Geonil Ko

Protective effect of curcumin in rat liver injury induced by carbon tetrachloride

This study was carried out to investigate the protective effects of curcumin on acute or subacute carbon tetrachloride‐induced liver damage in rats.

Scutellaria baicalensis inhibits liver fibrosis induced by bile duct ligation or carbon tetrachloride in rats

This study was carried out to investigate the antifibrotic effects of methanol extracts from the traditional Chinese medicinal herb, the root of Scutellaria baicalensis Georgi, on liver fibrosis induced by bile duct ligation and scission (BDL) or carbon tetrachloride (CCl4) in rats. Liver fibrosis was assessed by histological observations and by measuring levels of liver hydroxy‐proline, lipid peroxidation based on malondialdehyde (MDA) production, and serum enzyme activities. The morphological characteristics of liver tissue were examined by Massons trichrome staining and immunostaining against smooth muscle cell α‐actin. In both models, the levels of hydroxyproline and MDA in liver were significantly increased. Treatment with a methanol extract of S. baicalensis significantly reduced the levels of liver hydroxyproline and MDA, with improved histological findings. In both models, the liver areas positive for smooth muscle cell α‐actin were considerably decreased by treatment with oral methanol extract of S. baicalensis (150 mg kg−1 daily for 28 days). A methanol extract of S. baicalensis root inhibits fibrosis and lipid peroxidation in rat liver induced by BDL or CCl4.

Antiproliferative effects of alkaloids from Sedum sarmentosum on murine and human hepatoma cell lines.

The whole plant of Sedum sarmentosum (SS) has been traditionally used for the treatment of chronic viral hepatitis in China and South Korea. Certain hepatitis virus causes acute and chronic hepatitis and induces hepatocellular carcinoma (HC). In the present study, we examined whether the crude alkaloid fraction (CAF) of SS had any anticancer effects on hepatoma cell lines. Murine hepatoma (BNL CL. 2) and human hepatoma (HepG2) cell lines were cultured in the presence of CAF of SS at various doses (50-150 microg/ml) for 24 or 48 h. CAF caused a dose-dependent inhibition of cell proliferation without necrosis or apoptosis. Antiproliferative effects of CAF of SS were associated with an increase in the number of cells in the G1 phase of cell cycle. This study suggests that SS may improve survival of hepatoma patients via the inhibition of excessive growth of tumor cells.

Protective effect of Rhodiola sachalinensis extract on carbon tetrachloride-induced liver injury in rats

This study was carried out to investigate the protective effect of an aqueous extract from the root of Rhodiola sachalinensis (RSE) on liver injury induced by repetitive administration of carbon tetrachloride in rats. RSE was given orally to rats at doses of 50, 100 or 200 mg/kg throughout the carbon tetrachloride treatment for 28 days. In rats treated with carbon tetrachloride, the levels of hydroxyproline and malondialdehyde (MDA) in the liver, and serum enzyme activities were significantly increased. RSE treatment significantly reduced the levels of liver hydroxyproline and MDA, and serum enzyme activities, in accordance with improved histological findings. Immunohistological findings indicated RSE treatment inhibited hepatic stellate cell activation, which is a major step for collagen accumulation during liver injury. These data suggest that RSE protects the liver from repetitive injury induced by carbon tetrachloride in rats.

Antifibrotic effect of extracellular biopolymer from submerged mycelial cultures ofCordyceps militaris on liver Fibrosis induced by Bile duct ligation and scission in rats

The antifibrotic effects of hot water extract (WEC), intracellular biopolymer (IPC) and extracellular biopolymers (EPC) from myceiial liquid culture ofCordyceps militaris on liver fibrosis were studied. Liver fibrosis was induced by a bile duct ligation and scission (BDL/S) operation, duration of 4 weeks in rats. In BDL/S rats, the levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin in serum and hydroxyproline content in liver were dramatically increased. The WEC or IPC treatment (30 mg/kg/day for 4 weeks, p.o.) in BDL/S rats reduced the serum AST, ALT and ALP levels significantly (p<0.01). The EPC treatment (30 mg/kg/day for 4 weeks, p.o.) reduced the serum ALT, AST and ALP levels significantly (p<0.01). Malondialdehyde contents in liver treated with WEC, IPC or EPC were significantly reduced (p<0.05). But Liver hydroxyproline content was decreased only in EPC treated BDL/S rats to 55% that of BDL/S control rats (p<0.01). The morphological characteristics and expression of alpha smooth muscle like actin in fibrotic liver, which appeared in BDL/S control group were improved in EPC treated fibrotic liver. These results indicate that EPC (30 mg/kg/day for 4 weeks, p.o.) has an antifibrotic effect on fibrotic rats induced by BDL/S.

