Search

The corresponding author explained that 10 mice were used in each group whilst performing liver ischemia/reperfusion experiments, but that two liver samples of the Ago-mir-NC group were damaged during embedding or sectioning, and as a result this group only contained 8 samples. Specifically, the Fig 6D Ago-mir-146a panel appeared similar to the Fig 6G Ago-mir-146a panel despite being used to represent different experimental conditions. They provided an updated Fig 6 with the correct Fig 6D Ago-mir-146a image obtained in the original experiment, as well as the individual level data underlying the published results (S1 File). [Extracted from the article]

A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor– associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury invivo and invitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a invivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury invivo and hypoxia/reoxygenation injury invitro by directly suppressing IRAK1 and TRAF6. [ABSTRACT FROM AUTHOR]

Background: Allograft inflammatory factor-1 (AIF-1) plays an important role in immune response and vasculopathy in allografts. The present study investigated activation of AIF-1 in warm and cold ischemia-reperfusion (IR) injury of rat liver, and the potential inhibitory effect of FK506. Methods: We used warm IR injury, orthotopic transplantation, and allograft rejection models in this study. We assessed expression of AIF-1 mRNA and protein, as well as its inducers interferon-γ (IFN-γ) and interleukin-1β (IL-1β). The potential inhibitory effect of FK506 on AIF-1 in a rat macrophage cell line and in these three models was also assessed. Results: AIF-1 mRNA and protein, as well as its inducers IFN-γ and IL-1β, were significantly increased in the warm IR injury, orthotopic transplantation, and allograft rejection models. Real-time RT-PCR and Western blotting showed that pretreatment with low-dose FK506 partially inhibited AIF-1 activation as well as its inducers (IFN-γ and IL-1β) in these three models. Western blotting showed that IFN-γ and IL-1β activated AIF-1 in a macrophage cell line, but pretreatment with FK506 did not inhibit AIF-1 activation in vitro. Hematoxylin and eosin staining showed that edema and necrosis in the liver, as well as alanine aminotransferase (ALT) in serum, of these three groups was reduced after FK506 pretreatment. Conclusion: AIF-1 was activated in warm and cold IR injury, and pretreatment with low-dose FK506 partly inhibited AIF-1 activation and reduced warm and cold IR injury. [ABSTRACT FROM AUTHOR]

Background & Aims: In living-donor liver transplantation (LDLT), “small-for-size graft (SFSG) syndrome” is a complex process resulting primarily from ischemia–reperfusion injury (IRI) and portal hypertension associated with size mismatch between graft and recipient. In the early period of LDLT, molecular events related to subsequent apoptosis, necrosis, proliferation and regeneration appeared in specific protein expression patterns. Methods: We used 2D-PAGE and MALDI-TOF/TOF technology to construct a comparative proteome profile for small-for-size liver grafts (SFSGs) during the early period of LDLT in rats (ischemia 1h, and 2, 6, 24, 48h post-reperfusion); sham-operated liver was the control. Western blotting was used to confirm the proteomics results and immunohistochemistry was carried out to explore the cellular localization of selected proteins. We further performed cluster and bioinformatics analyses of differential proteins. Lastly, we overexpressed Prdx5 in liver grafts using an adenoviral vector to evaluate its protective role. Results: We identified 314 differential protein spots corresponding to 259 different proteins. Cluster analyses revealed six expression patterns, and bioinformatics analyses revealed that each pattern was related to many specific cell processes. We also showed that Prdx5 overexpression could attenuate injury to SFSGs and increase survival in recipients. Conclusions: Taken together, these results reveal an important proteome profile that is functional in SFSGs during early period of LDLT, and provide a strong basis for further research. [Copyright &y& Elsevier]

Abstract: Reperfusion injury causes liver dysfunction after warm or cold ischemia. Emerging data suggest a role of T cells as mediators in this ischemia/reperfusion (I/R) injury. In the T cells, a part of CD4+CD25+FoxP3+ T regulatory cells (Tregs) were reported to facilitate recovery from I/R injury. These Tregs can be induced by TGF-β in vitro. Interestingly, rapamycin was reported to selectively expand these Tregs in vitro. In the present study, addition of rapamycin to cultures containing TGF-β further increased the frequency and absolute number of functional CD4+ Tregs. Using a partial (70%) hepatic warm ischemia model, we investigated the effects of liver function recovery under the treatment of Tregs induced by rapamycin and TGF-β. The treatment of Tregs significantly reduced serum alanine aminotransferase and aspartate aminotransferase compared to I/R control animals at 24 h after reperfusion (P <0.05). They also significantly attenuated the up-regulation of IFN-γ and IL-17 compared to the I/R control animals (P <0.05). In conclusion, Tregs ameliorate the biochemical of hepatic I/R injury by preventing proinflammatory cytokines following a warm I/R insult. These data may pave the way to use Tregs as cell therapy to prevent hepatic I/R injury. [Copyright &y& Elsevier]

Abstract: Background: Inflammatory response plays a pathogenic role in liver ischemia/reperfusion (I/R) injury. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A with anti-inflammatory effects. However, there are few reports on the anti-inflammatory effects of ATRA on liver I/R injury. The purpose of this study was to investigate the effects of ATRA on liver I/R injury and related mechanisms. Methods: A total of 54 male Sprague–Dawley rats were randomly divided into three groups (18 rats each), namely, sham, I/R, and I/R+ATRA groups. ATRA was intraperitoneally administered at a dose of 15mg/kg/d 14d before ischemia surgery. The segmental (70%) hepatic ischemia model was used by clamping the portal vein, hepatic artery, and bile duct of the left and median for 1h. The rats were sacrificed 3, 6, and 24h after reperfusion, and blood and liver tissue samples were obtained. Liver injury was evaluated by biochemical and histopathologic examinations. Myeloperoxidase activity was spectrophotometrically measured. The expression of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6 was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Liver nuclear factor kappa B (NF-κB) was detected by immunohistochemistry. The expression of NF-κB p65 and inhibitor NF-κB-α (IκBα) was determined by Western blot analysis. Results: The serum alanine aminotransferase level, Suzuki scores of hepatic histology, and hepatic myeloperoxidase activity, as indices of hepatic injury, were increased after reperfusion. The increase was attenuated by preadministration with ATRA. Compared with the I/R group, ATRA treatment increased IκBα expression and suppressed NF-κB p65 expression. Subsequently, the levels of tumor necrosis factor-α and interleukin-6 after liver I/R were effectively downregulated. Conclusions: ATRA administration can significantly attenuate I/R injury in rat liver. The protective mechanism is related to its anti-inflammatory function of inhibiting NF-κB activation. [Copyright &y& Elsevier]