A nomogram based on psoas muscle index predicting long-term cirrhosis incidence in non-cirrhotic patients with HBV-related acute­on­chronic liver failure.

There is a lack of scoring system to predict the occurrence of cirrhosis in individuals with acute-on-chronic liver failure (ACLF) in the absence of cirrhosis. The goal of this study was to develop a psoas muscle index (PMI)-based nomogram for cirrhosis risk in non-cirrhotic patients with HBV-related ACLF. We included 274 non-cirrhotic HBV-ACLF patients who were randomly assigned to training and validation groups. Logistic analyses were performed to identify risk factors for cirrhosis. A nomogram was then constructed. The predictive performance of the nomogram was assessed using the area under the receiver operating characteristic curve (AUROC), calibration curve, and decision curve analysis (DCA). During the 360-day follow-up, 44.5% (122/274) of non-cirrhotic HBV-ACLF patients developed cirrhosis. A higher PMI at the L3 level was correlated with a decreased risk of long-term cirrhosis occurrence (OR 0.677, 95% CI 0.518-0.885, P = 0.004). The nomogram incorporating PMI, age, neutrophil-to-lymphocyte ratio (NLR), and international normalized ratio (INR), indicated satisfactory predictive performance for cirrhosis risk stratification in ACLF population. The nomograms had an AUROC of 0.812 (95% CI 0.747-0.866) and 0.824 (95% CI 0.730-0.896) in the training and validation cohorts, respectively. The calibration curves displayed excellent predictive accuracy of the nomogram in both sets. In both cohorts, the DCA verified the nomogram's clinical efficacy. In non-cirrhotic HBV-ACLF patients, a greater PMI appears to protect against long-term cirrhosis occurrence. Strong predictive performance has been demonstrated by PMI-based nomograms in assessing the likelihood of 1-year cirrhosis in those with HBV-ACLF.

USP9X-mediated NRP1 deubiquitination promotes liver fibrosis by activating hepatic stellate cells.

Liver fibrosis is a complex fibrotic process that develops early in the course of cirrhosis and is caused by chronic liver damage. The activation of hepatic stellate cells is primarily responsible for the fibrosis process. Studies show that NRP1 influences HSC motility and migration. However, whether NRP1 regulates HSC activation remains unknown. C57BL/6 male mice (6-8 weeks old) were intraperitoneally injected with 10% CCl4 in olive oil (5 µl/g body weight) every three days for four weeks to create an animal model of liver fibrosis. Control mice received olive oil (5 µl/g body weight). Different assays such as immunohistochemistry, immunostaining, Western blotting, qRT-PCR, immunoprecipitation, immunoprecipitation, and GST pull-down assays, and in vivo and in vitro ubiquitination assays were conducted. We found that NRP1 expression was significantly elevated both in mouse and human fibrotic livers, mainly in activated HSCs at the fibrotic foci. NRP1 promoted HSC activation via the cytokine TGF-ß1, VEGFA, and PDGF-BB. Moreover, USP9X was found to be a critical deubiquitinating enzyme for the stability and high activity of NRP1 and NRP1 deubiquitination mediated by USP9X enhanced HSC activation and liver fibrosis. NRP1 deubiquitination mediated by USP9X enhances HSC activation, implying that targeting NRP1 or USP9X potentiates novel options in the treatment of liver fibrosis.

Skeletal muscle mass index as a predictor of long-term cirrhosis onset in young non-cirrhotic males with acute-on-chronic liver failure.

