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High-mobility group box-1 (HMGB1) significantly increases and undergoes post-translational modifications (PTMs) in response to liver injury. Since oxidative stress plays a major role in liver fibrosis and induces PTMs in proteins, we hypothesized that redox-sensitive HMGB1 isoforms contribute to liver fibrosis progression and resolution. We used ESI-LC-MS (electrospray ionization-liquid chromatography-mass spectrometry) to study PTMs of HMGB1 during fibrosis progression and resolution. Conditional knockout mice were used for functional analyses. We identified that disulfide ([O]) and sulfonated ([SO 3 ]) HMGB1 increase during carbon tetrachloride-induced liver fibrosis progression, however, while [O] HMGB1 declines, [SO 3 ] HMGB1 drops but remains, during fibrosis resolution. Conditional knockout of Hmgb1 revealed that production of [O] and [SO 3 ] HMGB1 occurs mostly in hepatocytes. Co-injection of [O] HMGB1 worsens carbon tetrachloride-induced liver fibrosis more than co-injection of [H] HMGB1. Conversely, ablation of [O] Hmgb1 in hepatocytes reduces liver fibrosis. Moreover, ablation of the receptor for advanced-glycation end-products (Rage) reveals that the profibrogenic effect of [O] HMGB1 is mediated by RAGE signaling in hepatic stellate cells (HSCs). Notably, injection of [SO 3 ] HMGB1 accelerates fibrosis resolution due to RAGE-dependent stimulation of HSC apoptosis. Importantly, gene signatures activated by redox-sensitive HMGB1 isoforms in mice, classify patients with fibrosis according to fibrosis and inflammation scores. Dynamic changes in hepatocyte-derived [O] and [SO 3 ] HMGB1 signal through RAGE-dependent mechanisms on HSCs to drive their profibrogenic phenotype and fate, contributing to progression and resolution of liver fibrosis. Since oxidative stress plays a major role in liver fibrosis and induces post-translational modifications of proteins, we hypothesized that redox-sensitive HMGB1 isoforms contribute to liver fibrosis progression and resolution. This study is significant because a rise in [H] HMGB1 could flag 'patient at risk', the presence of [O] HMGB1 could suggest 'disease in progress or active scarring', while the appearance of [SO 3 ] HMGB1 could point at 'resolution under way'. The latter could be used as a readout for response to pharmacological intervention with anti-fibrotic agents. [Display omitted] • We identified post-translational modifications of HMGB1 during liver fibrosis progression ([O] and [SO 3 ] HMGB1) and resolution ([SO 3 ] HMGB1). • The pro-fibrogenic effect of [O] HMGB1 is mediated by RAGE signaling in hepatic stellate cells. • [SO 3 ] HMGB1 accelerates fibrosis resolution via RAGE-dependent stimulation of hepatic stellate cell apoptosis. • Gene signatures, activated by redox-sensitive HMGB1 isoforms in mice, classify patients according to fibrosis and inflammation scores. [ABSTRACT FROM AUTHOR]

Damage-associated molecular patterns are signalling molecules involved in inflammatory responses and restoration of homeostasis. Chronic release of these molecules can also promote inflammation in the context of liver disease. Herein, we provide a comprehensive summary of the role of damage-associated molecular patterns as danger signals in liver injury. We consider the role of reactive oxygen species and reactive nitrogen species as inducers of damage-associated molecular patterns, as well as how specific damage-associated molecular patterns participate in the pathogenesis of chronic liver diseases such as alcohol-related liver disease, non-alcoholic steatohepatitis, liver fibrosis and liver cancer. In addition, we discuss the role of damage-associated molecular patterns in ischaemia reperfusion injury and liver transplantation and highlight current studies in which blockade of specific damage-associated molecular patterns has proven beneficial in humans and mice. [ABSTRACT FROM AUTHOR]

Background: Dietary polyphenols including anthocyanins target multiple organs.Objective: We aimed to assess the involvement of glucagon-like peptide 1 (GLP-1), leptin, insulin and fibroblast growth factor 21 (FGF21) in mediating metabolic beneficial effects of purified anthocyanin cyanidin-3-glucoside (Cy3G).Methods: Intestinal proglucagon gene (Gcg; encoding GLP-1) and liver Fgf21 expression were assessed in 6-wk-old male C57BL-6J mice fed a low-fat-diet (LFD; 10% of energy from fat), alone or with 1.6 mg Cy3G/L in drinking water for 3 wk [experiment (Exp.) 1; n = 5/group]. Similar mice were fed the LFD or a high-fat diet (HFD; 60% energy from fat) with or without Cy3G for 20 wk. Half of the mice administered Cy3G also received 4 broad-spectrum antibiotics (ABs) in drinking water between weeks 11 and 14, for a total of 6 groups (n = 8/group). Metabolic tolerance tests were conducted between weeks 2 and 16. Relevant hormone gene expression and plasma hormone concentrations were assessed mainly at the end of 20 wk (Exp. 2).Results: In Exp. 1, Cy3G administration increased ileal but not colonic Gcg level by 2-fold (P < 0.05). In Exp. 2, Cy3G attenuated HFD-induced body-weight gain (20.3% at week 16), and improved glucose tolerance (26.5% at week 15) but not insulin tolerance. Although Cy3G had no effect on glucose tolerance in LFD mice, LFD/Cy3G/AB mice showed better glucose tolerance than LFD/Cy3G mice (23%). In contrast, HFD/Cy3G/AB mice showed worse glucose tolerance compared with HFD/Cy3G mice (15%). Beneficial effects of Cy3G in HFD mice were not associated with changes in plasma leptin, insulin or GLP-1 concentrations. However, Cy3G increased hepatic Fgf21 expression in mice in Exp. 1 by 4-fold and attenuated Fgf21 overexpression in HFD mice (Exp. 2, 22%), associated with increased expression of genes that encode FGFR1 and β-klotho (>3-fold, P < 0.05).Conclusions: Dietary Cy3G may reduce body weight and exert metabolic homeostatic effects in mice via changes in hepatic FGF21. [ABSTRACT FROM AUTHOR]

Objectives: To assess whether radiomics signature can identify aggressive behavior and predict recurrence of hepatocellular carcinoma (HCC) after liver transplantation.Methods: Our study consisted of a training dataset (n = 93) and a validation dataset (40) with clinically confirmed HCC after liver transplantation from October 2011 to December 2016. Radiomics features were extracted by delineating regions-of-interest (ROIs) around the lesion in four phases of CT images. A radiomics signature was generated using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The association between radiomics signature and recurrence-free survival (RFS) was assessed. Preoperative clinical characteristics potentially associated with RFS were evaluated to develop a clinical model. A combined model incorporating clinical risk factors and radiomics signature was built.Results: The stable radiomics features associated with the recurrence of HCC were simply found in arterial phase and portal phase. The prediction model based on the radiomics features extracted from the arterial phase showed better prediction performance than the portal vein phase or the fusion signature combining both of arterial and portal vein phase. A radiomics nomogram based on combined model consisting of the radiomics signature and clinical risk factors showed good predictive performance for RFS with a C-index of 0.785 (95% confidence interval [CI]: 0.674-0.895) in the training dataset and 0.789 (95% CI: 0.620-0.957) in the validation dataset. The calibration curves showed agreement in both training (p = 0.121) and validation cohorts (p = 0.164).Conclusions: Radiomics signature extracted from CT images may be a potential imaging biomarker for liver cancer invasion and enable accurate prediction of HCC recurrence after liver transplantation. [ABSTRACT FROM AUTHOR]