Liver Research最新文献

Background and aims

The primary goal of chronic hepatitis B (CHB) treatment is to reduce hepatitis B surface antigen (HBsAg). T helper 17 (Th17) and regulatory T (Treg) cells are essential for the development of CHB. However, how Th17 and Treg cells contribute to HBsAg loss is still unknown. Therefore, this study aimed to search for the predictive value of Th17 and Treg cells for HBsAg loss in CHB patients with low HBsAg quantification.

Methods

The study included 99 hepatitis B e antigen (HBeAg)-negative CHB patients who had completed a year of nucleos(t)ide analogue (NA) monotherapy and had received both NA and pegylated interferon (PEG-IFN) treatment for less than 96 weeks (96 wk). In the cured group, 48 patients lost HBsAg within 48 wk, while 51 patients did not (uncured group). Blood samples and clinical data were collected for research.

Results

During PEG-IFN and NA combination therapy, the proportion of Th17 cells in the cured group increased significantly, while the proportion of Treg cells in the uncured group increased. From 0 to 24 wk, the proportion of Th17 cells in the cured group was significantly higher than in the uncured group, while the opposite was true for Treg cells. Patients with alanine aminotransferase (ALT) ≥ 2.5 upper limit of normal (ULN) at 12 wk had a higher proportion of Th17 cells and a lower proportion of Treg cells than those with ALT <2.5 ULN at 12 wk. Additionally, the proportion of Th17 cells is inversely associated with the level of HBsAg, whereas the level of Treg cells is positively related to HBsAg quantification. The clinical cure index, including age, HBsAg quantification, and the proportions of Th17 and Treg cells, had a higher area under the curve (0.957) for predicting HBsAg loss when compared to the proportions of Th17 and Treg cells and HBsAg quantification alone.

Conclusions

Combined with quantification of HBsAg, the proportions of Th17 cells and Treg cells at baseline can be used as good predictors of HBsAg loss in patients with low HBsAg quantification treated with NA and PEG-IFN.

Adenosquamous carcinoma (ASC) is a rare histological type of intrahepatic cholangiocarcinoma, which includes both adenocarcinoma and squamous cell carcinoma. The clinical features, physical examination, routine laboratory tests, and imaging examinations of patients with ASC are nonspecific. ASC is easily misdiagnosed as hepatocellular carcinoma, and patients with ASC always have a poor prognosis. This study reports a patient with ASC who was diagnosed based on pathological results, underwent surgical resection, and received postoperative chemotherapy (gemcitabine plus cisplatin) combined with immunotherapy (sintilimab). During the 1-year follow-up, the patient was in good condition, and no signs of cancer recurrence were noted. This case highlights that surgical resection and chemotherapy combined with immunotherapy may be feasible for patients with ASC.

Local ablation technologies, such as radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation, have become a standard treatment option for hepatocellular carcinoma (HCC) less than 5 cm in size, particularly in individuals who are not candidates for hepatectomy. Except for equivalent prognosis and efficiency, RFA has various advantages over surgical excision, including a lower rate of complications, a cheaper cost, more normal tissue preservation, and a shorter hospital stay. However, the rate of tumor recurrence and/or distant metastasis after RFA therapy is still high. RFA has been widely employed in multiple cancers, large cancer, and lesion identified at “high-risk” sites in recent years, with the advancement of ablation types and operating techniques, particularly the combined use of many technologies. The real value of RFA technology has been more fully reflected. We will examine the status, progress, and problems of RFA in the treatment of HCC in this review.

Background and aims

Type 2 diabetes mellitus remains a substantial medical problem with increasing global prevalence. Pharmacological research is becoming increasingly focused on personalized treatment strategies. Drug development based on glucokinase (GK) activation is an important strategy for lowering blood glucose. This study aimed to investigate the effect of GK activation on glucose and lipid metabolism in diet-induced obese mice.

Materials and methods

Mice were fed with a high-fat diet (HFD) for 16 weeks to induce obesity, followed by a GK activator (GKA, AZD1656) or vehicle treatment by gavage for 4 weeks. The effect of GKA treatment on glucose metabolism was evaluated using glucose and insulin tolerance tests. Hepatic lipid accumulation was assessed by hematoxylin and eosin staining, Oil Red O staining, and transmission electron microscopy. The underlying mechanism of GK activation in glucose and lipid metabolism in the liver was studied using transcriptomic analysis, with a mechanistic study in mouse livers in vivo and AML12 cells in vitro.

Results

GK activation by GKA treatment improved glucose tolerance in HFD-fed mice while increasing hepatic lipid accumulation. Transcriptomic analysis of liver tissues indicated the lipogenesis and protein kinase RNA-like endoplasmic reticulum kinase (PERK)-unfolded protein response (UPR) pathway activations in GKA-treated HFD-fed mice. Inhibition of the ACC activity, which is an important protein in lipogenesis, attenuated GKA treatment-induced lipid accumulation and PERK-UPR activation in vitro.

