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Ping An, Zheng Zeng, Cheryl A Winkler
Background: Sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) was recently identified as a hepatocyte receptor for infection of Hepatitis B virus (HBV). The natural S267F variant in NTCP causes a loss of HBV receptor function of NTCP. Objective: We assessed the association of S267F with HBV resistance, HBV infection clearance, and HBV-related cirrhosis and HCC. Methods: We tested the effects of S267F in 1117 Han Chinese patients with various HBV infection outcomes using multivariate logistic regression analysis...
June 14, 2018: Journal of Infectious Diseases
Camillo Sargiacomo, Hoda El-Kehdy, Guillaume Pourcher, Bruno Stieger, Mustapha Najimi, Etienne Sokal
Sodium taurocholate cotransporter polypeptide (NTCP), mainly expressed on the sinusoidal membrane of hepatocytes, is one of the major transporters responsible for liver bile acid (BA) re-uptake. NTCP transports conjugated BA from the blood into hepatocytes and is crucial for correct enterohepatic circulation. Studies have shown that insufficient hepatic clearance of BA correlates with elevated serum BA in infants younger than 1 year of age. In the current study, we investigated human NTCP messenger RNA and protein expression by using reverse-transcription quantitative polymerase chain reaction and immunoblotting in isolated and cryopreserved human hepatocytes from two different age groups, below and above 1 year of age...
June 2018: Hepatology Communications
Ah Ram Lee, Keo-Heun Lim, Eun-Sook Park, Doo Hyun Kim, Yong Kwang Park, Soree Park, Dong-Sik Kim, Gu-Choul Shin, Hong Seok Kang, Juhee Won, Heewoo Sim, Yea Na Ha, Byeongjune Jae, Seong Il Choi, Kyun-Hwan Kim
Hepatitis B virus (HBV) infection is a leading cause of liver diseases; however, the host factors which facilitate the replication and persistence of HBV are largely unidentified. Cellular FLICE inhibitory protein (c-FLIP) is a typical anti-apoptotic protein. In many cases of liver diseases, the expression level of c-FLIP is altered, which affects the fate of hepatocytes. We previously found that c-FLIP and its cleaved form interact with HBV X protein (HBx), which is essential for HBV replication, and regulate diverse cellular signals...
June 6, 2018: Journal of Virology
Teruyuki Umetsu, Jun Inoue, Takayuki Kogure, Eiji Kakazu, Masashi Ninomiya, Tomoaki Iwata, Satoshi Takai, Takuya Nakamura, Akitoshi Sano, Tooru Shimosegawa
Hepatitis B virus (HBV) infection is a worldwide health problem because of its potential to cause liver cirrhosis and hepatocellular carcinoma. Silibinin is a constituent of an extract of milk thistle, which is empirically used as a herbal medicine for the protection of liver, but its detailed effects on HBV are unknown. Because a previous study reported that silibinin hinders clathlin-mediated endocytosis (CME), we aimed to test whether silibinin inhibits the entry of HBV into hepatocytes. Using HepG2-NTCP-C4 cells, which overexpress sodium taurocholate cotransporting polypeptide (NTCP), it was shown that silibinin inhibited HBV infection dose-dependently...
July 2018: Biochemistry and Biophysics Reports
Kei Miyakawa, Satoko Matsunaga, Yutaro Yamaoka, Mina Dairaku, Kento Fukano, Hirokazu Kimura, Tomoyuki Chimuro, Hironori Nishitsuji, Koichi Watashi, Kunitada Shimotohno, Takaji Wakita, Akihide Ryo
Sodium taurocholate cotransporting polypeptide (NTCP) is a major entry receptor of hepatitis B virus (HBV) and one of the most attractive targets for anti-HBV drugs. We developed a cell-mediated drug screening method to monitor NTCP expression on the cell surface by generating a HepG2 cell line with tetracycline-inducible expression of NTCP and a monoclonal antibody that specifically detects cell-surface NTCP. Using this system, we screened a small molecule library for compounds that protected against HBV infection by targeting NTCP...
