Metabolite profiling analysis of hepatitis B virus-induced liver cirrhosis patients with minimal hepatic encephalopathy using gas chromatography-time-of-flight mass spectrometry and ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry.

This study used gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) and ultra-performance liquid chromatography-quadrupole TOFMS (UPLC-QTOFMS) metabonomic analytical techniques in combination with bioinformatics and pattern recognition analysis methods to analyze the serum metabolite profiling of hepatitis B virus (HBV)-induced liver cirrhosis patients with minimal hepatic encephalopathy (MHE), to find the specific biomarkers of MHE, to reveal the pathogenesis of MHE, and to determine a promising approach for early diagnosis of MHE. Serum samples of 100 normal controls (NC group), 29 HBV-induced liver cirrhosis patients with MHE (MHE group), and 24 HBV-induced liver cirrhosis patients without MHE [comprising 12 cases of compensated cirrhosis (CS group) and 12 cases of decompensated cirrhosis (DS group)] were collected and employed into GC-TOFMS and UPLC-QTOFMS platforms for serum metabolite detection; the outcome data were then analyzed using principal component analysis and orthogonal partial least squares-discriminant analysis (OPLS-DA). There were no significant differential metabolites between the NC group and the CS group. A series of key differential metabolites were detected. According to the variable influence in projection values and P-values, 60 small-molecule metabolites were considered to be dysregulated in the MHE group (compared to the NC group); 27 of these 60 dysregulated differential metabolites were considered to be the potential biomarkers (see Table 4, marked in bold); 66 small-molecule metabolites were considered to be dysregulated in the DS group (compared to the NC group); 34 of these 66 dysregulated differential metabolites were considered to be the potential biomarkers (see Table 5, marked in bold). According to the fold-change values, 9 of these 27 metabolites, namely valine, oxalic acid, erythro-sphingosine, 4,7,10,13,16,19-docosahexaenoic acid, isoleucine, allo-isoleucine, thyroxine, rac-octanoyl carnitine, and tocopherol (vitamin E), were downregulated in the MHE group (compared to the NC group); the other 18, namely adenine, glycochenodeoxycholic acid, fucose, allothreonine, glycohyocholic acid, glycoursodeoxycholic acid, tyrosine, taurocheno-deoxycholate, phenylalanine, 2-hydroxy-3-methyl-butanoic acid, hydroxyacetic acid, taurocholate, sorbitol, rhamnose, tauroursodeoxycholate, tolbutamide, pyroglutamic acid, and malic acid, were upregulated; 6 of these 34 metabolites were downregulated in the DS group (compared to the NC group), and the other 28 were upregulated, as shown in Table 5. (a) GC-TOFMS and UPLC-QTOFMS metabonomic analytical platforms can detect a range of metabolites in the serum; this might be of great help to study the pathogenesis of MHE and may provide a new approach for the early diagnosis of MHE. (b) Metabonomics analysis in combination with pattern recognition analysis might have great potential to distinguish the HBV-induced liver cirrhosis patients who have MHE from the normal healthy population and HBV-induced liver cirrhosis patients without MHE.

Recent advances in pyroptosis, liver disease, and traditional Chinese medicine: A review.

In recent years, the incidence of liver disease has increased, becoming a major cause of death. Various liver diseases are intricately linked to pyroptosis, which is one of the most common forms of programmed cell death. As a powerful weapon in the fight against liver diseases, traditional Chinese medicine (TCM) can affect pyroptosis via a number of routes, including the classical, nucleotide oligomerization domain-like receptors protein 3/caspase-1/gasdermin D (GSDMD) pathway, the nonclassical lipopolysaccharide/caspase-11/GSDMD pathway, the ROS/caspase-3/gasdermin E pathway, the caspase-9/caspase-3/GSDMD pathway, and the Apaf-1/caspase-11/caspase-3 pathway. In this review, we provide an overview of pyroptosis, the interplay between pyroptosis and liver diseases, and the mechanisms through which TCM regulates pyroptosis in liver diseases. The information used in the text was collected and compiled from the databases of PubMed, Web of Science, Scopus, CNKI, and Wanfang Data up to June 2023. The search was not limited with regard to the language and country of the articles. Research and review articles were included, and papers with duplicate results or unrelated content were excluded. We examined the current understanding of the relationship between pyroptosis and liver diseases as well as the advances in TCM interventions to provide a resource for the identification of potential targets for TCM in the treatment of liver diseases.

The positive feedback loop of furin and TGFß1 enhances the immune responses of Tregs to hepatocellular carcinoma cells and hepatitis B virus in vitro.

