-targeted gene delivery vector was invented by electrostatically coating the cationic complex of pDNA and polyethylenimine (PEI) with Glycyrrhizin (GL). The ternary complex, pDNA/PEI/GL, was approximately 100 nm stable particles with a negative charge surface. The pDNA/PEI/GL showed high gene expression comparable to the complex of pDNA and PEI (pDNA/PEI) in human hepatoma cell line HepG2 without cytotoxicity and agglutination. After intravenous injection of pDNA/PEI/GL into mice, the highest gene expression was observed in the liver. pDNA/PEI/GL showed significantly higher gene expression in parenchymal cells than in nonparenchymal cells. Based on these results, we evaluated the pharmacological activity of the ternary complex including the pDNA encoding insulin (pCMV-Ins). The pCMV-Ins/PEI/GL decreased blood glucose concentrations 24 h after its intravenous administration into mice. The ternary complex of pDNA, PEI, and GL may be a promising liver targeted gene vector.Molecular Pharmaceutics 03/2014; 11(5). DOI:10.1021/mp400398f · 4.79 Impact Factor
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ABSTRACT: Context: Glycyrrhizin (GL), the major ingredient isolated from licorice, exerts multiple pharmacological activities. Objective: To elucidate the protective mechanism of GL towards lithocholic acid (LCA)-induced liver toxicity using lipidomics. Materials and methods: GL (200 mg/kg) dissolved in corn oil was treated intraperitoneally for 7 d. On the 4th day, 200 mg/kg LCA was used to treat mice (i.p., twice daily) for another 4 d. The protective role of GL towards LCA-induced liver toxicity was investigated through evaluating the liver histology and the activity of alanine transaminase (ALT). The complete lipid profile was employed using UFLC-Triple TOF MS-based lipidomics. Results: Intraperitoneal (i.p.) administration of 200 mg/kg GL can significantly protect LCA-induced liver damage, indicated by alleviated histology alteration and prevention of the ALT elevation. Lipidomics analysis can well separate the control group from LCA-treated group, and three lipid components were major contributors, including LPC 16:0, LPC 18:0, and LPC 18:2. GL treatment can significantly prevent LCA-induced reduction of these three lipid compounds, providing a new explanation for GL's protection mechanism towards LCA-induced liver toxicity. Discussion and conclusion: The recent study highlights the importance of lipidomics in elucidating the therapeutic mechanism of herbs.Pharmaceutical Biology 10/2014; 52(12). DOI:10.3109/13880209.2014.900810 · 1.34 Impact Factor
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ABSTRACT: Triptolide (TP), a major active component of Tripterygium wilfordii, possesses various pharmacological activities with narrow therapeutic window and severe toxicities. Glycyrrhizin (GL), the principal bioactive ingredient of licorice root extract, has been reported to be concomitantly administered with TP in treatment of rheumatoid arthritis with the aim of potentiated efficacy and reduced toxicity. To investigate the effect of GL on the pharmacokinetic profiles of TP and related mechanisms. Male and female Wistar rats were randomly divided into two groups: Control group and GL group (pretreated with GL at 100mg/kg/day for seven consecutive days). After oral administration of TP at a single dose of 450μg/kg, plasma concentrations of TP were determined using HPLC-MS/MS and pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 6.3 software. Since CYP3A is the primary isoform of cytochrome P450s responsible for the metabolism of TP, we further valued to what extent ketoconazole (KCZ), a potent CYP3A inhibitor, could influence the effect of GL on the pharmacokinetics of TP by comparing the pharmacokinetic profiles of TP in GL group (pretreated with GL) and GL+KCZ group (pretreated with both GL and KCZ), as well as verified whether pretreatment of GL could induce the activity of hepatic CYP3A by comparing the AUC parameters after intravenous administration of midazolam (MDZ), a typical probe drug for CYP3A, in rats pretreated with vehicle or GL. Our study revealed marked differences in pharmacokinetic profiling patterns of TP between male and female rats in the Control group; the plasma level of TP in males was extremely lower than that in females. After pretreatment with GL, the pharmacokinetic profiles of TP were significantly altered in both male and female rats; a remarkable decrease was found in the value of AUC∞, MRT∞ and t1/2 in the GL group, compared with the Control group. But such decrease was reversed by KCZ; compared with the GL group, the values of AUC∞, MRT∞ and t1/2 were significantly increased in the GL+KCZ group. Pretreatment with GL notably increased the AUC∞ of 1'-hydroxymidazolam (OH-MDZ) and the ratio of AUC∞ of OH-MDZ to MDZ, demonstrating induction of the activity of CYP3A by GL. Pretreatment with GL significantly accelerates the metabolic elimination of TP from the body mainly through induction of hepatic CYP3A activity. These results may help explain why toxicity of TP may be attenuated when concomitant use of GL.Journal of ethnopharmacology 01/2014; DOI:10.1016/j.jep.2014.01.026 · 2.94 Impact Factor