Hepatitis: Hirata Y

Hirata Y, Sudoh M, Kohara M. · Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, Japan. · Uirusu. · Pubmed #19374199 links to  free full text

Abstract: Hepatitis C virus (HCV) develops persistent infection in most infected patients, and eventually cause chronic hepatitis, liver cirrhosis and then hepatocellular carcinoma. The combination therapy of PEG-IFN and ribavirin improves the efficacy in many patients, while it does not lead to sufficient achievements in genotype1b patients. To invent new anti-HCV reagent, we focused on host factors which HCV take advantage of in its life-cycle. We identified serine palmitoyltransferase inhibitor as anti-HCV reagent through high-through put screenig using HCV replicon cells. Moreover, we evaluate the anti-HCV effect of SPT-inhibitor in vivo with humanized chimeric mice. SPT-inhibitor led to rapid decline in serum HCV-RNA of about 1-2log within 8 day, futhermore the combination therapy of SPT-inhibitor and PEG-IFN achieved about 3log reduction in serum HCV-RNA. At last, we investigated the mechanism of anti-HCV effect of SPT-inhibitor. It has been reported that sphingolipids and cholesterol compose the lipid raft, in which the replication of HCV occur. We investigated the influence of SPT-inhibitor to lipid rafts by analysing the detergent resistant membrane (DRM). The analysis proved that SPT inhibitor got HCV RNA dependent RNA polymerase (NS5B) to move to detergent soluble fraction from DRM, and Biacore analysis indicated the binding of sphingomyelin to NS5B. These results suggested SPT inhibitor got NS5B to release from replication complex.

Nagata T, Matsumoto A, Uehara Y, Tanaka G, Oonuma H, Hara K, Igarashi K, Hazama H, Hirata Y, Shiratori Y, Omata M. · Second Department of Medicine, University of Tokyo. · Intern Med. · Pubmed #12135174 links to  free full text

Abstract: OBJECTIVE: Nitric oxide (NO) production is enhanced in patients with liver cirrhosis (LC). Although most patients with mild LC have neither dyspnea nor platypnea, they might have mild oxygenation abnormalities due to intrapulmonary vasodilatation caused by increased NO. We investigated whether oxygenation abnormalities, such as hypoxemia and orthodeoxia, are present in patients with mild LC. METHODS: We investigated 148 consecutive patients with biopsy-proven chronic liver diseases such as CH (noncirrhotic chronic hepatitis) (n=46), LC(A), LC(B), and LC(C) (LC Child's A, B, and C) (n=18, 51, 33, respectively). The oxygen saturation by pulse oximetry (SpO2) in the supine and upright positions was determined in patients and controls (normal subjects, n=29). The change in SpO2 on standing was defined as deltaSpO2. NO output in exhaled air was measured in 16 patients. RESULTS: Four patients [two LC(B) and two LC(C)] had hypoxemia (supine SpO2< or =94% and/or upright SpO2< or =94%). Although there was no intergroup difference in the supine SpO2 or the upright SpO2, the deltaSpO2 decreased [control, +0.2+/-0.6%; CH, +0.1+/-0.9%; LC(A), -0.3+/-0.8%; LC(B), -0.2+/-0.9%; LC(C), -0.5+/-1.1%; mean+/-SD; p=0.005] with worsening liver disease, and the prevalence of desaturation on standing (deltaSpO2< or =-1%) increased [control, 7%; CH, 20%; LC(A), 33%; LC(B), 35%; LC(C), 42%; p=0.01]. The NO output was inversely correlated with deltaSpO2 (r=-0.66, p=0.006). CONCLUSIONS: Desaturation on standing is present in one-third of normoxemic patients with mild LC of Child's A, and is associated with the severity of liver disease. This postural desaturation is correlated with the exhaled NO, which suggests that intrapulmonary vasodilatation may play some role in this phenomenon.