Abstract:
BACKGROUND & AIMS:Current antiviral therapies help keep HBV under control, but they are not curative, as they are unable to eliminate the intracellular viral replication intermediate termed covalently closed circular DNA (cccDNA). Therefore, there remains an urgent need to develop strategies to cure CHB. Functional silencing of cccDNA is a crucial curative strategy that may be achieved by targeting the viral protein HBx. METHODS:We screened 2,000 small-molecule compounds for their ability to inhibit HiBiT-tagged HBx (HiBiT-HBx) expression by using a HiBiT lytic detection system. The antiviral activity of a candidate compound and underlying mechanism of its effect on cccDNA transcription were evaluated in HBV-infected cells and a humanised liver mouse model. RESULTS:Dicoumarol, an inhibitor of NAD(P)H:quinone oxidoreductase 1 (NQO1), significantly reduced HBx expression. Moreover, dicoumarol showed potent antiviral activity against HBV RNAs, HBV DNA, HBsAg and HBc protein in HBV-infected cells and a humanised liver mouse model. Mechanistic studies demonstrated that endogenous NQO1 binds to and protects HBx protein from 20S proteasome-mediated degradation. NQO1 knockdown or dicoumarol treatment significantly reduced the recruitment of HBx to cccDNA and inhibited the transcriptional activity of cccDNA, which was associated with the establishment of a repressive chromatin state. The absence of HBx markedly blocked the antiviral effect induced by NQO1 knockdown or dicoumarol treatment in HBV-infected cells. CONCLUSIONS:Herein, we report on a novel small molecule that targets HBx to combat chronic HBV infection; we also reveal that NQO1 has a role in HBV replication through the regulation of HBx protein stability. LAY SUMMARY:Current antiviral therapies for hepatitis B are not curative because of their inability to eliminate covalently closed circular DNA (cccDNA), which persists in the nuclei of infected cells. HBV X (HBx) protein has an important role in regulating cccDNA transcription. Thus, targeting HBx to silence cccDNA transcription could be an important curative strategy. We identified that the small molecule dicoumarol could block cccDNA transcription by promoting HBx degradation; this is a promising therapeutic strategy for the treatment of chronic hepatitis B.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Cheng ST,Hu JL,Ren JH,Yu HB,Zhong S,Wai Wong VK,Kwan Law BY,Chen WX,Xu HM,Zhang ZZ,Cai XF,Hu Y,Zhang WL,Long QX,Ren F,Zhou HZ,Huang AL,Chen Jdoi
10.1016/j.jhep.2020.09.019subject
Has Abstractpub_date
2020-09-25 00:00:00eissn
0168-8278issn
1600-0641pii
S0168-8278(20)33661-8pub_type
杂志文章abstract::Treatment of hepatic fibrosis by simple and inexpensive therapies is a new challenge for the near future. Hepatic fibrosis which may lead to cirrhosis, is indeed associated with most chronic liver diseases and affects millions of people. During the last decade, major breakthroughs have been accomplished in the field o...