Regulatory T cells (Tregs) can exert immunosuppressive activity. Furin can regulate Treg functions, hepatitis B virus (HBV) persistent infection, and hepatocellular carcinoma (HCC) development. However, it remains unknown whether furin can regulate the immune responses of Tregs to HBV and HCC cells. Here, coculture systems of HBV1.3P-HepG2.3P-HepG2 cells and Tregs transduced with or without lentiviral particles that could overexpress furin or knockdown furin/transforming growth factor ß1 (TGFß1) were established to investigate the regulatory relationship between furin and TGFß1 and the effect of furin/TGFß1 on Treg activity. Also, the effects of furin overexpression or furin/TGFß1 knockdown in Tregs on the immunological activity of effector T cells (Teffs)/cytotoxic T lymphocytes (CTLs) and HBV replication/expression were explored in the coculture system of Teff/CTL, Treg, and HBV1.3P-HepG2 cells. Our results showed that furin expression and TGFß1 secretion were notably increased in Tregs, and Furin and TGFß1 formed a positive feedback loop to activate Tregs in the coculture system of Tregs and HBV1.3P-HepG2 cells. Furin or TGFß1 knockdown in Tregs promoted Teff cell proliferation, stimulated interleukin-2 and interferon-γ secretion, and inhibited HBV replication/gene expression in the coculture system of Teff, Treg, and HBV1.3P-HepG2 cells. Moreover, furin or TGFß1 depletion in Tregs enhanced the killing activity of CTLs against HBV1.3P-HepG2 cells and curbed HBV replication/gene expression in the coculture system of Tregs, CTLs, and HBV1.3P-HepG2 cells. In conclusion, the positive feedback loop of furin and TGFß1 enhanced the immune responses of Tregs to HCC cells and HBV in vitro.

Artificial neural network-based models used for predicting 28- and 90-day mortality of patients with hepatitis B-associated acute-on-chronic liver failure.

BACKGROUND: This study aimed to develop prognostic models for predicting 28- and 90-day mortality rates of hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) through artificial neural network (ANN) systems. METHODS: Six hundred and eight-four cases of consecutive HBV-ACLF patients were retrospectively reviewed. Four hundred and twenty-three cases were used for training and constructing ANN models, and the remaining 261 cases were for validating the established models. Predictors associated with mortality were determined by univariate analysis and were then included in ANN models for predicting prognosis of mortality. The receiver operating characteristic curve analysis was used to evaluate the predictive performance of the ANN models in comparison with various current prognostic models. RESULTS: Variables with statistically significant difference or important clinical characteristics were input in the ANN training process, and eight independent risk factors, including age, hepatic encephalopathy, serum sodium, prothrombin activity, γ-glutamyltransferase, hepatitis B e antigen, alkaline phosphatase and total bilirubin, were eventually used to establish ANN models. For 28-day mortality in the training cohort, the model's predictive accuracy (AUR 0.948, 95% CI 0.925-0.970) was significantly higher than that of the Model for End-stage Liver Disease (MELD), MELD-sodium (MELD-Na), Chronic Liver Failure-ACLF (CLIF-ACLF), and Child-Turcotte-Pugh (CTP) (all p < 0.001). In the validation cohorts the predictive accuracy of ANN model (AUR 0.748, 95% CI: 0.673-0.822) was significantly higher than that of MELD (p = 0.0099) and insignificantly higher than that of MELD-Na, CTP and CLIF-ACLF (p > 0.05). For 90-day mortality in the training cohort, the model's predictive accuracy (AUR 0.913, 95% CI 0.887-0.938) was significantly higher than that of MELD, MELD-Na, CTP and CLIF-ACLF (all p < 0.001). In the validation cohorts, the prediction accuracy of the ANN model (AUR 0.754, 95% CI: 0.697-0.812 was significantly higher than that of MELD (p = 0.019) and insignificantly higher than MELD-Na, CTP and CLIF-ACLF (p > 0.05). CONCLUSIONS: The established ANN models can more accurately predict short-term mortality risk in patients with HBV- ACLF. The main content has been postered as an abstract at the AASLD Hepatology Conference (https://doi.org/10.1002/hep.30257).

Research Progress in Liver-Regenerating Microenvironment and DNA Methylation in Hepatocellular Carcinoma: The Role of Traditional Chinese Medicine.

The development, progression, recurrence, and metastasis of hepatocellular carcinoma (HCC) are closely associated with an abnormal liver-regenerating microenvironment (LRM). Therefore, preventing and reversing an abnormal LRM is a potential therapeutic strategy against HCC. Studies are increasingly focusing on the impact of regeneration, fibrosis, angiogenesis, inflammation, immunomodulation, and hepatic stem cells on HCC development and progression. As a key epigenetic mechanism, DNA methylation is extensively involved in regulating physiological and pathological pathways. In this review, we summarize recent findings on the role of DNA methylation in the fibrotic, angiogenic, inflammatory/immune, and stem cell microenvironments of HCC, and discuss new advances in Traditional Chinese Medicine (TCM) on influencing the abnormal LRM, so as to gain new insights into alleviating the abnormal LRM via regulating DNA methylation by TCM.

