Masaru Ueki

Preventive and therapeutic effects of angiotensin II type 1 receptor blocker on hepatic fibrosis induced by bile duct ligation in rats.

BackgroundThe aim of this study was to examine the preventive and therapeutic effects of an angiotensin II type 1 receptor blocker, candesartan, on cholestasis-induced liver fibrosis.MethodsCandesartan was administered orally for 21 days immediately after bile duct ligation to evaluate its preventive effect, and for 21 days starting 3 weeks after bile duct ligation to evaluate its therapeutic effect. Fibrosis was assessed by measuring hepatic hydroxyproline (Hyp) content. The activated hepatic stellate cells (HSCs) were assessed by α-smooth muscle actin (α-SMA) immunostaining. The gene expression of collagen I, transforming growth factor-β1 (TGF-β1), and connective tissue growth factor (CTGF) in the liver was examined by real-time reverse transcriptase-polymerase chain reaction.ResultsAs a preventive effect, candesartan reduced the hepatic Hyp content by 36%, α-SMA-positive cells by 65%, hepatic TGF-β1 content by 35%, and the expression of collagen I by 72%, TGF-β1 by 67%, and CTGF mRNA by 69%. As a therapeutic effect, candesartan reduced the hepatic Hyp content by 48%, TGF-β1 content by 54%, and the expression of collagen I by 47%, TGF-β1 by 43%, and CTGF mRNA by 53%. Significant decreases in lipid peroxidation markers, hepatic thiobarbituric acid-reactive substance, and 4-hydroxy-2-nonenal were observed in candesartan-treated rats.ConclusionsCandesartan attenuated liver fibrosis via suppression of collagen I and TGF-β1 expression, HSC activation, and lipid peroxidation protein, showing its preventive and therapeutic effects on cholestasis-induced liver fibrosis.

Therapeutic effects of angiotensin II type 1 receptor blocker, irbesartan, on non-alcoholic steatohepatitis using FLS-ob/ob male mice

Non-alcoholic steatohepatitis (NASH) is the hepatic manifestation of a metabolic syndrome characterized by accumulation of hepatic fat, inflammation and varying degrees of fibrosis. Angiotensin (AT)-II has been reported to play a role in the establishment of NASH. This study examined the effects of an AT-II receptor blocker, irbesartan, on NASH using fatty liver Shionogi (FLS)-ob/ob male mice as the closest animal model of human metabolic syndrome-related NASH. Irbesartan (30 mg/kg/day) was orally administered to FLS-ob/ob mice for 12 weeks (irbesartan group). The effects of irbesartan on steatohepatitis were examined using factors including steatosis, fibrosis, inflammation and oxidative stress. The areas of hepatic fibrosis and hepatic hydroxyproline content were significantly lower in the irbesartan group compared to controls. The areas of α-smooth muscle actin-positivity and F4/80-positive cells were significantly decreased in the irbesartan group. The percentage of 8-hydroxy-2-deoxyguanosine (8-OHdG)-positive cells and 8-OHdG DNA content were significantly decreased in the irbesartan group compared to controls. Levels of RNA expression for procollagen I, transforming growth factor β1, tumor necrosis factor-α, sterol regulatory element-binding protein 1c and fatty acid synthase were significantly lower in the irbesartan group compared to controls. In contrast, the gene expression of peroxisome proliferator activated receptor-α was significantly higher in the irbesartan group compared to controls. Irbesartan administration improved hepatic steatosis and attenuated the progression of hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Kupffer cells and reducing oxidative stress.

Expression of oxidative stress-related molecules in circulating leukocytes and urine in patients with chronic viral hepatitis

Abstract: Aims: Oxidative stress plays a role in pathogenesis of chronic viral hepatitis. Expression of oxidative stress‐related molecules remains to be clarified.

