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This study aims to explore the protective effects of nobiletin against hepatic ischemia–reperfusion (IR) injury after liver transplantation. Kupffer cells (KCs) were activated and co-cultured with different concentration of nobiletin for 24 h in vitro, inflammatory products and activity of TLR4/NF-κB signaling pathway were detected. Sprague–Dawley rats were selected and underwent orthotopic liver transplantation. Donors were injected intravenously with nobiletin (50 mg/kg) or saline solution, once a day for 1 week before the surgery. Recipients were randomly paired and sacrificed at the indicated time points (3, 6, and 24 h after the surgery), the graft liver tissues and blood samples were collected for analysis. Hepatic function, inflammatory mediators, apoptosis of hepatocytes, histological changes, KCs and CD4+ T-lymphocyte infiltration were assessed. Results showed nobiletin dose-dependently suppressed the expression of inflammatory mediators and the activity of TLR4/NF-κB signaling pathway in activated KCs. Furthermore, nobiletin alleviated liver damage induced by IR in vivo, significantly decreased the serum levels of alanine aminotransferase, aspartate transaminase, inflammatory cytokines and alleviated the histopathology changes. Moreover, liver in the nobiletin treated group exhibited less KCs and CD4+ lymphocyte infiltration and lower hepatocyte apoptosis after operation. In addition, activity of TLR4/NF-κB signaling pathway in KCs was also suppressed, consistent with the results in vitro. Collectively, Nobiletin can ameliorate IR injury after liver transplantation and may be a promising new strategy to protect against liver IR injury. [ABSTRACT FROM AUTHOR]

Objective We have evaluated the protective mechanism of tanshinone IIA in ischemia/reperfusion injury (IRI) induced by liver grafts, revealing novel supplementary immunotherapy for liver transplantation. Methods The tanshinone IIA preconditioning group (TP group) was pretreated with tanshinone IIA via intraperitoneal injection for 1 week before receiving orthotopic liver transplantation with hepatic arterial ischemia for 30 min. The sham-operation group (SO group), control graft group (CG group) and IRI group were pretreated with an equivalent volume of normal saline. The IRI group and CG group received orthotopic liver transplantation with or without hepatic arterial ischemia. Rats were sacrificed at each time point, serum was collected for ELISA detection, and Kupffer cells (KCs) were isolated to extract total protein and RNA for western blotting and real-time PCR, respectively. Results The levels of TNF-α and IL-4 in the TP group were significantly lower than those of in the IRI group; meanwhile the IL-10 and TGF-β levels were significantly higher than in the IRI group. The protein and mRNA expression levels of HMGB1 were significantly lower in TP group than in the IRI group at each time point. The TLR-4, Myd88, NLRP3 and p-NF-κb p65 expression levels in the TP groups were significantly lower than those in the IRI group, while the PTEN, PI3K and AKT phosphorylation levels in the TP groups were significantly higher than those in the IRI group. Conclusions Tanshinone IIA attenuates IRI caused by liver grafts via down-regulation of the HMGB1-TLR-4/NF-κb pathway in KCs and activation of PTEN/PI3K/AKT pathway, suggesting a potential role for prevention of liver cell IRI during liver transplantation. [ABSTRACT FROM AUTHOR]