Fisetin mitigates hepatic ischemia-reperfusion injury by regulating GSK3β/AMPK/NLRP3 inflammasome pathway

Background: Hepatic ischemia-reperfusion(I/R) injury(IRI) represents a crucial challenge in liver transplantation. Fisetin has anti-inflammatory, anti-aging and anti-oxidative properties. This study aimed to examine whether fisetin mitigates hepatic IRI and examine its underlying mechanisms. Methods: Sham or warm hepatic I/R operated mice were pretreated with fisetin(5, 10 or 20 mg/kg). Hepatic histological assessments, TUNEL assays and serum aminotransferase measurements were performed. An in vitro hypoxia/reoxygenation(H/R) model using RAW264.7 macrophages pretreated with fisetin(2.5, 5 or 10 μmol/L) was also used. Serum and cell supernatant concentrations of interleukin-1 β(IL-1 β), IL-18 and tumor necrosis factor-α(TNF-α) were determined by enzyme-linked immunosorbent assay(ELISA). Protein levels of p-GSK3 β, p-AMPK and NLR family pyrin domain-containing 3(NLRP3)-associated proteins were detected by Western blotting. Results: Compared with the I/R group, fisetin pretreatment reduced pathological liver damage, serum aminotransferase levels, serum concentrations of IL-1 β, IL-18 and TNF-α in the murine IRI model. Fisetin also reduced the expression of NLRP3 inflammasome-associated proteins(NLRP3, cleaved caspase-1, IL-1 β and IL-18) in I/R-operated liver. The experiments in vitro showed that fisetin decreased the release of IL-1 β, IL-18 and TNF-α, and reduced the expression of NLRP3 inflammasome-associated proteins in H/R-treated RAW264.7 cells. Moreover, fisetin increased the expressions of p-GSK3 β and p-AMPK in both models, indicating that its anti-inflammatory effects were dependent on GSK3 β/AMPK signaling. The antiinflammatory effects of fisetin were partially inhibited by the AMPK specific inhibitor compound C. Conclusions: Fisetin showed protective effects against hepatic IRI, countering inflammatory responses through mediating the GSK3 β/AMPK/NLRP3 inflammasome pathway.

IL-37b suppresses epithelial mesenchymal transition in hepatocellular carcinoma by inhibiting IL-6/STAT3 signaling

Background: Interleukin-37 b(IL-37 b), a vital negative regulator of the innate immune system, has been reported to be a tumor inhibitor in different type of cancers. However, little is known about the relationship between IL-37 b and hepatocellular carcinoma(HCC). The present study aimed to investigate the potential roles of IL-37 b in HCC progression. Methods: Subjects( n = 237) were recruited, and serum IL-37 b was measured using ELISA. The tumorsuppressive capacity and underlying mechanisms of IL-37 b in HCC were investigated in vitro and in vivo. Results: Compared to healthy controls, serum IL-37 b levels were elevated in chronic hepatitis B(CHB) patients but decreased significantly in HBV-HCC patients, especially for those with portal venous tumor thrombus. Low level serum IL-37 b in HBV-HCC patients correlated with high HCC stage and poor overall survival and disease-free survival. In vitro and in vivo, recombinant human IL-37 b inhibited proliferation and metastasis in HCC cells. Furthermore, IL-37 b inhibited epithelial mesenchymal transition in HCC cells in vitro by downregulating IL-6, pSTAT3(Y705), N-cadherin, and vimentin expression and by upregulating E-cadherin expression. These effects were partially reversed by transfection of adenovirus encoding human IL-6. Conclusions: IL-37 b inhibits HCC growth, metastasis and epithelial mesenchymal transition by regulating IL-6/STAT3 signaling. Serum IL-37 b may be a biomarker for HBV-HCC and its staging.

Everolimus in de novo liver transplant recipients: a systematic review

BACKGROUND： Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients.DATA SOURCES： Randomized controlled trials comparing everolimus for de novo liver transplant in Pub Med, the Cochrane Library, and Science Direct published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval（95% CI） for renal function, relative risk（RR） and 95% CI for treated biopsy-proven acute rejection（t BPAR）, graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with Rev Man version 5.10.RESULTS： A total of four randomized controlled trials covering 1119 cases were included. The meta-analyses revealed that compared with standard exposure of calcineurin inhibitors（CNIs）, everolimus combined with reduced CNIs improved creatinine clearance（calculated with the Cockcroft-Gault formula） by 5.13 m L/min at one year（95% CI： 0.42-9.84; P=0.03）, and decreased t BPAR（RR： 0.56; 95% CI： 0.35-0.90; P=0.02）. Everolimus initiation with CNIs elimination improved glomerular filtration rate（GFR, measured with the modification of diet in renal disease formula） of 10.42 m L/min/1.73 m2（95% CI： 3.44-17.41; P〈0.01） one year after treatment, but in-creased t BPAR（RR： 1.71; 95% CI： 1.15-2.53; P〈0.01）. Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant（RR： 0.60; 95% CI： 0.34-1.03; P=0.06）, but was associated with greater risk of adverse events which resulted in drug discontinuation（RR： 1.98; 95% CI： 1.49-2.64; P〈0.01）. CONCLUSIONS： Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of t BPAR one year after liver transplant, but everolimus administered without CNIs increases t BPAR.