May 4, 2018: Oncotarget
Jiwon Lee, Li Zong, Alexander Krotow, Yanli Qin, Lucy Jia, Jiming Zhang, Shuping Tong, Jisu Li
Sodium taurocholate cotransporting polypeptide (NTCP) has been identified as a hepatitis B virus (HBV) receptor, and its overexpression in HepG2 cell line leads to efficient secretion of hepatitis B e antigen (HBeAg) following challenge with a large dose of cell culture-derived HBV (cHBV) particles. However, NTCP-reconstituted HepG2 cells are inefficiently infected by patient serum-derived HBV (sHBV), and release very little hepatitis B surface antigen (HBsAg) following cHBV infection in comparison to differentiated HepaRG cells, which are naturally susceptible to both cHBV and sHBV particles...
May 23, 2018: Journal of Virology
Yanli Zeng, Zixi Li, Jia Shang, Yi Kang
Hepatitis B virus (HBV) infection and related liver complications remain severe public health problems worldwide. Previous investigations have shown that small interfering (si)RNAs can offer an effective strategy for the treatment of chronic hepatitis B. The present study aimed to develop a novel siRNA‑delivering system of therapeutic HBV nuclear localization sequence (NLS) siRNAs using the recombinant preS1‑truncated protamine (tP) proteins. The preS1 region of the LHB was used in place of scFv to construct the recombinant preS1‑tP proteins, which were applied to deliver siRNAs targeting the HBV NLS to inhibit HBV replication and infection in HepG2...
May 16, 2018: International Journal of Molecular Medicine
Shivali S Joshi, Carla S Coffin
The hepatitis B virus (HBV) is predominantly a hepatotropic virus but also infects cells of the lymphatic system. HBV genomes (DNA, messenger (m)RNA, covalently closed circular (ccc) DNA) and proteins have been found in extrahepatic sites such as peripheral blood mononuclear cells (PBMC), lymph nodes, spleen, bone marrow and cerebrospinal fluid. HBV entry into hepatocytes occurs by binding of the HBV preS1 surface protein to its specific receptor, the bile acid transporter, sodium taurocholate co-transporting polypeptide (NTCP)...
May 22, 2018: Biotechnology & Genetic Engineering Reviews
Toby Passioura, Koichi Watashi, Kento Fukano, Satomi Shimura, Wakana Saso, Ryo Morishita, Yuki Ogasawara, Yasuhito Tanaka, Masashi Mizokami, Camille Sureau, Hiroaki Suga, Takaji Wakita
Hepatitis B virus (HBV) constitutes a significant public health burden, and currently available treatment options are not generally curative, necessitating the development of new therapeutics. Here we have applied random non-standard peptide integrated discovery (RaPID) screening to identify small macrocyclic peptide inhibitors of HBV entry that target the cell-surface receptor for HBV, sodium taurocholate cotransporting polypeptide (NTCP). In addition to their anti-HBV activity, these molecules also inhibit cellular entry by the related hepatitis D virus (HDV), and are active against diverse strains of HBV (including clinically relevant nucleos(t)ide analog-resistant and vaccine escaping strains)...
May 2, 2018: Cell Chemical Biology
Wakana Saso, Senko Tsukuda, Hirofumi Ohashi, Kento Fukano, Ryo Morishita, Satoko Matsunaga, Mio Ohki, Akihide Ryo, Sam-Yong Park, Ryosuke Suzuki, Hideki Aizaki, Masamichi Muramatsu, Camille Sureau, Takaji Wakita, Tetsuro Matano, Koichi Watashi
Current anti-hepatitis B virus (HBV) agents have limited effect in curing HBV infection, and thus novel anti-HBV agents with different modes of action are in demand. In this study, we applied AlphaScreen assay to high-throughput screening of small molecules inhibiting the interaction between HBV large surface antigen (LHBs) and the HBV entry receptor, sodium taurocholate cotransporting polypeptide (NTCP). From the chemical screening, we identified that rapamycin, an immunosuppressant, strongly inhibited the LHBs-NTCP interaction...
