Search

Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration, and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether MF-derived OPN affects NASH progression is unknown. We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose, and cholesterol diet mimicking the Western diet, to induce NASH. This study demonstrated that MFs with high expression of SPP1 are enriched in patients and mice with nonalcoholic fatty liver disease (NAFLD), and show metabolic but not pro-inflammatory properties. Conditional knockin of Spp1 in myeloid cells (Spp1 KI Mye) or in hepatic macrophages (Spp1 KI LvMF) conferred protection, whereas conditional knockout of Spp1 in myeloid cells (Spp1 ΔMye) worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1 KI Mye mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1 KI Mye also protected through sex-specific extrahepatic mechanisms. MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN–OSM–ARG2 crosstalk between MFs and hepatocytes may be beneficial for patients with NASH. Currently, there are no approved treatments for nonalcoholic steatohepatitis, making this a major unmet clinical need. Although dynamic changes in liver macrophage subsets during the pathogenesis of nonalcoholic steatohepatitis link these shifts to pathologic tissue remodeling, macrophages also have potential to reduce steatosis and fibrosis, an aspect of macrophage function that has been understudied. Thus, the significance of this proposal lies in the delineation, of the not previously known, protective role of osteopontin in macrophages in nonalcoholic steatohepatitis. [ABSTRACT FROM AUTHOR]

To investigate the safety of using ABO incompatible (ABO-i) liver grafts in pediatric patients under our prophylactic strategies. A total number of 544 pediatric liver transplantations between January 2013 and December 2017 performed in Organ Transplant Center, Tianjin First Central Hospital were included in this study. The recipients were divided into 3 groups based on the compatibility of donor-recipient blood type matching (ABO-identical group, n = 352, ABO-compatible group, n = 121 and ABO-incompatible group, n = 71). Recipient characteristics, perioperative data, postoperative complications and recipient survival rate were compared. The recipient outcomes between living-related and non-living-related ABO-incompatible liver graft recipients were also compared. The median follow-up time in three groups were 3.4 (1.8, 6.4) years, 3.2 (1.8, 6.1) years and 2.8 (1.8, 6.2) years, without statistical difference. The cumulative 1-year and 3-year graft survival rate were 94.3% and 94.0% in ABO-id group, 93.1% and 93.1% in ABO-c group and 97.1% and 97.1% in ABO-i group. The cumulative 1-year and 3-year recipient survival rate were 96.1% and 95.5% in ABO-id group, 94.8% and 94.8% in ABO-c group and 97.1% and 97.1% in ABO-i group, respectively. No significant difference was seen among three groups. The recipient characteristics and perioperative data were similar among three groups. The recipients in ABO-i group showed significantly lower incidence of portal vein stenosis. Apart from that, three groups shared equal incidence of other surgical complications and acute rejection. Among ABO-i liver graft recipients, the cumulative 1-year and 3-year recipient survival rate were 98.2% and 98.2% in living donor liver transplant (LDLT) recipients and 92.9% and 92.9% in deceased donor liver transplant (DDLT) recipients, without significant difference. The incidence of hepatic artery thrombosis was significantly higher in DDLT group compared with LDLT group, while the other complications were similar between two groups. Our data revealed that the application of ABO-i liver grafts in pediatric liver transplantation under rational peri-operative management strategy is a safe measure to increase donor availability for pediatric patients in Chinese population. III [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]

Donors with low-body-weight were previously reported to be related to inferior recipient outcomes in pediatric liver transplantation. However, the scarce availability of age and size-matched organs has encouraged us to re-evaluate the feasibility and safety of using low-body-weight donors. We retrospectively analyzed 91 deceased donor pediatric liver transplantation between January 2014 and December 2016, donor weight less than 5 kg was defined as low-body-weight donors. The recipients were divided into two groups according to donor weight. (≤ 5 kg and 5 kg < to ≤ 20 kg). Donor and recipient characteristics, perioperative data, postoperative complications as well as graft and recipient survival rate were compared The recipients and grafts recovery after transplantation were comparable between two groups. The recipients receiving low-body-weight donors showed higher risk of hepatic artery thrombosis and small-for-size syndrome, however, these complications can effectively be treated by our strategies. The 2-year patient survival rates were 92.9% and 95.2%, 2-year graft survival rates were 92.9% and 93.7% in Groups 1 and 2, without significant difference. Our finding suggested that the utility of livers from low-body-weight donors is a potential strategy to increase donor availability in well-selected pediatric recipients. III [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]

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]