Nobiletin, a novel inhibitor, inhibits HBsAg production and hepatitis B virus replication.
Nobiletin，一种新型抑制剂，抑制 HBsAg 产生和乙型肝炎病毒复制。
- 作者列表："Hu Z","Hu J","Ren F","Xu H","Tan M","Wang Q","Ren J
:Chronic hepatitis B virus (HBV) infection is a serious problem due to its extensive worldwide distribution and poor prognosis including cirrhosis and/or hepatocellular carcinoma. The hepatitis B surface antigen(HBsAg) is a vital serum marker in HBV infection and a major obstacle for effective and subsequently virus clearance. However, Current anti-HBV drugs, such as nucleos(t)ide analogs (NA) and PegIFN, do not meet ideal result of sustained HBsAg loss (defined as functional cure). Therefore, there is an urgent need to identify a new compound targeting HBsAg. In this study, nobiletin was screened out from 1500 compounds due to its low cytotoxicity and high antiviral activity. The effect of nobiletin on HBV was determined in HepG2.2.15 and HepG2-NTCP cells. Furthermore, the antiviral capability of nobiletin was also verified in vivo. Unlike entecavir (ETV) therapy, which reduced HBV DNA but do not lead to an effective reduction in HBsAg, nobiletin significantly reduced the level of HBsAg as well as lowered HBV DNA in vivo and in vitro. Meanwhile, combination of nobiletin and ETV led to broad reductions of both HBV DNA and HBsAg level. This study may shed light on the development of a novel class of anti-HBV agents.
慢性乙型肝炎病毒 (HBV) 感染是一个严重的问题，由于其广泛的全球分布和不良的预后，包括肝硬化和/或肝细胞癌。乙型肝炎表面抗原 (HBsAg) 是 HBV 感染的重要血清标志物，是有效和随后病毒清除的主要障碍。然而，目前的抗 HBV 药物，如核苷 (t) ide 类似物 (NA) 和 PegIFN，不符合持续 HBsAg 消失 (定义为功能性治愈) 的理想结果。因此，迫切需要鉴定一种新的针对 HBsAg 的化合物。本研究从 1500 个化合物中筛选出川陈皮素，因其具有低细胞毒性和高抗病毒活性。在 HepG2.2.15 和 HepG2-NTCP 细胞中测定川陈皮素对 HBV 的影响。此外，还在体内验证了川陈皮素的抗病毒能力。与恩替卡韦 (ETV) 治疗，减少 HBV DNA，但不导致 HBsAg 的有效减少, 川陈皮素显着降低 HBsAg 的水平以及体内和体外 HBV DNA 的降低。同时，川陈皮素和 ETV 的组合导致 HBV DNA 和 HBsAg 水平的广泛降低。这项研究可能揭示了一类新型抗 HBV 药物的发展。
METHODS:BACKGROUND:Opioids are often prescribed for pain in cirrhosis and may increase the risk of hepatic encephalopathy (HE). AIMS:To assess the association between opioids and HE in patients with well-compensated cirrhosis. METHODS:We used the IQVIA PharMetrics (Durham, NC) database to identify patients aged 18-64 years with cirrhosis. We excluded patients with any decompensation event from 1 year before cirrhosis diagnosis to 6 months after cirrhosis diagnosis. Over the 6 months after cirrhosis diagnosis, we determined the duration of continuous opioid use and classified use into short term (1-89 days) and chronic (90-180 days). We assessed whether patients developed HE over the subsequent year (ie 6-18 months after cirrhosis diagnosis). We used a landmark analysis and performed multivariable Cox proportional hazards regression to assess associations between opioid use and HE, adjusting for relevant confounders. RESULTS:The cohort included 6451 patients with compensated cirrhosis, of whom 23.3% and 4.7% had short-term and chronic opioid prescriptions respectively. Over the subsequent year, HE occurred in 6.3% patients with chronic opioid prescriptions, 5.0% with short-term opioid prescriptions and 3.3% with no opioid prescriptions. In the multivariable model, an increased risk of HE was observed with short-term (adjusted hazard ratio, HR 1.44, 95% CI 1.07-1.94) and chronic opioid prescriptions (adjusted HR 1.83, 95% CI 1.07-3.12) compared to no opioid prescriptions. CONCLUSION:In this national cohort of privately insured patients with cirrhosis, opioid prescriptions were associated with the risk of incident HE. Opioid use should be minimised in those with cirrhosis and, when required, limited to short duration.
METHODS:BACKGROUND AND AIMS:Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS:We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS:Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS:We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.
METHODS:BACKGROUND:Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis. In recent years, it has been postulated that the rate of multidrug-resistant organisms (MDROs) is increasing, especially in nosocomial SBP patients. Aim of the present work was to investigate this hypothesis and its possible clinical consequences. MATERIALS AND METHODS:One hundred and three culture-positive patients between 2007 and 2014 were compared with 81 patients between 2015 and 2017, to study the change of microbiological profiles and their clinical consequences. The cirrhosis patients with bacterascites requiring treatment were included as well. RESULTS:The most prevalent Gram-negative bacteria isolated from ascites were Enterobacterales (31.6%) and in Gram-positive pathogens Staphylococci (22.8%). There was a significant increase in MDROs (22.3% ICU 40.7%, P = .048), accompanied by an increased incidence of sepsis (from 21.4% to 37.0%, P = .021), hepatorenal syndrome (from 40.8% to 58.0%, P = .007) and the need of catecholamine therapy (from 21.4% to 38.8%, P = .036). Nosocomial origin correlated with higher MDRO proportion, more complications and lower antimicrobial susceptibility rates in 12 commonly used antibiotics. MDROs were confirmed as an isolated predictor for inpatient mortality and complications in multivariable logistic regression. CONCLUSIONS:The feeling in clinical practice that MDROs have increased in the last 11 years could be confirmed in our study in Munich, Germany. Nosocomial SBP correlated with significantly higher MDRO rates (nearly 50%) and complication rates. In our opinion, an antibiotic combination with comprehensive effect should be taken into account in nosocomial SBP patients in this region.