Takaaki Sugihara

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.

Usefulness of contrast-enhanced ultrasound with Sonazoid for evaluating liver abscess in comparison with conventional B-mode ultrasound

The purpose of this study was to evaluate the usefulness of contrast‐enhanced ultrasound (CEUS) with Sonazoid (perfluorobutane) in patients with liver abscess. Sonazoid is a contrast agent with a low mechanical index and is phagocytosed by Kupffer cells.

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.

Renal shear wave velocity by acoustic radiation force impulse did not reflect advanced renal impairment.

Acoustic radiation force impulse is a noninvasive method for evaluating tissue elasticity on ultrasound. Renal shear wave velocity measured by this technique has not been fully investigated in patients with renal disease. The aim of the present study was to compare renal shear wave velocity in end‐stage renal disease patients and that in patients without chronic kidney disease and to investigate influencing factors.

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.

Preventative and therapeutic effects of perindopril on hepatic fibrosis induced by bile duct ligation in rats

The aim of this study was to examine the preventative and therapeutic effects of an angiotensin-converting enzyme inhibitor, perindopril, on cholestasis-induced liver fibrosis. Perindopril was administered orally for 21 days immediately after bile duct ligation at a dose of 2 mg/kg in order to evaluate the preventative effects, and for 21 days starting 3 weeks after bile duct ligation at doses of 2 and 8 mg/kg in order to evaluate the therapeutic effects. With regard to the preventative effects, perindopril reduced the hepatic hydroxyproline content by 33%, collagen-I mRNA by 38%, α-smooth muscle actin (α-SMA)-positive cells by 46%, α-SMA mRNA by 40%, transforming growth factor-β1 (TGF-β1) mRNA by 21% and connective tissue growth factor (CTGF) mRNA by 27%. With regard to the therapeutic effects, at 2 mg/kg perindopril had no inhibitory effects on the progression of liver fibrosis, but at 8 mg/kg, it reduced hepatic hydroxyproline contents by 63%, collagen-I mRNA by 94%, TGF-β1 mRNA by 79%, CTGF mRNA by 97% and tissue inhibitor of metalloproteinase-1 mRNA by 87%. Significant decreases in the oxidative stress markers hepatic 4-hydroxy-2-nonenal and 8-hydroxy-2-deoxyguanosine were noted for perindopril administration at 8 mg/kg, but not at 2 mg/kg. In conclusion, perindopril had preventative and therapeutic effects on cholestasis-induced liver fibrosis through the inhibition of oxidative stress and/or the activation of hepatic stellate cells, thus suggesting the possible application of perindopril as an antifibrotic drug.

Therapeutic effects of the dipeptidyl peptidase-IV inhibitor, sitagliptin, on non-alcoholic steatohepatitis in FLS-ob/ob male mice

Non-alcoholic steatohepatitis is characterized by hepatic fat accumulation, inflammation and varying degrees of fibrosis. The dipeptidyl peptidase‑IV enzyme is important in glucose metabolism, as well as lipid accumulation, extracellular matrix metabolism and immune stimulation. Furthermore, the enzyme activity of dipeptidyl peptidase‑IV is known to be increased in non‑alcoholic steatohepatitis. Therefore, dipeptidyl peptidase‑IV inhibitors are potential therapeutic agents for non‑alcoholic steatohepatitis. The present study assessed the therapeutic effects of sitagliptin, a dipeptidyl peptidase‑IV inhibitor, on non‑alcoholic steatohepatitis using fatty liver Shionogi‑ob/ob male mice. Sitagliptin (2 mg/kg/day; n=10) or placebo (control; n=10) was orally administered to fatty liver Shionogi‑ob/ob mice for 12 weeks, and hepatic steatosis, fibrosis, inflammation and oxidative stress were assessed in comparison with the controls. Sitagliptin administration reduced body weight and blood glucose levels, and improved hepatic fibrosis. It also inhibited the gene expression levels of fatty acid synthase, transforming growth factor‑β1, tissue inhibitor of metalloproteinases‑1, procollagen‑type 1, tumor necrosis factor‑α, monocyte chemoattractant protein‑1 and enhanced peroxisome proliferator activated receptor‑α. Furthermore, a marked attenuation of hepatic stellate cell activation and Kupffer cells was observed in the sitagliptin group. A decrease in oxidative stress and apoptosis was also observed. Sitagliptin attenuated the progression of hepatic fibrosis by improving lipid metabolism, inflammation and oxidative stress in non-alcoholic steatohepatitis.