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BackgroundThe branched-chain amino acids (BCAAs) to tyrosine (Tyr) ratio (BTR) test is used to evaluate the progression of chronic liver disease (CLD). However, the differences across sex, age, body mass index (BMI) and etiologies are still unclear.MethodsWe retrospectively reviewed data from 2,529 CLD cases with free amino acids (FAAs) in peripheral blood from four hospitals and 16,421 general adults with FAAs data from a biobank database. In total, 1,326 patients with CLD (covering seven etiologies) and 8,086 healthy controls (HCs) were analyzed after exclusion criteria. We investigated the change of BTR in HCs by sex, age and BMI and then compared these to patients divided by modified ALBI (mALBI) grade after propensity score matching.ResultsBTR is significantly higher in males than females regardless of age or BMI and decreases with aging in HCs. In 20 types of FAAs, 7 FAAs including BCAAs were significantly decreased, and 11 FAAs including Tyr were significantly increased by mALBI grade in total CLD. The decreasing timings of BTR were at mALBI grade 2b in all CLD etiologies compared to HCs, however in chronic hepatitis C (CHC), chronic hepatitis B (CHB) and alcoholic liver disease (ALD), BTR started to decrease at 2a. There was a positive correlation between BCAAs and albumin among parameters in BTR and mALBI. The correlation coefficients in PBC, ALD and MASLD were higher than those of other etiologies.ConclusionsBTR varies by sex and age even among healthy adults, and decreasing process and timing of BTR during disease progression is different among CLD etiologies.

The innate immune response has been reported to be perturbed by hepatitis B virus (HBV) infection. We hypothesized that the induction of the IFN-inducible dynamin family member, myxovirus resistance protein 2 (MxB), might support an innate immune response against HBV via mitochondrial alterations. The objective of this study was to elucidate the mechanism by which MxB suppresses HBV replication. Knockdown of MxB in HBV-expressing HepAD38 cells induced morphological changes in mitochondria. These cells exhibited a substantial increase in the release of enveloped HBV particles, as determined by immunoprecipitation or sucrose density-gradient centrifugation. The expression of envelope proteins L/M/SHBs was increased in the cells, and HBsAg in the culture supernatant was also increased by 4–10 fold. When cells were stimulated with poly(I: C), the downstream signaling of RIG-I including the mRNA of type I and III IFNs was suppressed. Mitochondrial antiviral signaling (MAVS) clustering, which is required for this pathway, was inhibited by MxB knockdown. In conclusion, these findings provide support for a new model implicating MxB-directed HBV inhibition initiated by downstream RIG-I signaling that could promote the formation of MAVS clusters in the mitochondria. Enhancement of this pathway could be a potential therapeutic option for suppressing HBV infection.

BackgroundIt is poorly understood how an imbalance of plasma-free amino acids (PFAAs) occurs and how the imbalance shows an association with the serum albumin (sAlb) level during the progression of chronic liver disease (CLDs). The aim of this study is to elucidate the profiles of PFAAs and the relationship between sAlb and PFAAs in recent patients with CLDs during the progression.MethodsWe retrospectively evaluated the 1569 data of PFAAs data obtained from 908 patients with various CLDs (CHC, CHB. alcoholic, NAFLD/NASH, PBC, AIH, PSC, and cryptogenic). In total, 1140 data of PFAAs could be analyzed in patients with CLDs dependent of their Child–Pugh (CP) score.ResultsVarious imbalances in PFAAs were observed in each CLDs during the progression. Univariate and multivariate analysis revealed that among 24 PFAAs, the level of plasma-branched chain amino acids (pBCAAs) was significantly associated with the CP score, especially the sAlb score, in patients with chronic hepatitis C virus (CHC), NAFLD/NASH and PBC. The correlation coefficient values between sAlb and pBCAAs-to-Tyrosine ratio (BTR) in these patients were 0.53, 0.53 and 0.79, respectively. Interestingly, although the pBCAAs in NAFLD/NASH patients varied even when the sAlb was within the normal range, the pBCAAs tended to be low when the sAlb was below the normal range.ConclusionsAlthough a decrease in the level of pBCAAs was observed during the progression regardless of the CLD etiology, the level of total pBCAAs was independently associated with the sAlb level in the PFAAs of CHC, PBC and NAFLD/NASH. The correlation between sAlb and BTR showed the highest value in PBC patients among the patients with CLDs. A decrease in pBCAAs often occurred in NASH even when the sAlb level was kept in the normal range.

