Hai-Tao Xu

MicroRNA-466l inhibits antiviral innate immune response by targeting interferon-alpha

Effective recognition of viral infections and subsequent triggering of antiviral innate immune responses are essential for the host antiviral defense, which is tightly regulated by multiple regulators, including microRNAs (miRNAs). A previous study showed that miR-466l upregulates IL-10 expression in macrophages by antagonizing RNA-binding protein tristetraprolin-mediated IL-10 mRNA degradation. However, the ability of miR-466l to regulate antiviral immune responses remains unknown. Here, we found that interferon-alpha (IFN-α) expression was repressed in Sendai virus (SeV)- and vesicular stomatitis virus (VSV)-infected macrophages and in dendritic cells transfected with miR-466l expression. Moreover, multiple IFN-α species can be directly targeted by miR-466l through their 3′ untranslated region (3′UTR). This study has demonstrated that miR-466l could directly target IFN-α expression to inhibit host antiviral innate immune response.

Postreperfusion syndrome during orthotopic liver transplantation: a single-center experience

BACKGROUND Marked hemodynamic alteration, commonly referred to as postreperfusion syndrome (PRS), often occurs after revascularization of the donor organ during orthotopic liver transplantation (OLT) and is associated with poor outcomes. This study aimed to investigate the incidence, predictive factors and clinical outcomes of PRS in Chinese patients following OLT at a liver transplantation center in China. METHODS Over a 5-year period, 330 consecutive patients who had undergone OLT for hepatocellular carcinoma or cirrhosis were included in this retrospective study. PRS was defined as a >30% decrease in the mean arterial pressure compared with that before revascularization for more than 1 minute during the first 5 minutes of graft reperfusion. The patients were divided into 2 groups according to the development of PRS: group 1 (patients with PRS, n=56) and group 2 (patients without PRS, n=274). The demographic characteristics, operative and postoperative courses, and outcomes of the patients were analyzed using SPSS version 18.0. RESULTS Multivariate regression analysis showed that left ventricular diastolic dysfunction determined by echocardiography and prolonged cold ischemia time were the independent risk factors for PRS. More patients in group 1 showed postoperative renal dysfunction than those in group 2 (19.23% vs 8.4%). Moreover, patients in group 1 also had higher intraoperative (7.14% vs 0%) and postoperative mortalities (26.92% vs 12.04%). CONCLUSION Left ventricular diastolic dysfunction and prolonged cold ischemia time contribute to a high incidence of PRS, which is associated with adverse outcomes in Chinese patients following OLT.

Autologous Transplantation of Peripheral Blood-derived Circulating Endothelial Progenitor Cells Attenuates Endotoxin-induced Acute Lung Injury in Rabbits by Direct Endothelial Repair and Indirect Immunomodulation

Background: Studies have demonstrated the role of circulating endothelial progenitor cells (EPCs) in maintaining normal endothelial function and in endothelial repairing. This study was aimed to observe the protective effects of autologous transplantation of circulating EPCs against endotoxin-induced acute lung injury in rabbits and to investigate the underlying mechanisms. Methods: One-hundred-and-fifty rabbits were enrolled. After acute lung injury was induced by endotoxin, autologous circulating EPCs, endothelial cell, or normal saline were transfused intravenously, respectively. PaO2/FiO2 ratios, concentrations of plasma nitric oxide, malonyldialdehyde, and activity of superoxide dismutase were examined. The lung wet-to-dry weight ratios were counted; polymorphonuclear cell ratios and areas of hyaline membrane formation and hemorrhage were measured. The levels of interleukin-1&bgr;, E-selectin, intercellular adhesion molecule-1, interleukin-10, vascular endothelial growth factor protein, and inducible nitric oxide synthase protein were analyzed. Results: PaO2/FiO2 ratios were significantly increased with EPC transfusion. Infiltration of polymorphonuclear cells, lung wet-to-dry weight ratios, and area of hyaline membrane and hemorrhage in lung tissue were significantly decreased after EPC transplantation. Plasma level of nitric oxide and malondialdehyde were significantly inhibited, and the activity of superoxide dismutase was enhanced in the EPC-treated animals. EPC transplantation significantly increased level of interleukin-10 and vascular endothelial growth factor protein and reduced levels of interleukin-1&bgr;, E-selectin, intercellular adhesion molecule-1, and inducible nitric oxide synthase in injury lung tissues. Conclusions: Autologous transplantation of circulating EPCs can partly restore the pulmonary endothelial function and effectively attenuate endotoxin-induced acute lung injury by direct endothelial repair and indirect immunomodulation of antioxidation and antiinflammation.

