Masashi Yamada

Different anti‐HCV profiles of statins and their potential for combination therapy with interferon

We recently developed a genome‐length hepatitis C virus (HCV) RNA replication system (OR6) with luciferase as a reporter. The OR6 assay system has enabled prompt and precise quantification of HCV RNA replication. Pegylated interferon (IFN) and ribavirin combination therapy is the world standard for chronic hepatitis C, but its effectiveness is limited to about 55% of patients. Newer therapeutic approaches are needed. In the present study, we used the OR6 assay system to evaluate the anti‐HCV activity of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitors, called statins, and their effects in combination with IFN‐α. Five types of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) were examined for their anti‐HCV activities. Fluvastatin exhibited the strongest anti‐HCV activity (IC50: 0.9 μmol/L), whereas atorvastatin and simvastatin showed moderate inhibitory effects. However, lovastatin, reported recently as an inhibitor of HCV replication, was shown to exhibit the weakest anti‐HCV activity. The anti‐HCV activities of statins were reversed by the addition of mevalonate or geranylgeraniol. Surprisingly, however, pravastatin exhibited no anti‐HCV activity, although it worked as an inhibitor for HMG‐CoA reductase. The combination of IFN and the statins (except for pravastatin) exhibited strong inhibitory effects on HCV RNA replication. In combination with IFN, fluvastatin also exhibited a synergistic inhibitory effect. In conclusion, statins, especially fluvastatin, could be potentially useful as new anti‐HCV reagents in combination with IFN. (HEPATOLOGY 2006;44:117–125.)

Preventive effect of long-chain fatty alcohol on ischemia–reperfusion injury in the rat bladder

We attempted in the present study to clarify the preventive effects of cyclohexenonic long-chain fatty alcohol on ischemia-reperfusion injury in the rat bladder. Rat bladders were exposed to 30 min of ischemia and a subsequent 30 min of reperfusion with or without several doses of cyclohexenonic long-chain fatty alcohol (0.5, 2, 8 mg/kg). Muscle-bath studies were performed, and malonaldehyde concentrations were measured in the bladder. Bladder dysfunction and lipid peroxidation caused by ischemia-reperfusion were prevented by cyclohexenonic long-chain fatty alcohol in a dose-dependent manner. Our data indicate that cyclohexenonic long-chain fatty alcohol can prevent the production of free radicals and ischemia-reperfusion injury in the bladder.

Catechin production in cultured Polygonum hydropiper cells

Abstract Callus and suspension-cultured cells were induced from hypocotyls of Polygonum hydropiper seedlings. Both the callus and suspension-cultured cells produced mainly (+)-catechin accompanied by (−)-epicatechin and (−)-epicatechin-3- O -gallate. The (+)-catechin production of suspension-cultured cells increased with cell growth and reached the maximal value (29.0xa0mgxa0g −1 dry wt) after 6xa0days from the start of subculture. This is the highest value of (+)-catechin content among reports on catechin production in vitro so far published. The amount of (−)-epicatechin was in the range of 1.1–7.7xa0mgxa0g −1 dry wt and that of (−)-epicatechin-3- O -gallate was in the range of 2.6–6.4xa0mgxa0g −1 dry wt for a culture period of 15xa0days, respectively. Comparing with plant parts in regard to (+)-catechin, the amount of suspension-cultured cells was about 1.5 times as much as callus cells, about 9 times that of leaves (3.2xa0mgxa0g −1 dry wt) and about 7 times that of stems (4.0xa0mgxa0g −1 dry wt). The maximal yield of total catechins in suspension-cultured cells was 4.3% dry wt.

Inhibition of Preadipocyte Differentiation by Germacranolides from Calea urticifolia in 3T3-L1 Cells

The effects of germacranolides isolated from Calea urticifolia on adipocytic differentiation of 3T3-L1 cells were examined. These germacranolides inhibited adipogenesis at a concentration of 1.25–5 μM. But no inhibitory activity against cell proliferation and no nonspecific binding activity to protein were observed. These results indicate that these germacranolides are the specific inhibitors of preadipocyte differentiation.