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Ryota Sueki,
Shinya Maekawa,
Mika Miura,
Makoto Kadokura,
Kazuki Komase,
Hiroko Shindo, Asuka Kanayama,
Takako Ohmori,
Kuniaki Shindo,
Fumitake Amemiya,
Yasuhiro Nakayama,
Tomoyoshi Uetake,
Taisuke Inoue,
Minoru Sakamoto,
Nobuyuki Enomoto
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ABSTRACT: The emergence of amino acid or nucleotide substitutions leads to lamivudine resistance in hepatitis B virus (HBV) infected patients. The aim of this study was to investigate whether viral sequences help predict the emergence of lamivudine resistance. The study subjects comprised 59 consecutive patients infected with HBV treated with daily therapy of 100 mg lamivudine. Among those, 32 patients with adequate pretreatment serum preservation were investigated for the correlation between viral amino acid substitutions and the appearance of lamivudine resistance with consideration of clinical background by determining dominant HBV full open reading frames. Viral resistance to lamivudine emerged in 28 of 59 patients (47%) in a median period of 2.45 years. Sequence comparisons of HBV genomes between patients who later developed lamivudine resistance and patients who did not revealed the existence of significant differences between the two groups in the pre-S1 84 (P = 0.042), pre-S2 1 (P = 0.017) and 22 (P = 0.015), and polymerase tp 95 (P = 0.046), judged by a log-rank test. Viral sequence analyses revealed the presence of amino acid substitutions in HBV pre-S1 and pre-S2 that may be associated with the emergence of lamivudine resistance during chronic HBV infection.
Journal of Medical Virology 09/2012; 84(9):1360-8. · 2.82 Impact Factor
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Mika Miura,
Shinya Maekawa,
Makoto Kadokura,
Ryota Sueki,
Kazuki Komase,
Hiroko Shindo,
Takako Ohmori, Asuka Kanayama,
Kuniaki Shindo,
Fumitake Amemiya,
Yasuhiro Nakayama,
Takatoshi Kitamura,
Tomoyoshi Uetake,
Taisuke Inoue,
Minoru Sakamoto,
Shunichi Okada,
Nobuyuki Enomoto
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ABSTRACT: BACKGROUND AND AIMS: The association between hepatitis C virus (HCV) sequences with interleukin 28B (IL28B) single-nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) has not been well clarified. METHODS: Complete HCV open-reading frame sequences were determined in 20 patients developing HCC and 23 non-HCC patients with HCV-1b infection in two distant time points. An additional 230 patients were studied cross-sectionally for core and NS5A sequences with HCC development. Among them, 98 patients with available samples were investigated for changes in viral core sequences over time. Finally, IL28B SNPs and HCC development were investigated in 228 patients. RESULTS: During observation period (HCC for 10.8 years, and non-HCC for 11.1 years), changes in core a.a. 70 and three amino acid positions in NS5A were characteristics of the patients developing HCC. In 230 patients, Q (glutamine) or H (histidine) to R (arginine) ratio at core a.a. 70 was significantly higher in the HCC group (HCC group 43:22 vs. non-HCC group 66:99, p = 0.001). A change in core R70Q was observed over time in 11 patients associated with a decrease in platelets (p = 0.005) and albumin (p = 0.005), while a Q70R change was observed in 4 patients without associated changes in platelets (nonsignificant) and albumin (nonsignificant). IL28B SNP showed significant correlation with the core a.a. 70 residue. There was no evident link between IL28B SNPs and the occurrence of HCC. CONCLUSIONS: Hepatitis C virus core a.a. 70 residue is associated with liver disease progression and is independent factor for HCC development in genotype-1b infection. IL28B SNPs are related to core a.a. 70 residue, but not to HCC. The functional relevance of core a.a. 70 residue in hepatitis C pathogenesis should be further investigated.
Hepatology International 08/2011; · 2.64 Impact Factor
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Shinichi Takano,
Takashi Ando,
Nobuhiko Hiramatsu, Asuka Kanayama,
Shinya Maekawa,
Yuko Ohnuma,
Nobuyuki Enomoto,
Hideoki Ogawa,
Adrienne W Paton,
James C Paton,
Masanori Kitamura,
Atsuhito Nakao
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ABSTRACT: The 78-kDa glucose-regulated protein (GRP78) is an important molecular chaperone in the endoplasmic reticulum (ER) induced by various stresses. This study showed that stimulation with anti-CD3 mAb, PMA plus ionomycin, or an antigen increased the levels of GRP78 mRNA in primary T cells, which was inhibited by Ca(2+) chelators EGTA and BAPTA-AM and by an inhibitor of calcineurin FK506. In addition, the specific knockdown of GRP78 protein expression induced apoptosis in mouse EL-4 T cell line associated with CHOP induction and caspase-3 activation. Furthermore, overexpression of GRP78 inhibited PMA/ionomycin-induced cell death in EL-4 cells. Collectively, GRP78 expression is induced by TCR activation via a Ca(2+)-dependent pathway and may play a critical role in maintaining T cell viability in the steady and TCR-activated states. These results suggest a novel regulatory mechanism and an essential function of GRP78 in T cells.
Biochemical and Biophysical Research Communications 08/2008; 371(4):762-6. · 2.48 Impact Factor
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Fumitake Amemiya,
Shinya Maekawa,
Yoshie Itakura, Asuka Kanayama,
Akira Matsui,
Shinichi Takano,
Tatsuya Yamaguchi,
Jun Itakura,
Takatoshi Kitamura,
Taisuke Inoue,
Minoru Sakamoto,
Kozue Yamauchi,
Shunichi Okada,
Atsuya Yamashita,
Naoya Sakamoto,
Masahiko Itoh,
Nobuyuki Enomoto
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ABSTRACT: Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called "lipid rafts") have been considered to act as a scaffold for the hepatitis C virus (HCV) replication complex. Using the HCV cell culture system, we investigated the effect of myriocin, a sphingomyelin synthesis inhibitor, on HCV replication. We also investigated the combined effect of myriocin with interferon (IFN) and myriocin with simvastatin. Myriocin suppressed replication of both a genotype 1b subgenomic HCV replicon (Huh7/Rep-Feo) and genotype 2a infectious HCV (JFH-1 HCV) in a dose-dependent manner (for subgenomic HCV-1b, maximum of 79% at 1000 nmol/L; for genomic HCV-2a, maximum of 40% at 1000 nmol/L). Combination treatment with myriocin and IFN or myriocin and simvastatin attenuated HCV RNA replication synergistically in Huh7/Rep-Feo cells. Our data demonstrate that the sphingomyelin synthesis inhibitor strongly suppresses replication of both the subgenomic HCV-1b replicon and the JFH-1 strain of genotype 2a infectious HCV, indicating that lipid metabolism could be a novel target for HCV therapy.
The Journal of Infectious Diseases 03/2008; 197(3):361-70. · 6.41 Impact Factor
