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Background and Aims: Apolipoprotein A‐1 (ApoA‐1), the major apolipoprotein of high‐density lipoprotein, plays anti‐atherogenic role in cardiovascular diseases and exerts anti‐inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA‐1 in hepatic ischaemia–reperfusion (I/R) injury is unknown. Methods: In this study, we measured ApoA‐1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA‐1 knockout mice, ApoA‐1 mimetic peptide D‐4F treatment mice and corresponding control mice to examine the effect of ApoA‐1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. Results: The results showed that ApoA‐1 expression was down‐regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA‐1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA‐1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA‐1 deficiency. Furthermore, the up‐regulated pyroptosis process was testified to be mediated by ApoA‐1 through TLR4–NF‐κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D‐4F ameliorated hepatic I/R injury. Conclusions: Our study has identified the protective role of ApoA‐1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4–NF‐κB pathway. The effect of ApoA‐1 may provide a novel therapeutic approach for hepatic I/R injury. [ABSTRACT FROM AUTHOR]

Background: The role of hepatic resection in the treatment of type I and II hilar cholangiocarcinoma (HCCA) remains controversial. In the present study, we aimed to identify whether hepatic resection was necessary for type I and II HCCA. Methods: A total of 23 patients classified as type I and II HCCA undergoing surgical resection were included in this study. The patients were divided into two groups: bile duct resection (BDR) group (n = 15) and hepatic resection (HR) group (n = 8). Systematic review and meta-analysis were performed to compare the R0 resection and long-term survival between BDR and HR for Bismuth type I and II HCCA. A total of 7 studies with 260 cases were included in this meta-analysis. Results: In our cohort, the R0 resection rate was 73.3% in BDR group and 87.5% in HR group. The HR group had a higher number of postoperative complications than the BDR group (P = 0.002). There was no difference in long-term survival (P = 0.544) and recurrence (P = 0.846) between BDR and HR in Bismuth type I and II HCCA. The meta-analysis showed that HR was associated with better R0 resection rate (RR 4.45, 95% CI 2.34–8.48) and overall survival (HR 2.15, 95% CI 1.34–3.44) compared with BDR group. There was no publication bias and undue influence of any single study. Conclusions: The meta-analysis showed that HR was associated with better R0 resection rate and overall survival compared with BDR for type I and II HCCA patients. More aggressive surgical strategies should be increasingly considered for the treatment of type I and II HCCA patients. [ABSTRACT FROM AUTHOR]

Background: In this study, we aimed to study the effect of FTY720 treatment in reducing circulating Tregs level and then suppressing liver tumor metastasis after hepatectomy and I/R injury in animal models. Furthermore, we also investigated the synergistic anti-tumor effect of FTY720 combined with rapamycin on hepatocellular carcinoma. Methods: The effect of FTY720 on suppressing Tregs mobilization and tumor metastasis after hepatectomy was investigated in an orthotopic liver tumor rat model with hepatectomy and hepatic ischemia/reperfusion (I/R) injury. The synergistic anti-tumor effect of FTY720 combined with rapamycin was further explored both in in vitro functional study and in orthotopic liver tumor mouse model. Results: In rat model, hepatic I/R promoted tumor metastasis and increased circulating Tregs after hepatectomy. The treatment of FTY720 reduced liver tumor metastasis and the number of circulating Tregs. Furthermore, FTY720 enhanced the anti-tumor capacity of rapamycin by inhibiting tumor cell proliferation and migration in vitro and reducing tumor growth in vivo through suppressing hepatic stellate cell activation and tumor angiogenesis. Conclusion: FTY720 suppressed liver tumor growth and metastasis by reducing the population of circulating Tregs and enhancing the anti-tumor effect of rapamycin. It was suggested that FTY720 single or combined with rapamycin might provide novel insight for suppressing tumor growth and metastasis for HCC patients. [ABSTRACT FROM AUTHOR]