Subchronic toxicity of herbal compound "Jiedu Huayu" granules in rats.

BACKGROUND: "Jiedu Huayu" (JDHY) granules are traditional Chinese herbal compounds that have been used to treat severe liver injury for many years. The purpose of the current study is to evaluate the safety of JDHY granules. METHODS: Subchronic toxicity was tested in male and female rats that were orally administered three different doses (80, 100, and 130 g/kg/d) of JDHY for 13 weeks. Clinical signs, bodyweight, food consumption, hematological and biochemical parameters, organ coefficients, and histological changes were observed during the study. RESULTS: There were no significant changes in toxicity observed in either sex at any dose of JDHY granules treatment. CONCLUSIONS: These results suggest that repeated oral administration of JDHY granules at dosage levels of ≤130 g/kg/d can be considered safe.

Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure.

Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.

Regression-based Chinese norms of number connection test A and digit symbol test for diagnosing minimal hepatic encephalopathy.

Number connection test A (NCT-A) and digit symbol test (DST), the preferential neuropsychological tests to detect minimal hepatic encephalopathy (MHE) in China, haven't been standardized in Chinese population. We aimed to establish the norms based on a multi-center cross-sectional study and to detect MHE in cirrhotic patients. NCT-A and DST were administered to 648 healthy controls and 1665 cirrhotic patients. The regression-based procedure was applied to develop demographically adjusted norms for NCT-A and DST based on healthy controls. Age, gender, education, and age by education interaction were all predictors of DST, while age, gender, and education by gender interaction were predictors of log10 NCT-A. The predictive equations for expected scores of NCT-A and DST were established, and Z-scores were calculated. The norm for NCT-A was set as Z ≤ 1.64, while the norm for DST was set as Z ≥ - 1.64. Cirrhotic patients with concurrent abnormal NCT-A and DST results were diagnosed with MHE. The prevalence of MHE was 8.89% in cirrhotic patients, and only worse Child-Pugh classification (P = 0.002, OR = 2.389) was demonstrated to be the risk factor for MHE. The regression-based normative data of NCT-A and DST have been developed to detect MHE in China. A significant proportion of Chinese cirrhotic patients suffered from MHE, especially those with worse Child-Pugh classification.

Crosstalk between lactic acid and immune regulation and its value in the diagnosis and treatment of liver failure.

Liver failure is a common clinical syndrome of severe liver diseases, which belongs to one of the critical medical conditions. Immune response plays a leading role in the pathogenesis of liver failure. Lactic acid as a target for the treatment and prediction of liver failure has not attracted enough attention. Since the emergence of the concept of "histone lactation," lactic acid has shown great promise in immune response and escape. Therefore, targeted lactic acid may be a reliable agent to solve immune and energy metabolism disorders in liver failure. Based on the relationship between lactic acid and immune response, the cross-talk between lactic acid metabolism, its compounds, and immune regulation and its significance in the diagnosis and treatment of liver failure were expounded in this article to provide new ideas for understanding and treating liver failure.

The relationship between non-alcoholic fatty liver disease and incidence of chronic kidney disease for diabetic and non-diabetic subjects: A meta-analysis.

INTRODUCTION: The prevalence of chronic kidney disease (CKD) rises with age and co-morbid diseases such as liver diseases. OBJECTIVES: The main aim of the current meta-analysis is to assess the relationship between Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease incidence in both diabetic and non-diabetic subjects compared with control. MATERIAL AND METHODS: A systematic literature search of papers published from January 1, 2005, till April 30, 2022, found 19 studies including 1,111,046 subjects; 310,804 were diagnosed with NAFLD, and 800,242 were non-NAFLD. The measured outcome was the incidence of CKD among NAFLD subjects compared to non-NAFLD subjects in diabetic and non-diabetic subjects. Dichotomous analysis methods were used within the random effects model to calculate the odds ratio (OR) with 95% confidence intervals (95% CIs). RESULTS: The incidence of CKD is highly significant in NAFLD subjects compared with controls (OR: 1.95; 95% CI: 1.65-2.31). The diabetic non-NAFLD subjects showed a significantly increased incidence of CKD compared to the non-diabetic subjects with NAFLD (OR: 1.79; 95% CI: 1.35-2.38).. In addition, the incidence of CKD was significantly higher in the NAFLD group compared with the non-NAFLD non-diabetic subjects (OR: 2.52; 95% CI: 1.91-3.32). Diabetes acts as an independent risk factor for CKD, as proven by a significant increase in incidence of diabetic subjects compared to non-diabetic NAFLD subjects (OR: 1.82; 95% CI: 1.15-2.88). CONCLUSION: Non-alcoholic fatty liver disease is significantly related to an increased incidence of CKD, which is significantly higher in diabetic subjects.