Ribonuclease attenuates hepatic ischemia reperfusion induced cognitive impairment through the inhibition of inflammatory cytokines in aged mice.

Elderly patients undergoing major surgery often develop cognitive dysfunction, and no optimum treatment exists for this postoperative complication. Ribonuclease, the counterpart of ribonucleic acid, has mostly been reported in terms of its use as a potential modality in anticancer therapy, and recent studies have demonstrated that ribonuclease can exert organ-protective effects in several pathological conditions. Our study also demonstrated that ribonuclease protects the liver against ischemia reperfusion injury. Nevertheless, it is unknown whether ribonuclease can attenuate the cognitive dysfunction that is induced by liver ischemia reperfusion. In this study, we aimed to evaluate the effect of ribonuclease on cognitive function after liver ischemia reperfusion. Aged mice underwent sham surgery or 60min of hepatic ischemia reperfusion, vehicle or ribonuclease, which were administered subcutaneously. The primary observation endpoint was the Morris water maze; following 24h, 3days, and 7days of reperfusion, the levels of serum and hippocampus proinflammatory cytokines were measured to reveal the underlying mechanism. A probe test was conducted on day 3 and a reversal probe test was conducted on day 7 after surgery; the results demonstrated a reduction in cognitive function after liver ischemia reperfusion and that ribonuclease treatment attenuated cognitive impairment. The levels of serum and hippocampus proinflammatory cytokines (interleukin-6 and interleukin-1β) and extracellular ribonucleic acid were significantly increased at 24h after reperfusion, but ribonuclease treatment markedly reduced the proinflammatory cytokine increase. The results of the study suggested that hepatic ischemia reperfusion leads to cognitive impairment in aged mice and an increase in inflammatory cytokine expression in both serum and the hippocampus; more importantly, ribonuclease showed protective effects against cognitive impairment through inhibiting the release of inflammatory cytokines.

Ma G ，Chen C ，Jiang H ，Qiu Y ，Li Y ，Li X ，Zhang X ，Liu J ，Zhu T ... -  《-》

A Mouse Model of Hepatic Ischemia-Reperfusion Injury Demonstrates Potentially Reversible Effects on Hippocampal Neurons and Postoperative Cognitive Function.

Wu W ，Wu Y ，Cheng G ，Zhang C ，Wang H ，Li Y ... -  《MEDICAL SCIENCE MONITOR》

Ribonuclease attenuates acute intestinal injury induced by intestinal ischemia reperfusion in mice.

Ribonuclease (RNase) reportedly exerts organ-protective effects in several pathological conditions, including ischemia reperfusion (I/R), but whether it can exhibit protective effect on intestinal I/R injury and potential mechanisms remain unknown. The present study was aimed to evaluate the effects of RNase on intestinal I/R injury and explore the underlying mechanisms. Thirty-two wild-type C57BL/6J adult male mice were evenly divided into a sham group, a sham + RNase group, an I/R group and an I/R + RNase group. Intestinal I/R was produced by clamping the superior mesenteric artery for 1 h followed by reperfusion for 2 h. All mice were treated with 3 doses of RNase or the same dosage of normal saline at different points. It was found that intestinal I/R caused significant intestinal injury and an increase in levels of extracellular RNAs (exRNAs). Treatment with RNase significantly reduced the inflammatory cytokine production, inhibited intestinal apoptosis and down-regulated the expression of toll like receptor 3 in intestinal tissues. In conclusion, increased exRNAs may contribute to intestinal I/R injury in adult mice, and RNase treatment during perioperative window is effective for attenuating intestinal I/R injury.

Zhang XY ，Liang HS ，Hu JJ ，Wan YT ，Zhao J ，Liang GT ，Luo YH ，Liang HX ，Guo XQ ，Li C ，Liu WF ，Liu KX ... -  《-》

Src is Implicated in Hepatic Ischemia Reperfusion-Induced Hippocampus Injury and Long-Term Cognitive Impairment in Young Mice via NMDA Receptor Subunit 2A Activation.

Hepatic ischemia reperfusion (HIR) has been found to induce hippocampus injury and cognitive dysfunction. The N-methyl-d-aspartate (NMDA) receptor subunit 2A (NR2A) is an important factor mediating excitotoxicity and neurons injury, and autophosphorylation of Src can up-regulate tyrosine phosphorylation of NR2A to improve its activity. However, the role of Src and NR2A in HIR-induced hippocampus injury in young mice remains unknown. In this study, we found that serum biomarkers of brain injury (S100β and NSE) increased significantly and reached highest after reperfusion of 3 days which had the same trend with the levels of p-Src and p-NR2A. Interactions between Src and NR2A or PSD95 were increased after HIR. Hippocampal neuron apoptosis was increased, and long-term cognitive impairment was found after reperfusion of 1 month. Inhibition of Src and NR2A with PP2 and NVP-AAM077 respectively not only down-regulated the levels of p-Src and p-NR2A, but also ameliorated hippocampal neurons apoptosis and long-term cognitive impairment after HIR. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ) and interleukin (IL)-6 were increased after reperfusion of 3 days, while PP2 and NVP-AAM077 treatment didn't attenuate the changes. And no difference was found in serum TNF-α, IFN-γ, IL-6 concentrations as well as the levels of Src, p-Src, NR2A, p-NR2A, PSD95 among the four groups after reperfusion of 1 month. In summary, HIR can lead to hippocampus injury and long-term cognitive dysfunction, and Src-PSD95-NR2A pathway plays an important role in the process.

Yu X ，Jia L ，Yin K ，Lv J ，Yu W ，Du H ... -  《-》

Galectin-1 attenuates hepatic ischemia reperfusion injury in mice.

Hepatic ischemia reperfusion injury (IRI) is a primary cause of organ dysfunction occurring during liver resection surgery and transplantation. Galectin-1, an endogenous lectin expressed on lymphoid organs, plays an important role in governing innate and adaptive immunity. This study was designed to determine the therapeutic role of galectin-1 and underlying mechanism in hepatic IRI. Male C57BL/6 mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion with or without treatment with recombinant galectin-1 (rGal-1) or neutralizing anti-IL-10 antibody. Mice were sacrificed at 6 and 24 h following reperfusion. Liver damage related enzymes were determined and cytokines/chemokines were measured by qPCR and ELISA. Administration of rGal-1 significantly attenuated hepatic IRI, including a remarkable reduction in serum ALT/AST levels and an improved liver histology score compared to controls. rGal-1 treatment reduced TUNEL positive apoptotic hepatocytes, attenuated proinflammatory cytokines (TNF-α, IL-6, IL-1β, IL-12, IFN-γ, IL-17) and chemokines (CXCL-1, CXCL-10) levels, but upregulated IL-10 expression, compared with controls. In addition, rGal-1 increased the production of IL-10 in hepatic macrophages in vivo and in vitro. Blockade of IL-10 using neutralizing anti-IL-10 antibody reversed the protection of galectin-1 in hepatic IRI in mice. These data suggest that galectin-1 may attenuate hepatic IRI via an IL-10-dependent mechanism, which is a promising therapeutic target.

Ye Y ，Wang W ，Zhang W ，Peng Y ，Liu Y ，Yu S ，Chen Q ，Geng L ，Zhou L ，Xie H ，Lai M ，Yu J ，Zheng S ... -  《-》