journal_title:Journal of hepatology
pub_type: 评论,杂志文章,评审
doi:10.1016/s0168-8278(05)80002-9
更新日期:1993-04-01 00:00:00
abstract:BACKGROUND & AIMS:To evaluate the prevalence and risk factors for low bone mineral density (BMD) in persons co-infected with HIV and Hepatitis C. METHODS:HIV/HCV co-infected study participants (n=179) were recruited into a prospective cohort and underwent dual-energy X-ray absorptiometry (DXA) within 1 year of a liver...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.01.035
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abstract:BACKGROUND & AIMS:miR-224 is up-regulated in human HCCs as compared to both paired peri-tumoral cirrhotic tissues and cirrhotic livers without HCC. Here, we have cloned the miR-224 regulatory region and characterized its transcriptional regulation by the NFκB-dependent inflammatory pathways. METHODS:Mature miRNA expre...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.11.017
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abstract::The aim of the present investigation was to study the number and acinar distribution of apoptotic bodies in normal liver as an approach to a better understanding of cell kinetics in the hepatic parenchyma. The material included 20 normal human needle liver biopsies and 20 normal male Sprague-Dawley rats. For each live...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(88)80004-7
更新日期:1988-12-01 00:00:00
abstract:BACKGROUND/AIMS:Hepatic undifferentiated (embryonal) sarcoma (HUS) is an exceptional hepatic malignant tumor in adults. Genetic studies were never reported in adult cases. METHODS:In this study concerning three cases of HUS occurring in adult, we studied the three classical ways of carcinogenesis i.e. the TP53 (p53), ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.10.021
更新日期:2005-03-01 00:00:00
abstract:BACKGROUND/AIMS:Type 2 autoimmune hepatitis (AIH) is characterized by the presence of anti-liver kidney microsome (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. However, the correlation between these autoantibodies and the genetic background has not been studied. METHODS:Frequencies of HLA cl...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.07.034
更新日期:2006-12-01 00:00:00
abstract::Tissue stress and cell death result in inflammation even in the absence of pathogens. Such sterile inflammation is dependent on a cytosolic complex of proteins inside immune cells termed the inflammasome. This complex converts two groups of extracellular signals into an inflammatory response via activation of caspase-...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.12.017
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abstract:BACKGROUND & AIMS:p53 mutations occur frequently in human HCC. Activation of the mammalian target of rapamycin (mTOR) pathway is also associated with HCC. However, it is still unknown whether these changes together initiate HCC and can be targeted as a potential therapeutic strategy. METHODS:We generated mouse models ...
journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2021-01-01 00:00:00
abstract:BACKGROUND/AIMS:The MAGE, GAGE and BAGE genes encode tumor antigens recognized by autologous cytotoxic T lymphocytes. The aim of this study was to evaluate the possibility of using these genes as molecular markers and as the targets of specific immunotherapy for human hepatocellular carcinoma (HCC). METHODS:The expres...
journal_title:Journal of hepatology
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doi:10.1016/s0168-8278(00)80223-8
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journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2009-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章
doi:10.1016/j.jhep.2006.05.010
更新日期:2006-10-01 00:00:00
abstract::Medical treatment of cirrhotic ascites is essentially supportive, dictated by the patient's discomfort, impaired cardiovascular or respiratory function and potential for infection. Treatment of 'simple' ascites (moderate fluid accumulation, serum albumin > 3.5 g/dl, serum creatinine < 1.5 mg/dl, no electrolyte disturb...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/s0168-8278(05)80447-7
更新日期:1993-01-01 00:00:00
abstract::We describe a new model of submaximal stimulation of liver regeneration in the rat. Removal of the right lateral lobes in the rat produced a 21% hepatectomy. The measurement accuracy of the incorporation rate of [14C]thymidine into DNA 24 h after 21% hepatectomy (n = 32) was less than that after the standard 34% hepat...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(91)90833-w
更新日期:1991-05-01 00:00:00
abstract:BACKGROUND & AIMS:Data on the natural history of chronic hepatitis C virus (HCV) genotype 6 is lacking. METHODS:We compared the natural history of 138 HCV genotype 1 patients (median age: 50) with 78 HCV genotype 6 patients (median age: 46.5). Baseline demographic data including gender, route of transmission, liver bi...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.04.009
更新日期:2010-09-01 00:00:00
abstract:BACKGROUND/AIMS:The molecules involved in the progression of hepatocellular carcinoma (HCC) are not fully understood. The aim of this study was to elucidate the crucial genes involved in cancer progression and metastasis. METHODS:Selectively expressed genes were screened using differential display analysis, and then f...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(01)00183-0
更新日期:2001-11-01 00:00:00
abstract::The oesophageal pH was recorded for 3 h after a test-meal in 27 healthy control subjects (group I), 40 patients with alcoholic cirrhosis (group II), and 22 patients with a normal liver and symptoms of gastro-oesophageal reflux (control refluxers). Gastro-oesophageal reflux was observed in 10 of the cirrhotic patients....
