BACKGROUND AND OBJECTIVE

Patients with liver cirrhosis have an increased risk for poor postoperative outcomes after non-hepatic surgery, with liver dysfunction being the most important predictor of poor outcomes. This study aims to determine the association of the albumin-bilirubin (ALBI) grade, aspartate aminotransferase-platelet ratio index (APRI) score, and ALBI-APRI score with postoperative outcomes among cirrhotic patients who have undergone non-hepatic surgery.

This was a retrospective cohort study involving 34 patients. Age, ASA class, urgency of surgery, etiology of liver cirrhosis, preoperative Child-Turcotte-Pugh (CTP) score, Model for End-Stage Liver Disease (MELD) score, ALBI grade, APRI score, and ALBI-APRI score were documented. The outcomes analyzed were postoperative hepatic decompensation (POHD) and in-hospital mortality. Bivariate analysis using the Mann-Whitney U test and Fisher’s exact test was performed. Receiver operating characteristic (ROC) curve analysis was performed to compare the ability of the liver scoring systems to predict the occurrence of study outcomes. Binary logistic regression was performed to measure the odds ratio.

The ALBI grade and ALBI-APRI score were significantly associated with both POHD and in-hospital mortality. Both scores were non-inferior to the CTP and MELD scores in predicting study outcomes. Compared to CTP and MELD scores, the ALBI grade was more sensitive but less specific in predicting POHD and as sensitive but more specific in predicting in-hospital mortality. The ALBI-APRI score was less sensitive but more specific than the ALBI grade in predicting both POHD and in-hospital mortality.

The ALBI grade and ALBI-APRI score were both associated with postoperative hepatic decompensation and in-hospital mortality and were noninferior to the CTP score and MELD score in predicting short-term in-hospital outcomes among cirrhotic patients after non-hepatic surgery.

OBJECTIVES: To observe the evolution of intrahepatic macrophage polarization in mice with liver fibrosis induced by iron overload. METHODS: Thirty-two C57BL/6 mice (6-8 weeks) were randomized into control group (n=8) and liver fibrosis model group (n=24) induced by aidly intraperitoneal injection of iron dextran. At the 3rd, 5th, and 7th weeks of modeling, 8 mice in the model group were sacrificed for observing liver fibrosis using Masson, Sirius Red and immunohistochemical staining and detecting serum levels of ALT, AST and the levels of serum iron, ferritin, liver total Fe and ferrous Fe. iNOS⁺/F4/80⁺ cells and CD206⁺/F4/80⁺ cells were detected by double immunofluorescence assay to observe the proportion and distribution of M1 and M2 macrophages. The hepatic expressions of Arg-1, iNOS, IL-6, IL-10, and TNF‑α proteins were detected using Western blotting or ELISA, and the expression of CD206 mRNA was detected using RT-PCR. RESULTS: The mice in the model group showed gradual increase of fibrous tissue hyperplasia in the portal area over time, structural destruction of the hepatic lobules and formation of pseudolobules. With the passage of time during modeling, the rat models showed significantly increased hepatic expressions of α-SMA and COL-1, elevated serum levels of ALT, AST, Fe, ferritin, and increased liver total Fe and ferrous Fe levels. The expressions of M1 polarization markers IL-6, TNF‑α, and iNOS all increased with time and reached their peak levels at the 3rd week; The expressions of M2 polarization markers (IL-10 and Arg-1 proteins and CD206 mRNA) significantly increased in the 3rd week and but decreased in the 5th and 7th weeks. CONCLUSIONS Iron overload promotes M1 polarization of macrophages in mice. Liver fibrosis in the early stage promotes M2 polarization of macrophages but negatively regulate M2 polarization at later stages.
Animals ; Mice ; Mice, Inbred C57BL ; Iron Overload/pathology* ; Macrophages/metabolism* ; Male ; Liver Cirrhosis/etiology* ; Nitric Oxide Synthase Type II/metabolism* ; Interleukin-10/metabolism* ; Liver/pathology* ; Interleukin-6/metabolism* ; Mannose Receptor ; Tumor Necrosis Factor-alpha/metabolism* ; Mannose-Binding Lectins/metabolism* ; Arginase