Inhibition of glycogen synthase kinase 3 ameliorates liver ischemia/reperfusion injury via an energy-dependent mitochondrial mechanism

BACKGROUND & AIMS The mechanisms of glycogen synthase kinase-3 (GSK-3)-mediated cytoprotection during liver ischemia/reperfusion (I/R) remain controversial, particularly in older organs. This study explores the role and potential mechanisms of GSK-3 in young and aging livers. METHODS A rodent partial warm I/R model was used to evaluate the therapeutic potential of GSK-3 modulation during hepatic I/R in young and aging Sprague-Dawley rats. RESULTS GSK-3 inhibition through IPC or SB216763 (SB21) preconditioning protected young rats from I/R-induced liver injury. This protection was absent in old animals but could be restored by glucose infusion prior to the I/R insult. The protection conferred by GSK-3 inhibition depended on mitochondrial metabolism regulation. Indeed, the inhibition of GSK-3 suppressed mitochondrial permeability transition pore (MPTP) opening, triggering mitohormesis in young animals, whereas insufficient fuel suppressed mitochondrial metabolism and inactivated the GSK-3-related protection in old animals. SB21 and glucose reactivated the mitochondrial F0F1-ATPase and subsequent protective cascades in the senescent liver. These effects were antagonized by an ATPase inhibitor and by an MPTP opener. CONCLUSIONS The protection conferred by GSK-3 inhibition during hepatic I/R insult is energy dependent, particularly in senescent livers. These findings demonstrate a key role for GSK-3-related mitochondrial energy homeostasis, which may shed new light on the clinical use of GSK-3 inhibitors to protect liver function in surgical settings, particularly for older patients.

Flurbiprofen, a Cyclooxygenase Inhibitor, Protects Mice from Hepatic Ischemia/Reperfusion Injury by Inhibiting GSK-3β Signaling and Mitochondrial Permeability Transition

Flurbiprofen acts as a nonselective inhibitor for cyclooxygenases (COX-1 and COX-2), but its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. Mice were randomized into sham, I/R and flurbiprofen (Flurb) groups. The hepatic artery and portal vein to the left and median liver lobes were occluded for 90 min and unclamped for reperfusion to establish a model of segmental (70%) warm hepatic ischemia. Pretreatment of animals with flurbiprofen prior to I/R insult significantly decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), and prevented hepatocytes from I/R-induced apoptosis/necrosis. Moreover, flurbiprofen dramatically inhibited mitochondrial permeability transition (MPT) pore opening, and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that flurbiprofen markedly inhibited glycogen synthase kinase (GSK)-3β activity and increased phosphorylation of GSK-3β at Ser9, which, consequently, could modulate the adenine nucleotide translocase (ANT)-cyclophilin D (CyP-D) complex and the susceptibility to MPT induction. Therefore, administration of flurbiprofen prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through inhibition of MPT and inactivation of GSK-3β, and provides experimental evidence for clinical use of flurbiprofen to protect liver function in surgical settings in addition to its conventional use for pain relief.

Propofol attenuates hypoxia-induced apoptosis in alveolar epithelial type II cells through down-regulating hypoxia-inducible factor-1α.