Background: The relationship between skeletal muscle mass index (SMI) and cirrhosis incidence in patients with non-cirrhotic acute-on-chronic (ACLF) has not been clarified. This study aimed to assess the predictive value of SMI on the incidence of long-term cirrhosis in male non-cirrhotic ACLF patients. Materials and methods: Male ACLF patients who were free of liver cirrhosis were retrospectively included in this study. Univariate and multivariate logistic analyses were conducted to determine the risk factors for the long-term (1-year) development of cirrhosis. The receiver operating characteristic curves (ROC) were used to assess the ability of SMI levels to predict the incidence of cirrhosis. Restricted triple spline (RCS) described the dose-response relationship between SMI and the risk of cirrhosis. Subgroup analysis was stratified by age (≤ 40 years and > 40 years). Results: A total of 230 subjects were included in this study, of whom 45.2% (104/230) were diagnosed with cirrhosis within 360 days. Patients who progressed to cirrhosis had a lower SMI [46.1 ± 6.9 versus 49.2 ± 6.5 cm2/m2, P = 0.001] and a higher proportion of sarcopenia (19.2% versus 6.3%, P = 0.003). In multivariate logistic regression, SMI remained a protective agent against 360-days progression to cirrhosis in males with ACLF after adjustment (OR 0.950, 95% CI: 0.908-0.994, P < 0.05). SMI exerted a non-linear dose-dependent effect on the risk of cirrhosis. The area under the ROC curve (AUC) for the L3-SMI to predict the incidence of cirrhosis in male non-cirrhotic ACLF patients was 0.636 (P < 0.001). We observed significant differences in SMI among male ACLF patients in different age groups. Further subgroup analysis by age revealed that lower SMI was associated with the 1-year incidence of cirrhosis in male ACLF patients aged less than 40 years (OR 0.908, 95% CI: 0.842-0.979, P < 0.05), whereas SMI did not affect the 1-year risk of cirrhosis in older subjects (age > 40 years). Conclusion: A higher SMI represents an independent protective factor for developing long-term cirrhosis in male ACLF patients who do not experience cirrhosis, especially in those under 40 years of age.

p22phox promotes Ang-II-induced vascular smooth muscle cell phenotypic switch by regulating KLF4 expression.

NADPH oxidase (Nox) is the main source of reactive oxygen species in vascular diseases, which have been implicated in promoting VSMCs phenotypic switch. P22phox, the indispensable component of the complex Nox, is required for their activity and stability. Krüppel-like factor 4 (KLF4) is an important transcriptional regulator of VSMCs phenotypic switch. Both KLF4 and p22phox are involved in the proliferation, migration and differentiation of VSMC. This study aims to determine whether and how p22phox regulates KLF4 expression in phenotypic switching of VSMCs. In cultured primary rat VSMCs, we noticed that the expression of P22phox was significantly increased in combination with VSMCs phenotypic switch and up-regulated KLF4 expression in Ang-II-treated cells. Ang-II-induced VSMC dedifferentiation, proliferation, migration, KLF4 expression, H2O2 production and the phosphorylation of AKT, ERK1/2 were all inhibited by knockdown of P22phox. Furthermore, H2O2 treatment effectively enhanced the phosphorylation of AKT, ERK1/2 and the expression of KLF4, whereas LY294002 (a specific inhibitor of PI3K), U0126 (a specific inhibitor of ERK1/2) significantly attenuated the H2O2-induced up-regulation of KLF4. In conclusion, these results demonstrated that p22phox promotes Ang-II-induced VSMC phenotypic switch via the H2O2-ERK1/2/AKT-KLF4 signaling pathway.

[Serum amyloid A promotes the inflammatory response via p38-MAPK/SR-BI pathway in THP-1 macrophages].

To investigate the effect and mechanism of serum amyloid A (SAA) on the expression of scavenger receptor class B type I (SR-BI) and inflammatory response in THP-1 macrophages, the human THP-1 cells were treated with SAA and p38-MAPK agonist (anisomycin) or p38-MAPK inhibitor (SB203580). Then, the expressions of SR-BI, phosphorylated p38-MAPK and inflammatory factors (MCP-1, TNF-α, IL-1ß) were examined by real-time quantitative PCR, Western blotting and ELISA, respectively. The results showed that, compared with control group, SAA increased the levels of inflammatory factors (MCP-1, TNF-α, IL-1ß), down-regulated the expressions of SR-BI, and up-regulated the expression of phosphorylated p38-MAPK protein in a concentration- and time-dependent manner in THP-1 cells (P < 0.05). After treatment with SAA and p38-MAPK agonist (anisomycin) in THP-1 cells, the expression of SR-BI was down-regulated, and the levels of inflammatory factors and phosphorylated p38-MAPK protein expression were increased, compared with the group only treated by SAA (P < 0.05). In contrast, the SR-BI expression was up-regulated, whereas inflammatory factors and phosphorylated p38-MAPK protein expressions were decreased after the cells were treated with SAA and p38-MAPK inhibitor (SB203580) (P < 0.05). The results suggest that SAA-promoted inflammatory response in THP-1 macrophages may be through the phosphorylation of p38-MAPK and inhibition of SR-BI expression.