OBJECTIVES: To explore the therapeutic mechanism of compound Centella asiatica formula (CCA) for alleviating Schistosoma japonicum (Sj)-induced liver fibrosis in mice. METHODS: The active components and targets of CCA were identified using the TCMSP database with cross-analysis of Sj-related liver fibrosis targets. A "drug-component-target-pathway-disease" network was constructed using Cytoscape 3.9.1. Functional enrichment analysis (GO/KEGG) was performed using DAVID. Molecular docking study was carried out to validate interactions between the core targets and the key compounds. For experimental validation of the results, 36 mice were divided into control group, Sj-infected model group, and CCA-treated groups. In the latter two groups, liver fibrosis was induced via abdominal infection with Sj cercariae for 8 weeks, followed by 8 weeks of daily treatment with CCA decoction or saline. Hepatic pathology of the mice was assessedwith HE and Masson staining, and hepatic expressions of collagen-I and collagen-III were detected using immunohistochemistry; serum IL-6 and TNF-α levels were determined with ELISA. Hepatic expressions of TLR4 and MyD88 proteins were analyzed with Western blotting. RESULTS: We identified a total of 107 bioactive CCA components and 791 targets, including 37 intersection targets linked to Sj-induced fibrosis. The core targets included TNF, TP53, JUN, MMP9, and CXCL8, involving the IL-17 signaling, lipid metabolism, TLR4/MyD88 axis, and cancer pathways. Molecular docking study confirmed strong binding affinity between quercetin (a primary CCA component) and TNF/TP53/JUN/MMP9. In Sj-infected mouse models, CCA treatment significantly attenuated hepatic inflammatory cell infiltration, reduced collagen-I and collagen-III deposition, improved tissue architecture, reduced serum IL-6 and TNF-α levels, and downregulated TLR4 and MyD88 expressions in the liver. CONCLUSIONS CCA mitigates Sj-induced liver fibrosis by targeting TNF, TP53, JUN, and MMP9 to modulate the TLR4/MyD88 pathway, thereby suppressing pro-inflammatory cytokine release, inhibiting hepatic stellate cell activation, reducing collagen deposition, and preventing granuloma formation in the liver.
Animals ; Toll-Like Receptor 4/metabolism* ; Mice ; Myeloid Differentiation Factor 88/metabolism* ; Schistosoma japonicum ; Liver Cirrhosis/parasitology* ; Schistosomiasis japonica ; Signal Transduction ; Molecular Docking Simulation ; Inflammation ; Centella/chemistry* ; Drugs, Chinese Herbal/pharmacology* ; Tumor Necrosis Factor-alpha/metabolism*

OBJECTIVES: To prepare a stable mouse model of chronic liver fibrosis induced by dietary vitamin A (VA) deficiency combined with CCl₄ injections. METHODS: A total of 126 Balb/c mice were randomized into 3 groups for feeding with a normal VA diet or a VA-deficient diet containing 500 or 200 IU/kg VA. After 4 weeks of feeding, half of the mice in each group were given intraperitoneal injections of 5% CCl₄ (10 mL/kg, twice a week) for 8 weeks. Serum retinol, ALT/AST and liver index of the mice were examined, liver tissue pathologies were observed with HE and Masson staining, and liver fibrosis score and oxidative stress level were evaluated. RESULTS: Four weeks of VA-deficient feeding, especially at 200 IU/kg, significantly lowered serum retinol level of the mice. CCl₄ injections for 8 weeks obviously increased liver index and ALT/AST and caused obvious liver fibrosis in all the mice, but liver pathologies were more severe in the 2 VA-deficient groups; severe liver necrosis with inflammatory cell infiltration was observed in 200 IU/kg VA group, where 2 mice died. After discontinuation of CCl₄, the mice with normal dietary VA showed gradual recovery of the liver index, ALT/AST, liver cord structure and liver fibrosis; the mice with VA deficiency, however, showed no significant improvements in these parameters, and the mice with 200 IU/kg VA still had serious abdominal adhesion, false lobules and massive inflammatory cell infiltration with a fibrosis stage score of 3. The oxidative damage index 8-OHdG was significantly higher in 500 IU/kg VA group than in normal VA group after CCl₄ modeling. CONCLUSIONS Feeding with diet containing 500 IU/kg VA for 4 weeks and 10 mL/kg CCl₄ injections for 8 weeks can result in stable moderate to severe liver fibrosis in mice without spontaneous reversal at 8 weeks of drug withdrawal.
Animals ; Mice ; Mice, Inbred BALB C ; Disease Models, Animal ; Carbon Tetrachloride ; Vitamin A Deficiency/complications* ; Male ; Liver Cirrhosis/etiology* ; Oxidative Stress ; Vitamin A/blood*

