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Dive into the research topics where Narayan Dharel is active.

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Featured researches published by Narayan Dharel.


Hepatology | 2005

Interaction between the HCV NS3 protein and the host TBK1 protein leads to inhibition of cellular antiviral responses

Motoyuki Otsuka; Naoya Kato; Masaru Moriyama; Hiroyoshi Taniguchi; Yue Wang; Narayan Dharel; Takao Kawabe; Masao Omata

The persistent nature of hepatitis C virus (HCV) infection suggests that HCV encodes proteins that enable it to overcome host antiviral responses. Toll‐like receptor 3 (TLR3)‐mediated signaling, which recognizes the double‐stranded RNA that is produced during viral replication and induces type I interferons, including interferon β (IFN‐β), is crucial to the host defense against viruses. Recent studies suggest that a TIR domain–containing adaptor protein, TRIF, and two protein kinases, TANK‐binding kinase‐1 (TBK1) and IκB kinase‐ϵ (IKKϵ), play essential roles in TLR3‐mediated IFN‐β production through the activation of the transcriptional factor interferon regulatory factor 3 (IRF‐3). We report that the HCV NS3 protein interacts directly with TBK1, and that this binding results in the inhibition of the association between TBK1 and IRF‐3, which leads to the inhibition of IRF‐3 activation. In conclusion, these results suggest the mechanisms of the inhibition of the innate immune responses of HCV infection by NS3 protein. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;41:1004–1012.)


Clinical Cancer Research | 2006

MDM2 Promoter SNP309 Is Associated with the Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

Narayan Dharel; Naoya Kato; Ryosuke Muroyama; Masaru Moriyama; Run-Xuan Shao; Takao Kawabe; Masao Omata

Purpose: A single nucleotide polymorphism (SNP) in the promoter region of MDM2 gene, SNP309, has recently been shown to be associated with accelerated tumor formation in both hereditary and sporadic cancers in humans. However, the association of SNP309 with hepatocellular carcinoma is unknown. We evaluated the association of SNP309 with the risk of hepatocellular carcinoma development among Japanese patients with chronic hepatitis C virus infection. Experimental Design: We genotyped the SNP309 at the MDM2 promoter in 435 Japanese patients with chronic hepatitis C virus infection, including 187 patients with hepatocellular carcinoma and 48 healthy subjects, using a fluorogenic PCR. Presence of SNP was also confirmed by direct sequencing of the MDM2 promoter region. Results: The proportion of G/G genotype of the SNP309 in patients with hepatocellular carcinoma (33%) was significantly higher than that in patients without hepatocellular carcinoma (23%), with an odds ratio (95% confidence interval) of 2.28 (1.30-3.98). A multivariate analysis revealed that MDM2 SNP309 (G/G versus T/T), age >60 years, male gender, presence of cirrhosis, serum α-fetoprotein >20 μg/L, and serum albumin <3.2 g/dL were independently associated with the hepatocellular carcinoma development at odds ratio of 2.27, 2.46, 3.08, 4.15, 4.87, and 6.33, respectively. Conclusions: The MDM2 promoter SNP309 is associated with the presence of hepatocellular carcinoma in Japanese patients with chronic hepatitis C.


Hepatology | 2005

Large‐scale search of single nucleotide polymorphisms for hepatocellular carcinoma susceptibility genes in patients with hepatitis C

Naoya Kato; Guijin Ji; Yue Wang; Masanori Baba; Yujin Hoshida; Motoyuki Otsuka; Hiroyoshi Taniguchi; Masaru Moriyama; Narayan Dharel; Tadashi Goto; Run-Xuan Shao; Tadashi Matsuura; Keisuke Ishii; Shuichiro Shiina; Takao Kawabe; Masaaki Muramatsu; Masao Omata

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC). The host genetic factors that are involved in the development of HCC in patients with HCV infection remain to be investigated. To search for single nucleotide polymorphisms (SNPs) in HCC susceptibility genes, 393 SNPs in 171 candidate genes were examined in 188 Japanese patients with chronic HCV infection, including 77 patients with HCC. HCC‐related SNPs were then examined in another 188 patients (including 93 patients with HCC) with chronic HCV infection. Haplotype analyses of HCC‐related genes were performed in a total of 376 patients. Of the 393 SNPs, 31 SNPs in 29 genes were significantly associated with HCC based on an initial screening (P < .05). Of these 31 SNPs, 3 SNPs of 3 genes (SCYB14, GFRA1, and CRHR2) were significantly associated with HCC in a secondary screening. Haplotype analyses of these 3 genes identified 2 haplotype blocks associated with HCC. In conclusion, these SNPs and haplotypes located in the SCBY14, CRHR2, and GFRA1 genes will be used as markers to identify a subgroup of Japanese patients with chronic HCV infection who are at high risk of developing HCC. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270‐9139/suppmat/index.html). (HEPATOLOGY 2005;42:846–853.)


Hepatology | 2007

Potential contribution of tumor suppressor p53 in the host defense against hepatitis C virus.