Agents with novel mechanisms are clinically needed for the functional cure of chronic hepatitis B virus (HBV) infection. This study aimed to identify compounds that inhibit an interaction between large hepatitis B surface (LHBs) and hepatitis B core (HBc) proteins, which are considered to be important for HBV envelope formation. Using a high-throughput screening method to evaluate the protein-protein interaction in HepG2 cells by the NanoBRET system, 3,200 compounds from our library were tested. Then, the inhibitory effects of the hit compounds on HBV particles with the envelope were evaluated in HBV-expressing HepG2.2.15.7 cells. 40 hit compounds were found to inhibit the interaction between LHBs and HBc, of which 10 compounds inhibited HBV particles. The top 5 compounds with the least variation were considered as candidates. These compounds showed little effects on HBV proteins and RNAs, whereas a hit compound 16, which showed the lowest IC50 (0.9 µM), decreased precore mRNA significantly. When the culture supernatant from cells with hit compound 16 was subjected to sucrose density gradient centrifugation, HBV particles with the envelope were found to be reduced. In conclusion, we identified compounds that might inhibit the envelope formation of HBV through disturbing the interaction between LHBs and HBc.

Little is known about how blood free amino acids (FAAs) change in metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to identify the imbalance of FAAs in MASLD and explore its correction as a potential therapeutic target. We analyzed plasma FAAs data from 23,036 individuals with steatosis information from a biobank in Japan, and 310 patients with MASLD were enrolled. According to diagnostic criteria for steatotic liver disease (SLD) or cardiometabolic criteria (CC), we divided the subjects into five groups: MASLD, metabolic dysfunction and alcohol-associated liver disease (MetALD), CC-SLD-, CC + SLD-, and CC-SLD + . Twenty FAAs were compared among these groups and among MASLD patients with pathological information. Among the 20 FAAs, the levels of 16 FAAs increased in CC + SLD- according to the number of matches with CC items associated with insulin resistance (IR). Steatosis enhanced most of these changes but serine (Ser) and threonine (Thr) were unaffected. Glycine (Gly), Ser and Thr were significantly decreased in patients according to steatosis grade. We investigated the association between these FAAs imbalances and pathogenesis using MASLD mouse models. In mice fed a high-fat, fructose, and cholesterol (FFC) diet, metabolomics and RNA sequencing analyses indicated that abnormality in Gly, Ser, and Thr metabolism in the liver was associated with mitochondrial dysfunction and enhanced glycolysis via pyruvate. High-Gly, Ser, and Thr diet ameliorated pathogenesis of MASLD in leptin-deficient mice. Most FAAs increase due to cardiometabolic abnormalities, particularly IR. However, interventions targeting the metabolism of Gly, Ser, and Thr have the potential to improve MASLD.

It is difficult to determine whether an individual therapy contributes to the elongation of survival because of the difficulty of organizing clinical research in patients who receive multiple treatments in HCC. We aimed to establish a new model of survival prediction in patients with intermediate stage HCC to establish standards in the recent and coming multi-MTA era. This analysis was prepared using a data set of 753 patients diagnosed HCC prior to 2017. Multiple regression analysis showed age, naïve or recurrence, the size of the largest tumor nodule, the number of nodules, total bilirubin, albumin and α-fetoprotein as independent predictors of survival. A Weibull model had the best fit and, based on these predictors, we established a new predicted survival model. The survival duration can be predicted the proposed model; EXP (4.02580 + (− 0.0086253) × age + (− 0.34667) × (naïve/recurrence) + (− 0.034962) × (number of nodules) + (− 0.079447) × (the size of the largest nodule) + (− 0.21696) × (total bilirubin) + 0.27912 × (albumin) + (− 0.00014741) × (α-fetoprotein)) × (− natural logarithm(0.5))^0.67250. This model is useful for the planning and evaluating the efficacy of recent sequential therapies in multi-MTA era.

The frequency of HBV genomic methylation in the liver was reported to vary among patients, but the detailed mechanism is still unknown. In this study, the effects of HBV genome methylation on HBV replication were investigated in vitro. A total of 6 plasmids containing 1.24-fold the HBV genome of different genotypes (subgenotypes A1, A2, B1, and C2) were purified after in vitro methylation with CpG methyltransferase (M.SssI) and transfected into HepG2 cells. In genotype B and C strains, methylation markedly decreased the amount of hepatitis B e antigen (HBeAg) in the culture supernatant. A reduction of hepatitis B surface antigen (HBsAg) was found in some HBV strains but the reduction was smaller than that of HBeAg. There was no significant difference in particle-associated HBV DNA in the culture supernatant. These findings suggest that HBV genomic methylation might be involved in the HBeAg decline in genotype B and C, in part, and that the reduction of HBsAg was less than that of HBeAg. In conclusion, this study showed that the effect of HBV genomic methylation differs among HBV genotypes, suggesting a potential explanation for the different clinical outcomes of genotypes A, B, and C.