OBJECTIVES: To investigate the expression of the long non-coding RNA maternally expressed gene 3 (LncRNA Meg3) in patients with the Wilson disease (WD) and its correlation with the severity of liver fibrosis and autophagy-related markers. METHODS: A total of 100 WD patients and 50 healthy individuals were enrolled from the First Affiliated Hospital of Anhui University of Chinese Medicine. Serum biomarkers, including platelet count, hyaluronic acid (HA), laminin (LN), type III procollagen N-terminal peptide (PIIINP), type IV collagen (C‑IV), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), were measured, and the non-invasive indices APRI and FIB-4 were calculated. Peripheral blood levels of LncRNA Meg3, Beclin-1 and LC3B were detected using RT-qPCR, and liver stiffness (LSM) and shear wave velocity (SWV) were evaluated using two-dimensional shear wave elastography (2D-SWE). The liver tissues from 10 WD patients and 10 patients with hepatic hemangioma were examined using histochemical staining, transmission electron microscopy, and RT-qPCR. RESULTS: The expression level of LncRNA Meg3 was significantly lower, while the levels of AST, ALT, HA, LN, PIIINP, C‑IV, APRI, FIB-4, LSM and SWV were significantly higher in WD patients than in the healthy individuals (all P<0.01). LncRNA Meg3 was negatively correlated with LSM, SWV, APRI, FIB-4, Beclin-1 and LC3B (P<0.05). ROC analysis demonstrated that LncRNA Meg3 effectively discriminated >F4 stage fibrosis (AUC=0.902) with a sensitivity of 92.9% and a specificity of 83.7% at the optimal cut-off value, outperforming APRI (AUC=0.746) and FIB-4 (AUC=0.661). The liver tissues from WD patients exhibited characteristic histopathological changes and lowered expression of LncRNA Meg3, which was negatively correlated with Beclin-1 and LC3B expressions (P<0.05). Liver fibrosis staging (7 S4 cases and 3 S3 cases) was significantly associated with LSM and SWV levels (P<0.05). CONCLUSIONS The expression level of LncRNA Meg3 is significantly decreased in WD patients, which is negatively correlated with the severity of liver fibrosis and closely related to the level of autophagy.
Humans ; RNA, Long Noncoding/metabolism* ; Liver Cirrhosis/metabolism* ; Adult ; Female ; Male ; Hepatolenticular Degeneration/metabolism* ; Case-Control Studies ; Young Adult ; Adolescent ; Middle Aged

Developing and identifying effective medications and targets for treating hepatic fibrosis is an urgent priority. Our previous research demonstrated the efficacy of artesunate (ART) in alleviating liver fibrosis by eliminating activated hepatic stellate cells (HSCs). However, the underlying mechanism remains unclear despite these findings. Notably, endocytic adaptor protein (NUMB) has significant implications for treating hepatic diseases, but current research primarily focuses on liver regeneration and hepatocellular carcinoma. The precise function of NUMB in liver fibrosis, particularly its ability to regulate HSCs, requires further investigation. This study aims to elucidate the role of NUMB in the anti-hepatic fibrosis action of ART in HSCs. We observed that the expression level of NUMB significantly decreased in activated HSCs compared to quiescent HSCs, exhibiting a negative correlation with the progression of liver fibrosis. Additionally, ART induced senescence in activated HSCs through the NUMB/P53 tumor suppressor (P53) axis. We identified NUMB as a crucial regulator of senescence in activated HSCs and as a mediator of ART in determining cell fate. This research examines the specific target of ART in eliminating activated HSCs, providing both theoretical and experimental evidence for the treatment of liver fibrosis.
Hepatic Stellate Cells/cytology* ; Liver Cirrhosis/genetics* ; Artesunate/pharmacology* ; Cellular Senescence/drug effects* ; Membrane Proteins/genetics* ; Animals ; Humans ; Nerve Tissue Proteins/genetics* ; Tumor Suppressor Protein p53/genetics* ; Male ; Mice

Two novel skeleton sesquiterpenoids (1 and 6), along with four new iphionane-type sesquiterpenes (2-5) and six new cyperane-type sesquiterpenes (7-11), were isolated from the whole plant of Artemisia hedinii (A. hedinii). The two novel skeleton compounds (1 and 6) were derived from the decarbonization of iphionane and cyperane-type sesquiterpenes, respectively. Their structures were elucidated through a comprehensive analysis of spectroscopic data, including high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) and 1D and 2D nuclear magnetic resonance (NMR) spectra. The absolute configurations were determined using electronic circular dichroism (ECD) spectra, single-crystal X-ray crystallographic analyses, time-dependent density functional theory (TDDFT) ECD calculation, density functional theory (DFT) NMR calculations, and biomimetic syntheses. The biomimetic syntheses of the two novel skeletons (1 and 6) were inspired by potential biogenetic pathways, utilizing a predominant eudesmane-type sesquiterpene (A) in A. hedinii as the substrate. All compounds were evaluated in LX-2 cells for their anti-hepatic fibrosis activity. Compounds 2, 8, and 10 exhibited significant activity in downregulating the expression of α-smooth muscle actin (α-SMA), a protein involved in hepatic fibrosis.
Artemisia/chemistry* ; Sesquiterpenes/chemical synthesis* ; Molecular Structure ; Humans ; Liver Cirrhosis/genetics* ; Biomimetics ; Plant Extracts/pharmacology*

