Liver Research最新文献

Background and aim

Hepatitis C virus (HCV) infection is one of the major global health challenges, leading to a significant increase in rates of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. A comprehensive nationwide survey of trends in prevalence and associated factors could facilitate preventive behavioral interventions. Herein, we sought to determine prevalence, diagnosis, treatment, and risk factors for HCV infection in the general United States (US) population.

Methods

This was a secondary analysis of the publicly available data from the US National Health and Nutrition Examination Survey (NHANES). The prevalence of HCV-RNA-positive (HCV-RNA+) was weighted using patient serum sample data collected from 1999 to 2018. A propensity score matching model was used due to the imbalance in the number of HCV-RNA+ and HCV-RNA-negative (HCV-RNA−) patients. Matched variables included gender, age, educational level, marital status, language, household size, alcohol consumption, smoking, number of family members and family income to poverty ratio.

Results

The weighted prevalence of HCV-RNA+ was 1.11% (95% confidence interval (CI): 1.02–1.20), 1.58% (95% CI: 1.42–1.74) for men and 0.67% (95% CI: 0.57–0.77) for women aged 20 years or older in the US from 1999 to 2018. The weighted prevalence of HCV-RNA+ increased from 0.87% (95% CI: 0.62–1.12) in 2013–2014, 0.95% (95% CI: 0.68–1.22) in 2015–2016 to 1.00% (95% CI: 0.72–1.28) in 2017–2018, respectively. In propensity-matched analysis, patients with HCV-RNA+ were more likely to be non-Hispanic black, and have had drug use and blood transfusions. Meanwhile, the weighted diagnostic and treatment rates were 56.27% (95% CI: 50.90–61.64) and 35.40% (95% CI: 27.64–43.16) from 1999 to 2018, respectively.

Conclusions

Active HCV infection rate increased between 2013 and 2018, varied by demographic and risk variables. In the direct-acting antiviral era, affordable treatment and universal screening have the potential to improve overall national health.

Background and aims

The herbal supplement Gancao, also known as licorice, belongs to the genus Glycyrrhiza and has been used worldwide for its hepatoprotective effect. Recent studies have raised concerns about potential herb-drug interactions associated with Gancao via pregnane X receptor (PXR)-mediated induction of hepatic cytochrome P450 3A4 (CYP3A4). The current work aimed to determine the phytochemicals in Gancao that activate PXR and induce CYP3A4.

Methods

DPX2 cells were used for cell-based PXR reporter assays. The phytochemicals in Gancao extract were identified using a metabolomics approach. The effects of PXR activators identified from in vitro studies were further investigated in PXR- and CYP3A4-humanized mouse models.

Results

Gancao was verified to be a PXR-activating herb. Two major phytochemicals in Gancao, glycyrrhizin (GZ) and glycyrrhetinic acid (GA), did not activate PXR in the cell-based reporter assays. However, glabridin was shown to activate PXR in a dose-dependent manner. In vivo studies confirmed that GZ is not a PXR activator and glabridin is a weak PXR activator. Although GA did not active PXR in vitro, it induced CYP3A4 expression in a PXR-dependent manner in the PXR- and CYP3A4-humanized mice.

Conclusions

GZ is not a PXR activator. GA could not activate PXR in cell-based reporter assays but it could activate PXR in vivo. Glabridin is a weak PXR activator. This work provides novel insights into the underlying mechanisms of Gancao-related herb-drug interactions via PXR.

Background and aim

Non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of chronic liver disease worldwide. The molecular events that influence disease progression from non-alcoholic fatty liver (NAFL) to aggressive non-alcoholic steatohepatitis (NASH) remain incompletely understood, leading to lack of mechanism-based targeted treatment options for NASH. This study aims to identify early signatures associated with disease progression from NAFL to NASH in mice and humans.

Materials and methods

Male C57BL/6J mice were fed a high-fat, -cholesterol, and -fructose (HFCF) diet for up to 9 months. The extent of steatosis, inflammation, and fibrosis was evaluated in liver tissues. Total RNA sequencing (RNA-seq) was conducted to determine liver transcriptomic changes.

Results

After being fed the HFCF diet, mice sequentially developed steatosis, early steatohepatitis, steatohepatitis with fibrosis, and eventually spontaneous liver tumor. Hepatic RNA-seq revealed that the key signatures during steatosis progression to early steatohepatitis were pathways related to extracellular matrix organization and immune responses such as T cell migration, arginine biosynthesis, C-type lectin receptor signaling, and cytokine-cytokine receptor interaction. Genes regulated by transcription factors forkhead box M1 (FOXM1) and negative elongation factor complex member E (NELFE) were significantly altered during disease progression. This phenomenon was also observed in patients with NASH.

Conclusions

In summary, we identified early signatures associated with disease progression from NAFL to early NASH in a mouse model that recapitulated key metabolic, histologic, and transcriptomic changes seen in humans. The findings from our study may shed light on the development of novel preventative, diagnostic, and therapeutic strategies for NASH.

