Liver Research最新文献

Non-alcoholic fatty liver disease (NAFLD), defined as the presence of fat accumulation in imaging or histology in more than 5% of hepatocytes and exclusion of other causes for secondary hepatic fat accumulation, is one of the major causes of chronic liver disease worldwide. Metabolic syndrome is associated with an increased risk of progression from NAFLD to non-alcoholic steatohepatitis (NASH), fibrosis, and forthcoming liver failure. Also, genetic predisposition contributes to the risk of NAFLD development. This review explores the role of diets and nutraceuticals in delaying the development and the evolution of NAFLD to chronic liver disease. The Mediterranean diet, high-protein diet, low-carbohydrate/high-fat diet, high-carbohydrate/low-fat diet, and intermittent fasting are the dietary approaches investigated given the presence of relevant literature data. Moreover, this review focused on nutraceuticals with proven efficacy in ameliorating NAFLD and grouped them into four different categories: plant-based nutraceuticals (Ascophyllum nodosum and Fucus vesiculosus, Silymarin, Berberine, Curcumin, Resveratrol, Nigella sativa, Quercetin), vitamin-like substances (vitamin E, vitamin D, vitamin C, coenzyme Q10, inositol), fatty acids (omega-3), and microbiota-management tools (probiotics).

Bile acids (BAs) play important roles in the digestion of dietary fats and molecular signal transduction, and modulation of the BA composition usually affects the progression of metabolic diseases. While the liver produces primary BAs, the gut microbiota modifies these products into various forms that greatly increase their diversity and biological functions. Mechanistically, BAs can regulate their own metabolism and transport as well as other key aspects of metabolic processes via dedicated BA receptors. Disruption of BA transport and homeostasis leads to the progression of liver diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we summarize the microbial transformations of BAs and their downstream signaling in the development of metabolic diseases and present new insights into novel therapeutic strategies targeting BA pathways that may contribute to these diseases.

The liver plays an important role in both metabolism and immunity. Disruption of the hepatic immune microenvironment is closely associated with various liver diseases. To gain a better understanding of how different types of immune cells contribute to the progression of liver diseases, it is crucial to thoroughly characterize hepatic immune cells. Although direct digestion of liver tissue is a relatively simple method for isolating immune cells, it often induces excessive hepatocyte death, which causes a release of intracellular components that leads to the activation of stress responses and injury in the surrounding cells. This injury can lead to excessive death in the hepatic immune cells, making isolation and accurate characterization of the immune profile challenging, especially in diseased livers. The method described here addresses these challenges by utilizing Phosphate buffered saline (PBS) and digestion buffer perfusions to eliminate contaminating blood cells, ensure a pure hepatic immune population, and minimize hepatic immune cell death. Further ex vivo digestion of the liver enables the isolation of the immune cells from the hepatic tissues and the generation of a single-cell suspension that can be stained for spectral flow cytometry. To enhance intracellular cytokine detection and maintain signaling under different physiological and pathological conditions, this protocol uses an in vivo administration of Brefeldin A, a less toxic inhibitor of cytokine secretion. This in vivo administration of Brefeldin A allows for a more accurate representation of the immune cell function and cytokine expression compared to the traditionally used ex vivo Brefeldin A administration. A comprehensive spectral flow cytometry panel, comprising extracellular and intracellular staining, is used for deep immunophenotyping and immune cell effector function profiling. While this protocol is specifically designed for liver digestion of Mdr2 knockout mice (a model for primary sclerosing cholangitis) and flow cytometry staining, it can also be applied to other liver diseases and sensitive tissues.

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.