Liver Research最新文献

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.

Acute-on-chronic liver failure (ACLF) can be cured by liver transplantation; however, perioperative complications still affect posttransplant outcomes. In recent years, early rehabilitation for critical illness, liver disease, and surgery have significantly improved organ reserve function, surgery tolerance, and postoperative quality of life. They could also be applied in the perioperative period of liver transplantation in patients with ACLF. Therefore, the Transplantation Immunology Committee of Branch of Organ Transplantation Physician of Chinese Medical Doctor Association, the Organ Transplant Committee of China Association Rehabilitation Medicine, and the Guangdong Medical Doctor Association of Organ Transplantation conducted a comprehensive review of rehabilitation in end-stage liver disease, critical illness and surgical patients by summarizing current evidence and best clinical practices and proposed a practice consensus on evaluation of cardiopulmonary and physical function, rehabilitation or physiotherapies, as well as the safety concerns in perioperative liver transplant recipients. It will be a valuable resource for hepatologists, transplant surgeons, and intensivists as they care for ACLF patients during transplantation.

As evolutionarily conserved signals, roof plate-specific spondins (R-spondins; RSPOs) are a family with four members (RSPO1–4) exerting distinctly different functions. RSPOs have five receptors and correlate with different signaling pathways through these receptors and then perform various functions. Moreover, their best-known molecular function is the capacity to enhance WNT signaling pathways, which play critical roles in several processes. A recent study shows that RSPOs not only potentiate the WNT/beta (β)-catenin signaling pathway but are also involved in the WNT/planar cell polarity signaling pathway. RSPOs influence liver homeostasis and the development of multiple liver diseases. RSPO1 increases cell proliferation, protects hepatocytes from injury, improves liver regenerative potential, and affects liver metabolic zonation. RSPO2 not only regulates proliferation-associated genes and promotes differentiation in the liver but also participates in liver fibrosis through the WNT/β-catenin signaling pathway. RSPO3 is a key determinant of proper liver function, such as promoting hepatocyte regeneration and maintaining liver zonation. RSPO3 is upregulated in liver fibrosis and livers of patients with non-alcoholic steatohepatitis. Besides, RSPO2 and RSPO3 are confirmed as oncogenes and involved in the occurrence of liver cancer. The role of RSPO4 in the liver remains unclear. In this review, the structural and biochemical properties of RSPOs and their receptors and their roles in liver homeostasis and disease are summarized.

Hepatocellular carcinoma (HCC), a typical inflammatory-related cancer, mainly occurs in patients with chronic liver diseases. Moreover, the liver is an immunologically privileged apparatus with multiple immunosuppressive cell groups. The long process of inflammation-mediated carcinogenesis turns the HCC tumor microenvironment (TME) into one with strong immunosuppression, facilitating the immune escape of HCC cells. Accumulated data have manifested that tumor-associated cell-derived exosomes carry diverse molecular cargoes (e.g., proteins and nucleic acids) for mediating cell-to-cell communication and are implicated in TME remodeling to promote tumor-infiltrating immune cell reprogramming, ultimately creating a tumor-friendly microenvironment. Characterized by several intrinsic attributes, such as good stability (bilayer-like structure) and high biocompatibility (cell secretion), exosomes can be modified or engineered as nanocarriers to deliver tumor-specific antigens or antitumor drugs to targeted cells or organs, thus effectively triggering the HCC cell elimination by the immune system. This review aimed to highlight the pivotal role of exosomes in regulating immune escape mechanisms in HCC and recent advances in exosome-mediated immunotherapy for HCC.