To investigate the protective effect of propofol against hypoxia-induced apoptosis in alveolar epithelial type II (ATII) cells and to explore whether hypoxia-inducible factor-1α (HIF-1α) is involved in this process. Primary cultured rat ATII cells were randomly assigned to one of the following four groups, namely, Group C: treated under normoxia (21% O(2)), Group P(20): treated with propofol (20 μM) under normoxia (21% O(2)), Group H: treated under hypoxia (5% O(2)), and Group P(20)-H: pre-treated with propofol (20 μM) before hypoxia exposure (5% O(2)). Apoptosis in ATII cells was detected by Annexin V-FITC binding using FACScan. Expressions of HIF-1α and Bnip3L mRNA and protein in ATII cells were examined by quantitative real-time polymerase chain reaction and Western blotting analysis, respectively. Hypoxia exposure (Group H) significantly increased HIF-1α protein expression (P<0.01 vs. Group C) and significantly promoted apoptosis in ATII cells (P<0.01 vs. Group C). Expression of Bnip3L, a target gene of HIF-1α, was also significantly increased at both mRNA and protein levels in response to hypoxia (P<0.01 vs. Group C). Pretreatment with propofol (20 μM, Group P(20)-H) significantly decreased HIF-1α protein expression (P<0.01 vs. Group H) and significantly inhibited apoptosis in ATII cells (P<0.01 vs. Group H), accompanied by decreased expression of Bnip3L at both mRNA and protein levels (P<0.01 vs. Group H). Propofol (20 μM) can attenuate hypoxia-induced apoptosis in ATII cells and inhibit HIF-1α-hypoxia responsive element (HRE) axis involving Bnip3L, which may partly mediate the cytoprotective effects of propofol.

Hydroxyethyl starch for cardiovascular surgery: a systematic review of randomized controlled trials

PurposeThe objective of this study was to appraise the safety profiles of HES preparations and to find out which HES preparation was the most acceptable in cardiovascular surgery through a comparison with control solutions.MethodsPertinent randomized controlled trials were selected through a search of Pubmed, Embase, and Cochrane Controlled Trials Register. Quantitative and qualitative analysis was carried out to evaluate blood loss, blood transfusion, renal function, complications, reoperation, and mortality.ResultsA total of 3,234 patients from 52 randomized controlled trials were included. HES preparations versus control solutions in blood loss: HES 130 kD vs. albumin (SMD −0.61, 95% CI −0.82, −0.40), HES 200 kD vs. albumin (SMD −0.01, 95% CI −0.29, 0.28), HES 450 kD vs. albumin (SMD 0.47, 95% CI 0.26, 0.68). When comparing control solutions with HES preparations, 50% (HES 450 kD), 40.9% (HES 200 kD), and 18.2% (HES 130 kD) of the comparisons showed more blood/blood products infusion with HES than with control solutions. A numerically lower mortality rate seemed to be related to HES preparations (2.68 vs 4.23%). No difference was found in terms of complications, renal failure, or reoperation.ConclusionsPerioperative administration of HES preparations is comparatively safe. The data appraising safety profiles of HES preparations are insufficient to make direct comparisons among themselves. As the third generation of HES preparations, HES 130 kD showed a trend toward lower blood loss and transfusion rates and is a suitable choice for cardiovascular surgery.