May 3, 2018: Biochemical and Biophysical Research Communications
Yasunori Nio, Yuichi Akahori, Hitomi Okamura, Koichi Watashi, Takaji Wakita, Makoto Hijikata
Fasiglifam is a selective partial agonist of G-protein-coupled receptor 40 (GPR40), which was developed for the treatment of type 2 diabetes mellitus. However, the clinical development of fasiglifam was voluntarily terminated during phase III clinical trials due to adverse liver effects. Fasiglifam showed an inhibitory effect on sodium taurocholate cotransporting polypeptide (NTCP) in human and rat hepatocytes. Recently, NTCP was reported to be a functional receptor for human hepatitis B virus (HBV) infections...
April 30, 2018: Biochemical and Biophysical Research Communications
C-L Lin, J-H Kao
BACKGROUND: Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. AIMS: To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. METHODS: Recent published studies identified from PubMed were comprehensively reviewed...
May 3, 2018: Alimentary Pharmacology & Therapeutics
Andrew D Huber, Jennifer J Wolf, Dandan Liu, Anna T Gres, Jing Tang, Kelsey N Boschert, Maritza N Puray-Chavez, Dallas L Pineda, Thomas G Laughlin, Emily M Coonrod, Qiongying Yang, Juan Ji, Karen A Kirby, Zhengqiang Wang, Stefan G Sarafianos
Heteroaryldihydropyrimidines (HAPs) are compounds that inhibit hepatitis B virus (HBV) replication by modulating viral capsid assembly. While their biophysical effects on capsid assembly in vitro have been previously studied, the effect of HAP treatment on capsid protein (Cp) in individual HBV-infected cells remains unknown. We report here that the HAP Bay 38-7690 promotes aggregation of recombinant Cp in vitro and causes a time- and dose-dependent decrease of Cp in infected cells, consistent with previously studied HAPs...
April 25, 2018: MSphere
O N Nfor, M-F Wu, T Debnath, C-T Lee, W Lee, W-H Liu, D M Tantoh, S-Y Hsu, Y-P Liaw
Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for hepatitis B virus (HBV) infection. NTCP rs2296651 is believed to be an Asian-specific variant responsible for HBV susceptibility. We investigated the relationship between rs2296651 and HBV infection in Taiwan based on stratification by gender and menopausal status. We recruited 10 017 Taiwan Biobank participants aged 30-70 years with complete genetic data and sociodemographic information. Gender-stratified multivariate logistic regression models were used to determine the relationship between NTCP variant and HBV infection...
April 16, 2018: Journal of Viral Hepatitis
Ji-Hua Ren, Jie-Li Hu, Sheng-Tao Cheng, Hai-Bo Yu, Vincent Kam Wai Wong, Betty Yuen Kwan Law, Yong-Feng Yang, Ying Huang, Yi Liu, Wei-Xian Chen, Xue-Fei Cai, Hua Tang, Yuan Hu, Wen-Lu Zhang, Xiang Liu, Quan-Xin Long, Li Zhou, Na-Na Tao, Hong-Zhong Zhou, Qiu-Xia Yang, Fang Ren, Lin He, Rui Gong, Ai-Long Huang, Juan Chen
Hepatitis B virus (HBV) infection remains a major health problem worldwide. Maintenance of the covalently closed circular DNA (cccDNA) which serves as a template for HBV RNA transcription is responsible for the failure of eradicating chronic HBV during current antiviral therapy. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications. In this study, we identified SIRT3 as a host factor restricting HBV transcription and replication by screening seven members of Sirtuin family which is the class III histone deacetylase...
April 6, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Rosario Casillas, David Tabernero, Josep Gregori, Irene Belmonte, Maria Francesca Cortese, Carolina González, Mar Riveiro-Barciela, Rosa Maria López, Josep Quer, Rafael Esteban, Maria Buti, Francisco Rodríguez-Frías
AIM: To determine the variability/conservation of the domain of hepatitis B virus (HBV) preS1 region that interacts with sodium-taurocholate cotransporting polypeptide (hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism (S267F, NTCP variant) in a Spanish population. METHODS: Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection (CHB) ( n = 41, 73% Caucasians), patients with resolved HBV infection ( n = 100, 100% Caucasians) and an HBV-uninfected control group ( n = 105, 100% Caucasians)...