Assessment of ablative margin after radiofrequency ablation for hepatocellular carcinoma; comparison between magnetic resonance imaging with ferucarbotran and enhanced CT with iodized oil deposition

BACKGROUND AND PURPOSE Our aim was to investigate whether magnetic resonance imaging (MRI) with ferucarbotran administered prior to radiofrequency ablation could accurately assess ablative margin when compared with enhanced computed tomography (CT) with iodized oil marking. MATERIALS AND METHODS We enrolled 27 patients with 32 hepatocellular carcinomas in which iodized oil deposits were visible throughout the nodule after transcatheter arterial chemoembolization. For these nodules, radiofrequency ablation was performed after ferucarbotran administration. We then performed T2-weighted MRI after 1 week and enhanced CT after 1 month. T2-weighted MRI demonstrated the ablative margin as a low-intensity rim. We classified the margin into three grades; margin (+): high-intensity area with a continuous low-intensity rim; margin zero: high-intensity area with a discontinuous low-intensity rim; and margin (-): high-intensity area extending beyond the low-intensity rim. RESULTS In 28 (86%) of 32 nodules, there was agreement between MRI and CT. The overall agreement between for the two modalities in the assessment of ablative margin was good (κ=0.759, 95% confidence interval: 0.480-1.000, p<0.001). In four nodules, ablative margins on MRI were underestimated by one grade compared with CT. CONCLUSION MRI using ferucarbotran is less invasive and allows earlier assessment than CT. The MRI technique performed similarly to enhanced CT with iodized oil marking in evaluating the ablative margin after radiofrequency ablation.

Assessment of the ablated area after radiofrequency ablation by contrast-enhanced sonography; comparison with virtual sonography with magnetic navigation

This study investigated whether contrast-enhanced sonography can accurately predict the ablated area by radiofrequency ablation using virtual sonography by computed tomography as a gold standard. Thirty-one hepatocellular carcinoma nodules were treated by radiofrequency ablation and then examined. The defect of contrast-enhanced sonography (puncture direction: r=.868, P<.0001; perpendicular direction; r=.925, P<.0001) was closely correlated with the unenhanced area of virtual sonography. Contrast-enhanced sonography can be used for early and accurate prediction of the ablated area and is helpful for assessing local control of radiofrequency ablation.

Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in rats

Aim:  The aim of this study was to examine the preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation (BDL) in rats.

Therapeutic effects of the direct renin inhibitor, aliskiren, on non‐alcoholic steatohepatitis in fatty liver Shionogi ob/ob male mice

Non‐alcoholic steatohepatitis (NASH) is a manifestation of metabolic syndrome in the liver that is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The renin–angiotensin system (RAS) appears to play important roles in NASH. Direct renin inhibitors (DRI) reduce plasma renin activity (PRA) through interaction with the active site of the enzyme and reduce the formation of angiotensin‐II (AT‐II). Therefore, the DRI aliskiren may further suppress the RAS. This study examined the effects of aliskiren on NASH in fatty liver Shionogi (FLS)‐ob/ob male mice that are the closest animal model of metabolic syndrome‐related NASH in humans.

Fatty liver Shionogi‐ob/ob mouse: A new candidate for a non‐alcoholic steatohepatitis model

The fatty liver Shionogi (FLS) mouse develops hereditary fatty liver without obesity. The FLS‐ob/ob mouse made by transferring the leptinob gene demonstrates several metabolic disorders and marked fat deposition in the liver. The aim was to evaluate which mouse model, the FLS or FLS‐ob/ob, is more useful for non‐alcoholic steatohepatitis research.

Therapeutic effects of ezetimibe for non-alcoholic steatohepatitis in fatty liver shionogi-ob/ob mice

Aim:  An effective therapy for non‐alcoholic steatohepatitis has yet to be defined. This study examined the therapeutic effects of ezetimibe, a lipid‐lowering medication, on steatosis and hepatic fibrosis in fatty liver Shionogi ob/ob (FLS‐ob) mice.

Contrast-enhanced ultrasonography revealed active thoracic bleeding

A 61-year-old woman with a hepatocellular carcinoma located in the subphrenic region was treated by radiofrequency ablation (RFA) under artificial pleural effusion. During RFA, B-mode ultrasonography showed a swirling high echoic lesion in the artificial pleural effusion. A real-time scan performed using contrast-enhanced ultrasonography (CEUS) revealed a jet-like extravasation of contrast medium and pooling of microbubbles in the pleural cavity, which were confirmed by angiography. CEUS successfully identified the site of bleeding and can be regarded an effective tool for detecting active bleeding in an emergency.