The significance of m6A RNA methylation regulators in diagnosis and subtype classification of HBV-related hepatocellular carcinoma.

In recent years, abnormal m6A alteration in hepatocellular carcinoma (HCC) has been a focus on investigating the biological implications. In this study, our objective is to determine whether m6A modification contributes to the progression of HBV-related HCC. To achieve this, we employed a random forest model to screen top 8 characteristic m6A regulators from 19 candidate genes. Subsequently, we developed a nomogram model that utilizes these 8 characteristic m6A regulators to predict the prevalence of HBV-related HCC. According to decision curve analysis, patients may benefit from the nomogram model. The clinical impact curves exhibited a robust predictive capability of the nomogram models. Additionally, consensus molecular subtyping was employed to identify m6A modification patterns and m6A-related gene signature. The quantification of immune cell subsets was accomplished through the implementation of ssGSEA algorithms. PCA algorithms were developed to compute the m6A score for individual tumors. Two distinct m6A modification patterns, namely cluster A and cluster B, exhibited significant correlations with distinct immune infiltration patterns and biological pathways. Notably, patients belonging to cluster B demonstrated higher m6A scores compared to those in cluster A, as determined by the m6A score metric. Furthermore, the expression of IGFBP3 proteins was validated through immunofluorescence, revealing their pronounced lower expression in tumor tissues. In summary, our study underscores the importance of m6A modification in the advancement of HBV-related HCC. This research has the potential to yield novel prognostic biomarkers and therapeutic targets for the identification of HBV-related HCC.

Syndecan-1: A Novel Diagnostic and Therapeutic Target in Liver Diseases.

Syndecan-1 (SDC-1), known as a coreceptor of various growth factors or an integrin binding partner, regulates various cell behaviours. Under certain pathological conditions, SDC-1 is shed from the cell surface and plays a protective or pathogenic role in various diseases. In the liver, SDC-1 is highly expressed in hepatocytes, where it is localized on the basolateral surface. It is critical to the cellular and molecular functions of hepatocytes, including their attachment to hepatitis viruses. Previous studies have reported that SDC-1 may function as a novel and promising diagnostic and therapeutic marker for various liver diseases, such as drug-induced liver injury, liver fibrosis, and liver cancer. In this review, we summarize related research and highlight the mechanisms by which SDC-1 participates in the pathogenesis of liver diseases, as well as its potential diagnostic and therapeutic applications. This review is expected to lay the foundation for further therapeutic strategies to target SDC-1 in liver diseases.

Transcriptomic analysis of hepatocytes reveals the association between ubiquitin-specific peptidase 1 and yes-associated protein 1 during liver regeneration.

Objectives: The liver has an excellent ability to regenerate, and disrupted liver regeneration after various injuries leads to an unfavorable prognosis for patients. In this study, we sought to identify novel therapeutic hallmarks that are associated with yes-associated protein 1 (YAP1)-mediated hepatocyte proliferation during the process of liver regeneration. Methods: Partial hepatectomy was conducted to induce liver regeneration in rats. Primary hepatocytes were isolated and cultured. Hepatocyte proliferation was assessed using immunohistochemistry staining, and expression of YAP1 was detected. RNA sequencing and bioinformatics analysis were used to search for potential regulators of YAP1. The association between ubiquitin-specific peptidase 1 (USP1) and YAP1 was validated using in vivo and in vitro experiments. Results: YAP1 was significantly elevated in regenerative hepatocytes, especially in the nucleus. Knockdown of YAP1 using small interfering RNA or pharmacological inhibition using verteporfin significantly attenuated the proliferation of hepatocytes. The bioinformatics analysis results revealed that USP1 was associated with YAP1-mediated hepatocyte proliferation during liver regeneration. ML-323, a specific inhibitor of USP1-USP1 associated factor 1 (UAF1), significantly decreased the expression of YAP1, Cyclin D1, and proliferating cell nuclear antigen, while these decreased expressions could be rescued by YAP1 overexpression. Furthermore, ML-323 treatment significantly inhibited liver regeneration following partial hepatectomy. Conclusions: In conclusion, we identified USP1 as a novel biomarker that is associated with YAP1-mediated hepatocyte proliferation in liver regeneration. Pharmacological inhibition of USP1 by ML-323 substantially impairs hepatocyte proliferation during liver regeneration.

Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy.

Background and aim: Sepsis is a syndromic response to infection and is associated with high mortality, thus imposing a significant global burden of disease. Although low-molecular-weight heparin (LMWH) has been recommended to prevent venous thromboembolism, its anticoagulant and anti-inflammatory effects in sepsis remain controversial. Owing to the modification of the Sepsis-3 definition and diagnostic criteria, further evaluation of the efficacy and benefit population of LMWH is required. Methods: We performed a retrospective cohort study to assess whether LMWH improved the inflammation, coagulopathy, and clinical outcomes against Sepsis-3 and to identify the target patients. All patients diagnosed with sepsis at the First Affiliated Hospital of Xi'an Jiaotong University (the largest general hospital in northwest China) from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria. Results: After 1:1 propensity score matching, 88 pairs of patients were categorized into the treatment and control groups based on subcutaneous LMWH administration. Compared with the control group, a significantly lower 28-day mortality was observed in the LMWH group (26.1 vs. 42.0%, p = 0.026) with a comparable incidence of major bleeding events (6.8 vs. 8.0%, p = 0.773). Cox regression analysis showed that LMWH administration was the independent protective factor for septic patients (aHR, 0.48; 95% CI, 0.29-0.81; p = 0.006). Correspondingly, the LMWH treatment group showed a significant improvement in inflammation and coagulopathy. Further subgroup analysis showed that LMWH therapy was associated with favorable outcomes in patients younger than 60 years and diagnosed with sepsis-induced coagulopathy (SIC), ISTH overt DIC, non-septic shock, or non-diabetics and in patients included in the moderate-risk group (APACHE II score 20-35 or SOFA score 8-12). Conclusion: Our study results showed that LMWH improves 28-day mortality by improving inflammatory response and coagulopathy in patients meeting Sepsis-3 criteria. The SIC and ISTH overt DIC scoring systems can better identify septic patients who are likely to benefit more from LMWH administration.