Conclusions

GK activation improved glucose tolerance and insulin sensitivity while inducing hepatic lipid accumulation by increasing the lipogenic gene expression, which subsequently activated the hepatic PERK-UPR signaling pathway.

Background

Metabolic dysfunction-associated fatty liver disease (MAFLD) is now the most prevalent chronic liver disease worldwide, with an increasing incidence rate. MAFLD is a heterogeneous disease that can have a low or high-risk profile for developing severe liver disease in its natural course. Recent evidence has highlighted the critical role of RNA methylation modification in the pathogenesis of various liver diseases. However, it remains unclear whether the RNA N1-methyladenosine (m¹A) modification of immune cells could potentially contribute to the pathogenesis and heterogeneity of MAFLD.

Materials and methods

To address this issue, we conducted an integrated bioinformatics analysis of MAFLD bulk and single-cell RNA sequencing (scRNA-seq) data to pinpoint m¹A regulators in the network. This was followed by a description of the immune landscape, pathway enrichment analysis, and molecular subtyping.

Results

The expression patterns of m¹A regulatory genes stratify MAFLD into two molecular subtypes, Cluster 1 and Cluster 2. These subtypes demonstrate different immune cell infiltration with distinct inflammation characteristics, which suggest different immune-inflammatory responses in the liver. Notably, Cluster 2 is associated with pro-inflammation and may be more likely to lead to progressive stages of MAFLD. Through intersection analysis of weighted gene co-expression network analysis (WGCNA) and m¹A regulatory genes, three true hub genes (ALKBH1, YTHDC1, and YTHDF3) were identified, all of which were strongly correlated with infiltrating immune cells. The specific signaling pathways involved in the three core genes were derived from genomic variation analysis. Furthermore, scRNA-seq data from 33,168 cells from six liver samples identified 26 cell clusters and eight cell types, with endothelial cells, macrophages, and monocytes showing the most significant differences between MAFLD and normal controls. The cell-cell communication network between immune cells and non-parenchymal cells was extremely sophisticated and changed significantly in MAFLD.

Conclusions

In summary, these findings demonstrate the involvement of m¹A in MAFLD heterogeneity and emphasize the crucial role of m¹A modulation of immune cells in regulating inflammation in MAFLD. These results may suggest potential therapeutic strategies for MAFLD.

Liver failure is a group of clinical syndromes with a mortality rate of >50%. The accurate evaluation of severity in patients with liver failure has been a meaningful and hot topic in clinical research and an important guide for liver transplantation. Numerous prognosis studies have emerged in recent years with high accuracy and adequate validity. Nonetheless, different models utilize distinct parameters and have unequal efficiencies, leading to a specific value and unique application situations for each model. This review focused on the progress in recent prognostic studies including the model for end-stage liver disease, sequential organ failure assessment and its derivative models, the Chinese Group on the Study of Severe Hepatitis B Acute-on-Chronic Liver Failure, the Tongji prognostic predictor model, and other emerging prognostic models and predictors. This review aims to assist clinicians understand the framework of recent models and choose the appropriate model and treatment.

Metabolic diseases have overtaken infectious diseases as the most serious public health issue and economic burden in most countries. Moreover, metabolic diseases increase the risk of having infectious diseases. The treatment of metabolic disease may require a long-term strategy of taking multiple medications, which can be costly and have side effects. Attempts to expand the therapeutic use of vaccination to prevent or treat metabolic diseases have attracted significant interest. A growing body of evidence indicates that Bacillus Calmette-Guérin (BCG) offers protection against non-infectious diseases. The non-specific effects of BCG occur likely due to the induction of trained immunity. In this regard, understanding how BCG influences the development of chronic metabolic health including liver diseases would be important. This review focuses on research on BCG, the constellation of disorders associated with metabolic health issues including liver diseases and diabetes as well as how BCG affects the gut microbiome, immunity, and metabolism.

Non-alcoholic fatty liver disease (NAFLD) is characterized by a spectrum of hepatic diseases, including fatty liver, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. NAFLD is a hepatic manifestation of metabolic syndrome and has become the leading cause of liver transplantation, necessitating an in-depth understanding of its underlying pathogenic mechanisms and the identification of viable drug targets. Although fatty liver is benign and does not exert marked liver damage or inflammation, NAFLD progression involves inflammatory processes facilitated by immune cells. Macrophages and monocytes constitute the pool of innate immune cells that contribute to NAFLD development in association with other cell types, such as neutrophils, T cells, and natural killer cells. The concept that macrophages contribute to the inflammatory processes in NAFLD development has long been debated; however, the remarkable advances in experimental techniques have rapidly uncovered new subpopulations of macrophages and monocytes, whose functions need to be comprehensively elucidated. The current review focuses on the recent expansion of our knowledge of the heterogeneous population of macrophages crucially involved in NAFLD development. In addition, the present paper discusses ongoing efforts to target macrophages and inflammatory processes to develop optimal therapeutic agents against non-alcoholic steatohepatitis.