KB-34, a newly synthesized chalcone derivative, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 macrophages via heme oxygenase-1 induction and blockade of activator protein-1

Chalcones, a subclass of the flavonoid family, are widely known for their anti-inflammatory and anti-oxidative properties. In the present study, we synthesized the chalcone derivative, KB-34 (3-Phenyl-1-(2,4,6-tris (methoxymethoxy)phenyl)prop-2-yn-1-one), and examined its effect on nitric oxide (NO) production. KB-34 potently inhibited nitrite production in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). KB-34 treatment also markedly inhibited inducible nitric oxide synthase (iNOS) expression, as assessed by Western blot and quantitative RT-PCR analyses. Treatment of cells with KB-34 significantly inhibited LPS-induced transcriptional activation by activator protein-1 (AP-1) as determined by luciferase reporter gene assay, whereas nuclear factor-kappaB (NF-kappaB) activity was not affected by KB-34, indicating that down-regulation of iNOS gene expression by KB-34 is mainly attributed by blockade of AP-1 activation. We also demonstrated that KB-34 treatment led to an increase in heme oxygenase-1 (HO-1) mRNA and protein expression, mediated by stimulating the expression of nuclear factor-erythroid 2-related factor 2 (Nrf2). Treatment with SnPP, a selective inhibitor of HO-1, reversed the KB-34-mediated inhibition of nitrite production, suggesting that HO-1 plays an important role in the suppression of NO production by KB-34. In contrast, SnPP treatment did not counteract the KB-34-mediated suppression of AP-1 activity, suggesting that inhibition of AP-1 activation by KB-34 is independent of HO-1 induction. Taken together, these results indicate that KB-34 suppresses NO production in LPS-stimulated RAW 264.7 macrophages via simultaneous induction of HO-1 expression and blockade of AP-1 activation. This study reveals that KB-34 would be a promising agent for the treatment of inflammation-associated disease.

Antifibrotic effect ofStephania tetrandra on experimental liver fibrosis induced by bile duct ligation and scission in rats

We examined the antifibrotic effect of a methanol extract fromStephania tetrandra (ST) on experimental liver fibrosis. Liver fibrosis was induced by bile duct ligation and scission (BDL/S) in rats. In BDL/S rats, activity levels of aspartate transaminase (AST), alanine transaminse (ALT), alkaline phosphatase (ALP), concentration of total bilirubin in serum, and hydroxyproline content of the liver were significantly increased. The ST treatment (either 100 mg/kg/day or 200 mg/kg/day, p.o. for 4 weeks) in BDL/S rats reduced the serum AST, ALT and ALP activity levels significantly (p<0.01). Similarly, when compared to the control group, the concentration of hydroxyproline in the livers of the BDL/S rats treated with 100mg or 200mg ST treated rats decreased by 40% and 33% respectively, when compared to the BDL/S control group (p<0.01). The morphological characteristics of fibrotic liver that were observed in the BDL/S control group, improved in the ST treated BDL/S group. In the fibrotic liver of BDL/S rats treated with ST, a marked reduction in the numbers of alpha smooth muscle cell actin positive stellate cells was observed. These results indicate that doses of either 100 or 200 mg/kg/day of methanol extract fromS. tetrandra, had an antifibrotic effect in rats with liver fibrosis induced by bile duct ligation and scission.

Isoliquiritigenin inhibits cell proliferation by a heme oxygenase-dependent pathway in rat hepatic stellate cells.

We evaluated whether the antiproliferative effects of isoliquiritigenin (ISL) on rat hepatic stellate cells (HSCs) are related to the induction of heme oxygenase 1 (HO-1) expression. ISL significantly inhibited serum- or growth factor-induced HSC proliferation. The inhibition of platelet-derived growth factor (PDGF)-induced proliferation by ISL was associated with the mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt-p70 (S6K) pathways. ISL induced the expression of HO-1 in HSCs. Using the chemical inhibitor tin protoporphyrin, we also found that the inhibitory action of ISL on PDGF-induced proliferation is mediated by HO-1. These data suggest that HO-1 expression is responsible for the antiproliferative effect of ISL on HSCs.

Biotransformation of theophylline in cirrhotic rats induced by biliary obstruction.

The object of this work was to study the pharmacokinetic differences and the cause of these differences in cirrhotic rats induced by biliary obstruction when aminophylline (8 mg/kg as theophylline, i.v.) was administered. The concentrations of theophylline and its major metabolite (1,3-dimethyluric acid) in plasma were determined by HPLC. In addition, formation of 1,3-dimethyluric acid from theophylline in microsomes and the changes in the activity of drug metabolizing enzymes, which are suggested to be involved in theophylline metabolism, were determined. In cirrhotic rats, the systemic clearance of theophylline was reduced to 30% of the control value while AUC (area under the plasma concentration-time curve) and (t1/2)β were increased 1.3 fold and 3.5 fold, respectively. The formation of 1,3-dimethyluric acid was decreased to 30% of the control value in microsomes of cirrhotic rat liver. In cirrhotic rat liver, activities of aniline hydroxylase (CYP2E1 related), erythromycin-N-demethylase (CYP3A related), and methoxyresorufin-O-demethylase (CYP1A2 related), which were reported to be related with theophylline metabolism, were decreased to 67%, 53% and 76% that of normal rat liver, respectively. From the results, it can be concluded that in cirrhotic rats induced by biliary obstruction, the total body clearance of theophylline is markedly reduced and it may be due to decreased activity of drug metabolizing enzymes in liver.

HPLC Assay and Bioequivalence Evaluation of Biphenyl Dimethyl Dicarboxylate (DDB) Products

Abstract A high-performance liquid chromatographic (HPLC) method was developed for biphenyl dimethyl dicarboxylate (DDB) detection in human serum and bioequivalence (BE) of two commercial DDB tablets was evaluated in 14 normal male subjects. The most suitable extracting solvent for DDB in serum was evaluated among dichloromethane, ether, ethylacetate, hexane, and pentane. Pentane:ether (9:1) mixture showed good extraction recovery of DDB from serum and also excluded serum components, which interfere the peak of DDB when assayed. HPLC conditions were as follows: UV absorbance detector, 280 nm; column, μ-Bondapak C