Narayan Dharel; Naoya Kato; Ryosuke Muroyama; Hiroyoshi Taniguchi; Motoyuki Otsuka; Yue Wang; Amarsanaa Jazag; Run-Xuan Shao; Jin-Hai Chang; Mark K. Adler; Takao Kawabe; Masao Omata

Infection by hepatitis C virus (HCV) usually results into chronic hepatitis that can ultimately lead to cirrhosis and hepatocellular carcinoma. Type 1 interferons (IFN‐α/β) constitute the primary cellular defense against viral infection including HCV. IFN binding to their receptors activates associated Jak1 and Tyk2 kinases, which ultimately leads to phosphorylation and assembly of a signal transducer and activator of transcription protein (STAT)1‐STAT2‐interferon regulatory factor (IRF)9 trimetric complex called interferon‐stimulated gene factor 3 that translocates into the nucleus and binds to the interferon‐ stimulated response elements (ISRE), leading to transcriptional induction of several antiviral genes, including double‐stranded RNA‐activated protein kinase (PKR), 2′,5′‐ oligoadenylate synthetase (OAS), and myxovirus resistance protein A (MxA). Understanding the mechanisms of how the virus evades this cellular innate defense and establishes a chronic infection is the key for the development of better therapeutics against HCV infection. Here, we demonstrate that p53 could have a crucial role in the cellular innate defense against HCV. We observed significantly higher levels of HCV RNA replication and viral protein expression in the Huh7 cells when their p53 expressions were knocked down. Moreover, IFN treatment was less effective in inhibiting the HCV RNA replication in the p53–knocked‐down (p53kd) Huh7 cells. In fact, the activation of the ISRE and the induction of ISGs were significantly attenuated in the p53kd Huh7 cells and p53 was found to directly interact with IRF9. Conclusion: These observations underscore the potential contributions of the tumor suppressor p53 in cellular antiviral immunity against HCV with possible therapeutic implications. (HEPATOLOGY 2008.)


Liver International | 2009

Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication.

Chang‐Zheng Li; Naoya Kato; Jin-Hai Chang; Ryosuke Muroyama; Run-Xuan Shao; Narayan Dharel; Radsamee Sermsathanasawadi; Takao Kawabe; Masao Omata

Background: Progression of disease after hepatitis C virus (HCV) infection differs among individuals, indicating a possibility of participation of host genetic factors. 2′‐5′‐oligoadenylate synthetase 1 (OAS‐1), an important component of the innate immune system, has an antiviral function, and may therefore have a certain relationship with progression of disease.


Oncogene | 2007

Absence of tyrosine kinase mutations in Japanese colorectal cancer patients

Run-Xuan Shao; Naoya Kato; Lin Lj; Ryosuke Muroyama; Masaru Moriyama; Tsuneo Ikenoue; Watabe H; Motoyuki Otsuka; Bayasi Guleng; Miki Ohta; Yasuo Tanaka; Kondo S; Narayan Dharel; Jin-Hai Chang; Haruhiko Yoshida; Takao Kawabe; Masao Omata

Tyrosine kinases, which are important regulators of intracellular signal-transduction pathways, have mutated forms that are often associated with oncogenesis and are attractive targets for therapeutic intervention. Recently, systematic mutational analyses of tyrosine kinases revealed that a minimum of 30% of colorectal cancer contain at least one mutation in the tyrosine kinases. To further explore these mutations, we examined all reported mutations of NTRK3, FES, KDR, EPHA3, NTRK2, JAK1, PDGFRA, EPHA7, EPHA8, ERBB4, FGFR1, MLK4 and GUCY2F genes in the 24 colorectal cancer cell lines. Unexpectedly, among 24 colorectal cancer cell lines, only two cell lines (LoVo and CaR1) harbored mutation C1408T (R470C) in MLK4 gene. The mutation rate was extremely low compared to that previously reported. Therefore, we analyzed mutations in 46 colorectal cancer samples resected from the same number of Japanese patients. Surprisingly, none of the 46 samples contained any of the mutations reported. Based on our study, we advise that a more comprehensive tyrosine kinase gene mutation assay is necessary in the future.


Liver International | 2008

Association of interferon regulatory factor-7 gene polymorphism with liver cirrhosis in chronic hepatitis C patients.

Radsamee Sermasathanasawadi; Naoya Kato; Ryosuke Muroyama; Narayan Dharel; Run-Xuan Shao; Jin-Hai Chang; Chang‐Zheng Li; Takao Kawabe; Masao Omata

Background and aims: Interferon (IFN) regulatory factor 7 (IRF‐7) has been shown to play an essential role in the transcriptional activation of virus‐inducible cellular genes, especially IFN genes. Polymorphisms of the IRF‐7 gene may probably affect both the quality and the quantity of IRF‐7. We investigated the role of IRF‐7 polymorphisms in Japanese patients with chronic hepatitis C virus (HCV) infection.


Liver International | 2010

Double‐stranded RNA‐activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment

Jin-Hai Chang; Naoya Kato; Ryosuke Muroyama; Hiroyoshi Taniguchi; Bayasi Guleng; Narayan Dharel; Run-Xuan Shao; Keisuke Tateishi; Amarsanaa Jazag; Takao Kawabe; Masao Omata

Background: Double‐stranded RNA‐activated protein kinase (PKR), an interferon (IFN)‐stimulated gene, is activated by binding with double‐stranded RNA, a putative replicative intermediate of the hepatitis C virus (HCV). Activated PKR phosphorylates the α subunit of eukaryotic initiation factor‐2 to inhibit the translation of viral protein.


Gastroenterology | 2006

Hepatitis C Virus Core Protein Is a Potent Inhibitor of RNA Silencing-Based Antiviral Response

Yue Wang; Naoya Kato; Amarsanaa Jazag; Narayan Dharel; Motoyuki Otsuka; Hiroyoshi Taniguchi; Takao Kawabe; Masao Omata


Journal of Hepatology | 2006

Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma.

Ryosuke Muroyama; Naoya Kato; Haruhiko Yoshida; Motoyuki Otsuka; Masaru Moriyama; Yue Wang; Run-Xuan Shao; Narayan Dharel; Yasuo Tanaka; Miki Ohta; Ryosuke Tateishi; Shuichiro Shiina; Masashi Tatsukawa; Kenichi Fukai; Fumio Imazeki; Osamu Yokosuka; Yasushi Shiratori; Masao Omata

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