February 14, 2018: World Journal of Gastroenterology: WJG
Manabu Kaneko, Yushi Futamura, Senko Tsukuda, Yasumitsu Kondoh, Tomomi Sekine, Hiroyuki Hirano, Kento Fukano, Hirofumi Ohashi, Wakana Saso, Ryo Morishita, Satoko Matsunaga, Fumihiro Kawai, Akihide Ryo, Sam-Yong Park, Ryosuke Suzuki, Hideki Aizaki, Naoko Ohtani, Camille Sureau, Takaji Wakita, Hiroyuki Osada, Koichi Watashi
Current anti-hepatitis B virus (HBV) agents including interferons and nucleos(t)ide analogs efficiently suppress HBV infection. However, as it is difficult to eliminate HBV from chronically infected liver, alternative anti-HBV agents targeting a new molecule are urgently needed. In this study, we applied a chemical array to high throughput screening of small molecules that interacted with sodium taurocholate cotransporting polypeptide (NTCP), an entry receptor for HBV. From approximately 30,000 compounds, we identified 74 candidates for NTCP interactants, and five out of these were shown to inhibit HBV infection in cell culture...
February 9, 2018: Scientific Reports
Xiaoqiong Duan, Shilin Li, Jacinta A Holmes, Zeng Tu, Yujia Li, Dachuan Cai, Xiao Liu, Wenting Li, Chunhui Yang, Baihai Jiao, Esperance A Schaefer, Dahlene N Fusco, Shadi Salloum, Limin Chen, Wenyu Lin, Raymond T Chung
Hepatitis C virus (HCV) infection has been shown to regulate microRNA 130a (miR-130a) in patient biopsy specimens and in cultured cells. We sought to identify miR-130a target genes and to explore the mechanisms by which miR-130a regulates HCV and hepatitis B virus (HBV) replication. We used bioinformatics software, including miRanda, TargetScan, PITA, and RNAhybrid, to predict potential miR-130a target genes. miR-130a and its target genes were overexpressed or were knocked down by use of small interfering RNA (siRNA) or clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 guide RNA (gRNA)...
April 1, 2018: Journal of Virology
Tung-Hung Su, Hung-Chih Yang, Tai-Chung Tseng, Jyh-Ming Liou, Chen-Hua Liu, Chi-Ling Chen, Pei-Jer Chen, Ding-Shinn Chen, Chun-Jen Liu, Jia-Horng Kao
Background: We investigated the patterns and predictors for virological relapse (VR), clinical relapse (CR), and sustained clinical response (SCR) and the outcomes of retreatment after nucleos(t)ide analogue (NUC) therapy discontinuation. Methods: Patients with chronic hepatitis B who were discontinuing NUC therapy were prospectively enrolled. Viral and host predictors of relapse were evaluated, including hepatitis B virus (HBV) surface antigen (HBsAg) level, anti-HBV core antibody level, and presence of single-nucleotide polymorphisms in the genes encoding the receptors NTCP (rs2296651) and CTLA4 (rs231775) and in the 3' untranslated regions of the genes encoding HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277535); posttherapy predictors of relapse were also investigated...
March 28, 2018: Journal of Infectious Diseases
Peng Wang, Ruidong Mo, Rongtao Lai, Yumin Xu, Jie Lu, Gangde Zhao, Yuhan Liu, Zhujun Cao, Xiaolin Wang, Ziqiang Li, Lanyi Lin, Huijuan Zhou, Wei Cai, Hui Wang, Shisan Bao, Xiaogang Xiang, Qing Xie
Sodium taurocholate cotransporting polypeptide (NTCP), encoded by gene SLC10A1, is a receptor for hepatitis B virus (HBV). The aim of the current study was to investigate the role of NTCP polymorphisms in HBV susceptibility, cirrhosis and hepatocarcinogenesis. A total 1221 cases [including 866 chronic hepatitis B (CHB), 238 liver cirrhosis (LC), 117 hepatocellular carcinoma (HCC) patients] and 1232 healthy controls (HCs) were recruited, and 6 single nucleotide polymorphisms (SNPs) were genotyped. Meta-analysis was executed among 14591 CHBs and 12396 HCs to determine the association between NTCP polymorphisms and HBV infection, cirrhosis or hepatocarcinogenesis...
December 1, 2017: Oncotarget
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