Acute-phase inflammation plays a critical role in liver graft injury. Inflammasomes, multi-molecular complexes in the cytoplasm, are responsible for initiating inflammation. Here, we aimed to explore the role of inflammasomes in liver graft injury and further to investigate the regulatory mechanism. In a clinical liver transplant cohort, we found that intragraft expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 ( NLRP3) inflammasomes was significantly up-regulated post-transplantation. Importantly, overexpression of NLRP3 was strongly associated with poor liver function characterized by high levels of ALT, AST, and urea, as well as neutrophil infiltration after transplantation. The significant correlation between NLRP3 and IL-1β mRNA levels led us to focus on one of the associated upstream regulators, telomere-independent repressor activator protein 1 ( RAP1), which was further proved to be co-localized with NLRP3 in neutrophils. In the liver of a mouse model (hepatic ischaemia/reperfusion and hepatectomy model) and isolated neutrophils from RAP1−/− mice, the expression levels of NLRP3 and keratinocyte chemoattractant ( KC) were significantly down-regulated in contrast to those in wild types. The levels of ALT and AST, as well as the neutrophil infiltration, were also decreased by RAP1 deficiency. In our clinical validation, intragraft KC expression was associated with NLRP3 and co-localized with RAP1 in neutrophils. Furthermore, NLRP3 inflammasomes were up-regulated by recombinant KC in the isolated neutrophils and liver of the mouse model. Our data demonstrated that NLRP3 inflammasomes, activated by the RAP1/ KC axis, played a critical role in initiating inflammation during the early stage of liver graft injury. Targeting RAP1/ KC/ NLRP3 inflammasomes may offer a new therapeutic strategy against liver graft injury. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

LV, left ventricle; RV, right ventricle gl At the age of 21, the patient had been diagnosed with adult-onset Still's disease (AOSD) because of sustaining fever, generalized body rash and multiple arthralgias for several months, when any other possible etiologies had been ruled out. A remarkably high level of ferritin >2000 ng/mL had lasted for years since the onset of AOSD, which had been regarded as one of criteria for the diagnosis. Although arthralgia and hyperferritinemia are commonly observed in both conditions, hyperpyrexia (in 60%-100% cases of AOSD) and skin rash (60%-80%) as two most frequent clinical manifestations of AOSD have never been reported in JH.[4] Therefore, it is highly suspected that AOSD might coexist with the genetic disorder of JH in this young woman, which to the best of our knowledge, should be the first case report. [Extracted from the article]

Background: Surgical therapies are the first-line treatments for hepatocellular carcinoma (HCC) patients. However, the high incidence of tumor metastasis after liver surgery remains a severe problem. We aim to investigate the roles and the underlying mechanism of YQ23, stabilized non-polymeric diaspirin cross-linked tetrameric hemoglobin, in liver tumor metastasis after major hepatectomy and partial hepatic ischemia reperfusion (I/R) injury.Methods: An orthotopic liver tumor model in Buffalo rat was established using the hepatocellular carcinoma cell line McA-RH7777. Major hepatectomy for tumor-bearing lobe and partial hepatic I/R injury were performed at two weeks after orthotopic liver tumor implantation. YQ23 (0.2 g/kg) was administered at 1 hour before ischemia and immediately after reperfusion. Blood samples were collected at day 0, 1, 7, 14, 21 and 28 for detection of circulating endothelial progenitor cells (EPCs) and regulatory T cells (Tregs).Results: Our results showed that YQ23 treatment effectively inhibited intrahepatic and lung metastases together with less tumor angiogenesis at 4 weeks after major hepatectomy and partial hepatic I/R injury. The levels of circulating EPCs and Tregs were significantly decreased in YQ23 treatment group. Furthermore, YQ23 treatment also increased liver tissue oxygenation during hepatic I/R injury. Up-regulation of HO1 and down-regulation of CXCR3, TNF-α and IL6 were detected after YQ23 treatment.Conclusions: YQ23 treatment suppressed liver tumor metastasis after major hepatectomy and partial hepatic I/R injury in a rat liver tumor model through increasing liver oxygen and reducing the populations of circulating EPCs and Tregs. [ABSTRACT FROM AUTHOR]