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(87)80088-0
更新日期:1987-04-01 00:00:00
abstract:BACKGROUND & AIMS:Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.02.033
更新日期:2018-08-01 00:00:00
abstract:BACKGROUND/AIMS:Selective cyclooxygenase (COX)-2 inhibitors do not adversely affect renal function in experimental cirrhosis. In the current study, we investigated the molecular mechanisms underlying the effects of the selective COX-2 inhibitor, celecoxib, and assessed the influence of albumin on its actions. METHODS:...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.09.011
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abstract:BACKGROUND/AIMS:The aim of our study was to evaluate the proportion of patients with severe alcoholic cirrhosis who would need orthotopic liver transplantation (OLT) and to determine the optimal delay to evaluate an abstinent patient for transplantation. METHODS:Survival without OLT, improvement in liver function and ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(01)00228-8
更新日期:2002-01-01 00:00:00
abstract::Surveillance of patients at risk of developing hepatocellular carcinoma (HCC) is based on ultrasound (US) examinations performed at either 6 or 12 month intervals. Early detection of HCC in patients with cirrhosis is a challenging issue, since the different entities that are involved in the multi-step process of hepat...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2008.02.005
更新日期:2008-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:
更新日期:1996-01-01 00:00:00
abstract::Hepatocellular carcinoma (HCC) is an accepted indication for liver transplantation (LT). Pre-LT adjuvant ablation treatments to prevent tumour progression and drop out from the waiting list have been increasingly adopted at most transplant centers. Trans-catheter arterial chemo-embolization (TACE) is frequently used, ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2008.02.021
更新日期:2008-07-01 00:00:00
abstract:BACKGROUND & AIMS:Individuals born between 1945 and 1965 account for nearly 75% of hepatitis C virus (HCV) infections in the United States. As this cohort ages, progressive HCV-related liver disease leading to cirrhosis and hepatocellular carcinoma (HCC) will place a significant burden on the healthcare system. We aim ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2015.09.006
更新日期:2016-02-01 00:00:00
abstract:BACKGROUND & AIMS:High oxidative stress plays a major role in increasing hepatic vascular resistance in cirrhosis, by facilitating liver fibrosis and by increasing hepatic vascular tone. This study is aimed at investigating whether the use of the novel isoform of recombinant human manganese superoxide dismutase (rMnSOD...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.09.010
更新日期:2013-02-01 00:00:00
abstract:BACKGROUND/AIMS:The applicability of adult-to-adult living donor liver transplantation has not been established yet. We report the first data in a European center of the process leading to this procedure from the first moment the patients were informed about it. METHODS:In phase 1 of the process, 121 adult patients en...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2005.02.016
更新日期:2005-07-01 00:00:00
abstract:BACKGROUND & AIMS:Although antiviral treatment for hepatitis C (HCV) is highly effective, side effects often occur, including weight loss, digestive symptoms, and impaired quality of life. We aimed at exploring the beneficial effects of preventive nutritional support. METHODS:In a randomized controlled trial, 53 HCV p...
journal_title:Journal of hepatology
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.jhep.2012.06.029
更新日期:2012-11-01 00:00:00
abstract::This volume explores these and other issues of relevance to our understanding of the HBV life cycle and clinical management of chronic HBV infections. The ultimate goals of these studies is not just to obtain a more precise understanding of the HBV life cycle, but to also acquire an understanding that will lead to mor...
journal_title:Journal of hepatology
pub_type: 社论
doi:10.1016/j.jhep.2016.01.006
更新日期:2016-04-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatitis B e antigen (HBeAg) seroconversion is an important clinical and virological "landmark" during chronic hepatitis B virus (HBV) infection. Mutant viruses carrying the precore G1896A and/or the basal core promoter (BCP) A1762T/G1764A mutations are associated with HBeAg seroconversion. However, ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2011.11.012
更新日期:2012-04-01 00:00:00
abstract:BACKGROUND & AIMS:Myeloperoxidase exocytosis and production of hydrogen peroxide via the neutrophil superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contribute to efficient elimination of bacteria. Cirrhosis impairs immune functions and increases susceptibility to bacterial infection. W...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2015.12.005
更新日期:2016-05-01 00:00:00
abstract:BACKGROUND:Although bacterial infections are frequent in patients with liver cirrhosis, only isolated cases of bacterial meningitis have been reported. METHODS:We have reviewed a series of 16 cases of bacterial meningitis in patients with cirrhosis, diagnosed in a single hospital over a 30-year period. RESULTS:Thirte...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80320-0
更新日期:1997-11-01 00:00:00