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide, and is closely associated with the increased risk of the prevalence of obesity and diabetes. NAFLD begins with the presence of >5% excessive lipid accumulation in the liver, and potentially develops into non-alcoholic steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. Therefore, insight into the pathogenesis of NAFLD is of key importance to its effective treatment. Iron is an essential element in the life of all mammalian organisms. However, the free iron deposition is positively associated with histological severity in NAFLD patients due to the production of reactive oxygen species via the Fenton reaction. Recently, several iron metabolism-targeted therapies, such as phlebotomy, iron chelators, nanotherapeutics. and ferroptosis, have shown their potential as a therapeutic option in the treatment of NAFLD and as a clinical strategy to intervene in the progression of NAFLD. Herein, we review the recent overall evidence on iron metabolism and provide the mechanism of hepatic iron overload-induced liver pathologies and the recent advances in iron metabolism-targeted therapeutics in the treatment of NAFLD.

Background and aim

Immune checkpoint inhibitors (ICIs) are widely used in the treatment of liver cancer. However, the interaction with other drugs may change the efficacy of ICIs. Few studies investigated the effects of antibiotics (ATBs) on the efficacy of immunotherapy and the survival of patients with primary liver cancer receiving immunotherapy. This study aimed to explore the impact of ATBs on the efficacy of immunotherapy in patients with primary liver cancer.

Methods

In total, 215 patients with primary liver cancer who received ICIs from June 2018 to October 2020 were included for retrospective analysis. The progression-free survival (PFS), disease control rate (DCR), and overall survival (OS) were compared between patients treated with and without ATBs within 30 days before and after immunotherapy.

Results

No significant differences in PFS (P = 0.376) and OS (P = 0.121) were found between patients treated with and without ATBs. Univariate and multivariate analyses showed that using ATBs was not associated with PFS, DCR, and OS.

Conclusion

The use of ATBs within 30 days before and after immunotherapy in patients with primary liver cancer had no adverse effects on PFS, DCR, and OS.

Background and aim

Some previous studies supported that rifampicin was an effective treatment for benign intrahepatic cholestasis. However, the efficacy and safety of rifampicin remain unclear. Therefore, this study aimed to evaluate its efficacy and safety on benign intrahepatic cholestasis.

Methods

A retrospective, single-center, observational study was conducted on patients diagnosed with benign intrahepatic cholestasis between 2019 and 2021, who were administered 150 mg of rifampicin orally once a day. We collected and analyzed the data at baseline and post-treatment, including total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA), gamma-glutamyl transferase (GGT), alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase levels. Statistical analysis was performed using appropriate tests.

Results

A total of 17 rifampicin-treated patients were enrolled in the study from January 2019 to January 2021. Among them, 14 patients (82%) improved, with significantly decreased TBIL, DBIL, and TBA levels after 3 weeks of treatment (all P < 0.05), whereas the remaining 3 had no improvement. Moreover, GGT levels of the former were significantly lower than those of the latter (34 (12–227) U/L vs. 244 (76–293) U/L, P = 0.023) at baseline. No severe adverse effect was observed during treatment.

Conclusions

Low-dose rifampicin (150 mg per day) was an effective and safe treatment for benign intrahepatic cholestasis. Low GGT level at baseline and a significant decrease of TBIL, DBIL, and TBA levels within the first 3 weeks of treatment may lead to the good curative effect.

Background and aims

Berberine is one of the most promising clinically tested natural alkaloids, and immunotherapy using natural killer (NK) cells is a potentially effective treatment for hepatocellular carcinoma (HCC). This study aims to elucidate the effect of berberine on the anti-HCC effect of NK92-MI cells.

Materials and methods

Human HCC SMMC-7721 and Hep3B cells were co-incubated with NK92-MI cells, berberine (60 or 80 μmol/L), or their combination for 36 h. To evaluate the killing effect of NK92-MI cells on HCC cells, the release of lactate dehydrogenase (LDH) in HCC cells was measured. The anti-tumor effects of berberine, NK92-MI cells, and their combinations were evaluated by MTS, EdU, Tunel, and Western blot assays. A male BALB/c nude mouse subcutaneous tumor model was used to investigate the anti-HCC effect of berberine and NK92-MI cells in vivo.

Results

The LDH assay showed that berberine enhanced the cytotoxicity of NK92-MI cells on HCC cells. The combination of berberine and NK92-MI cells demonstrated more obvious anti-HCC effect than did the berberine or NK92-MI single treatment in inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanistically, the expression of programmed cell death-ligand 1 (PD-L1) in HCC cells was upregulated after co-culture with NK-92MI cells. PD-L1 expression was knocked down, thereby inhibiting the proliferation and promoting apoptosis of HCC cells, and inhibited by berberine that blocked the secretion of interferon gamma (IFN-γ), thereby enhancing the anti-tumor effect of NK92-MI cells.

Conclusions

Current data show that the immunomodulatory role of berberine is to enhance the cytotoxic effect of NK92-MI cells and inhibit tumor immune escape by reducing the expression of PD-L1. Our study provides a rationale for the clinical application of berberine in combination with NK cells for the treatment of HCC.