Chronic, unresolved inflammation correlates with persistent hepatic injury and fibrosis, ultimately progressing to hepatocellular carcinoma (HCC). Bisdemethoxycurcumin (BDMC) demonstrates therapeutic potential against HCC, yet its mechanism in preventing hepatic "inflammation-carcinoma transformation" remains incompletely understood. In the current research, clinical HCC specimens underwent analysis using hematoxylin-eosin (H&E) staining and immunohistochemistry (IHC) to evaluate the expression of fibrosis markers, M2 macrophage markers, and CXCL12. In vitro, transforming growth factor-β1 (TGF-β1)-induced LX-2 cells and a co-culture system of LX-2, THP-1, and HCC cells were established. Cell functions underwent assessment through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and Transwell assays. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunofluorescence evaluated the differential expression of molecules. The interaction between β-catenin/TCF4 and CXCL12 was examined using co-immunoprecipitation (Co-IP), dual luciferase, and chromatin immunoprecipitation (ChIP) assays. A DEN-induced rat model was developed to investigate BDMC's role in liver fibrosis-associated HCC (LFAHCC) development in vivo. Our results showed that clinical HCC tissues exhibited elevated fibrosis and enriched M2 macrophages. BDMC delayed liver fibrosis progression to HCC in vivo. BDMC inhibited the inflammatory microenvironment induced by activated hepatic stellate cells (HSCs). Furthermore, BDMC suppressed M2 macrophage-induced fibrosis and HCC cell proliferation and metastasis. Mechanistically, BDMC repressed TCF4/β-catenin complex formation, thereby reducing CXCL12 transcription in LX-2 cells. Moreover, CXCL12 overexpression reversed BDMC's inhibitory effect on macrophage M2 polarization and its mediation of fibrosis, as well as HCC proliferation and metastasis. BDMC significantly suppressed LFAHCC development through CXCL12 in rats. In conclusion, BDMC inhibited LFAHCC progression by reducing M2 macrophage polarization through suppressing β-catenin/TCF4-mediated CXCL12 transcription.
Animals ; Liver Neoplasms/etiology* ; Humans ; Carcinoma, Hepatocellular/immunology* ; Liver Cirrhosis/complications* ; Macrophages/drug effects* ; Male ; Rats ; Chemokine CXCL12/genetics* ; Diarylheptanoids/pharmacology* ; Rats, Sprague-Dawley ; beta Catenin/genetics*

OBJECTIVE: To compare the therapeutic efficacy of portal and tail vein transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) against cholestatic liver fibrosis in mice. METHODS: BMSCs were isolated and co-cultured with starvation-activated hepatic stellate cells (HSCs). HSC activation markers were identified using immunofluorescence and qRT-PCR. BMSCs were injected into the liver tissues of bile duct ligation (BDL) mice via the tail and portal veins. Histomorphology, liver function, inflammatory cytokines, and the expression of key proteins were all determined in the liver tissues. RESULTS: BMSCs inhibited HSC activation by reducing α-SMA and collagen I expression. Compared to tail vein injection, DIL-labeled BMSCs injected through the portal vein maintained a high homing rate in the liver. Moreover, BMSCs transplanted through the portal vein resulted in greater improvement in liver color, hardness, and gallbladder size than did those transplanted through the tail vein. Furthermore, BMSCs injected by portal vein, but not tail vein, markedly ameliorated liver function, reduced the secretion of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, and decreased α-SMA + hepatic stellate cell (HSC) activation and collagen fiber formation. CONCLUSION The therapeutic effect of BMSCs on cholestatic liver fibrosis in mice via portal vein transplantation was superior to that of tail vein transplantation. This comparative study provides reference information for further BMSC studies focused on clinical cholestatic liver diseases.
Animals ; Mice ; Mesenchymal Stem Cell Transplantation ; Liver Cirrhosis/etiology* ; Male ; Cholestasis/therapy* ; Mice, Inbred C57BL ; Hepatic Stellate Cells ; Mesenchymal Stem Cells

Hepatitis E is the liver inflammation caused by a hepatitis E virus infection.Immunocompetent patients with acute hepatitis E can spontaneously clear the infection,whereas immunosuppressed patients may not be able to clear the hepatitis E virus infection and develop chronic hepatitis.Most patients with hepatitis E are asymptomatic and present only with mild and persistent liver function abnormalities.This article reports a case of hepatitis E in an immunocompetent adult with elevated aminotransferases as the main manifestation.Hepatic fibrosis was detected by hepatic puncture biopsy.This report aims to remind other physicians to evaluate liver fibrosis when encountering acute hepatitis E,especially in patients with chronic liver disease.
Adult ; Humans ; Acute Disease ; Hepatitis E/complications* ; Liver Cirrhosis/etiology*