The variety of treatments available makes it difficult to determine whether a treatment would be effective for an individual case in advanced‐stage hepatocellular carcinoma. We aimed to establish a new model of survival prediction in patients to establish standards in the recent and coming multimolecular targeted agents era. This analysis was prepared using a data set of 518 patients diagnosed with hepatocellular carcinoma prior to 2017. Multiple regression analysis showed the size of the largest tumor nodule, the number of nodules, macrovascular invasion, extrahepatic metastasis, total bilirubin, albumin, prothrombin time (PT), α‐fetoprotein, and des‐γ‐carboxyprothrombin (DCP) as independent predictors of survival. A Weibull model had the best fit and, based on these predictors, we established two new predicted survival models with or without incorporating PT and DCP. This model is useful for planning and evaluating the efficacy of recent sequential therapies in the multimolecular targeted agents era.

Reactivation of hepatitis B virus (HBV) is known to occur frequently after hematopoietic stem cell transplantation (HSCT). The reactivation can be prevented by nucleos(t)ide analogue (NA), but it is unclear how long NA should be continued. Here, we report 3 cases of HBV reactivation with discontinuation of NA following the discontinuation of immunosuppressive therapies after HSCT. Three male patients aged 34, 59, and 54 years received allogeneic HSCT (allo-HSCT) for chronic myeloid leukemia, mixed phenotype acute leukemia, and myelodysplastic syndrome, respectively. Before HSCT, 2 patients were positive for hepatitis B surface antigen (HBsAg) and 1 patient was negative for HBsAg and positive for antibodies to hepatitis B core antigen. NA (lamivudine or entecavir) was started at the same time as HSCT and stopped after the discontinuation of immunosuppressive therapies. In all patients, the serum HBV DNA levels were increased after the discontinuation of NAs. Two of the three patients developed severe hepatitis with high levels of HBV DNA (7.5 and 7.4 log IU/mL, respectively). A patient without hepatitis was re-administered NA soon after the HBV DNA started to increase (3.3 log IU/mL). Interestingly, the 2 patients who developed hepatitis cleared HBsAg promptly after the recovery from hepatitis and they could stop NAs without the reversion of HBsAg. It was speculated that transplanted immune cells, which were naïve for HBV, react strongly with HBV antigens that were increased after the NA discontinuation. The discontinuation of NA after allo-HSCT is not recommended generally because strong hepatitis might be induced even after several years.

Although hepatitis B surface antigen (HBsAg) removal is considered the goal of chronic hepatitis B treatment, it can rarely be achieved with nucleos(t)ide analogues (NAs). It has been reported that tenofovir disoproxil fumarate (TDF) is superior in reducing HBsAg compared with entecavir (ETV) in treatment-naïve patients; however, the effect of TDF in patients who have received NAs is still unclear. The aim of the present study was to evaluate the efficacy of switching from ETV to TDF in patients who were already receiving ETV. A pilot randomized controlled study for 2 years in patients who had been treated with ETV for >1 year and did not exhibit drug resistance was performed (Clinical trial registration: UMIN000021948, UMIN-CTR, May 1, 2016). A total of 20 patients were enrolled and 19 patients were randomized into 2 groups, a TDF-switching group (n=12) or an ETV-continuing group (n=7). The mean change in HBsAg levels after 2 years was greater in the TDF group compared with the ETV group, but the difference was not significant (-0.25 vs. -0.06 log IU/ml). In the TDF group, hepatitis B e antigen (HBeAg)-positive patients at baseline showed significantly greater changes in HBsAg (-0.63 vs. -0.03 log IU/ml; P=0.030). In contrast, no difference between HBeAg-positive and HBeAg-negative patients was observed in the ETV group. No significant differences of estimated glomerular filtration rate and inorganic phosphorus changes were observed among the TDF and ETV groups. In conclusion, a significant HBsAg decrease was not achieved after switching from ETV to TDF in the overall analysis, but HBeAg-positive patients showed a larger HBsAg decrease after switching treatment.