Salidroside protects rat liver against ischemia/reperfusion injury by regulating the GSK-3β/Nrf2-dependent antioxidant response and mitochondrial permeability transition

Abstract Salidroside (Sal) is a natural antioxidant that elicits cardioprotective and neuroprotective effects in vivo and in vitro; however, its impact on hepatic ischemia/reperfusion (I/R) injury remains unclear. The purpose of this study was to investigate the hepatoprotective effects of salidroside against segmental (70%) warm hepatic I/R injury in rats. Animals were randomized into Sham, Sham+salidroside pretreatment (Sal), Sham+Sal+carboxyatractyloside (CATR), Sham+CATR, I/R, I/R+Sal, I/R+Sal+CATR and I/R+CATR groups. The hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Pretreatment with salidroside (20 mg/kg/day for 7 days, intraperitoneally) significantly decreased serum alanine aminotransferase (sALT) and serum aspartate aminotransferase (sAST) levels after 6 h and 24 h of reperfusion and protected the liver against I/R‐induced injury. However, this protective effect could be reversed by CATR, a mitochondrial permeability transition pore (MPTP) opener (5 mg/kg 30 min before I/R insult, intraperitoneally). Mechanistic studies have revealed that salidroside inhibits glycogen synthase kinase‐3 beta (GSK‐3&bgr;) activity and enhances the NF‐E2‐related factor (Nrf2)‐dependent antioxidant response by activating the Akt signaling pathway, thereby reducing mitochondrial reactive oxygen species generation, increasing MPTP resistance and preventing apoptosis by suppressing cytochrome c release and caspase activation during reperfusion. Therefore, salidroside ameliorates hepatocyte death and apoptosis through activation of the GSK‐3&bgr;/Nrf2‐dependent antioxidant response and subsequent MPTP inhibition. These results provide experimental evidence supporting the clinical use of salidroside for hepatoprotection in surgical settings.

The Vagus Nerve Attenuates Fulminant Hepatitis by Activating the Src Kinase in Kuppfer Cells

The parasympathetic nervous system has been known to modify innate immune responses. In animal models, acetylcholine (Ach) released from the distal ends of nerves has been shown to inhibit inflammatory responses such as endotoxic shock, pancreatitis, intestinal inflammation, etc. However, its role in LPS‐induced fulminant hepatitis remains to be elucidated. Here, we demonstrate that the vagus nerve acts as a suppressor in the liver after challenge with LPS plus D‐gal. The vagus nerve acts through the α7 AchR expressed on the surface of Kupffer cells, inhibiting the production of the proinflammatory cytokines TNF and IL‐6. A mechanism study revealed that the suppressive effect of Ach may occur through the activation of Src kinase and subsequent inhibition of the Myd88 signal pathway. Our study has suggested a suppressive role of vagus nerve in the modulation of liver inflammatory responses, which should be noticed during clinical massive hepatectomy and liver transplantation. The nicotinic anti‐inflammatory pathway may also be a potential target for sepsis after liver transplantation.

Electrical Impedance Tomography-guided PEEP Titration in Patients Undergoing Laparoscopic Abdominal Surgery.

AbstractThe aim of the study is to utilize electrical impedance tomography (EIT) to guide positive end-expiratory pressure (PEEP) and to optimize oxygenation in patients undergoing laparoscopic abdominal surgery.Fifty patients were randomly assigned to the control (C) group and the EIT (E) group (n = 25 each). We set the fraction of inspired oxygen (FiO2) at 0.30. The PEEP was titrated and increased in a 2-cm H2O stepwise manner, from 6 to 14 cm H2O. Hemodynamic variables, respiratory mechanics, EIT images, analysis of blood gas, and regional cerebral oxygen saturation were recorded. The postoperative pulmonary complications within the first 5 days were also observed.We chose 10 cm H2O and 8 cm H2O as the “ideal” PEEP for the C and the E groups, respectively. EIT-guided PEEP titration led to a more dorsal shift of ventilation. The PaO2/FiO2 ratio in the E group was superior to that in the C group in the pneumoperitoneum period, though the difference was not significant (330 ± 10 vs 305.56 ± 4 mm Hg; P = 0.09). The C group patients experienced 8.7% postoperative pulmonary complications versus 5.3% among the E group patients (relative risk 1.27, 95% confidence interval 0.31–5.3, P = 0.75).Electrical impedance tomography represents a new promising technique that could enable anesthesiologists to assess regional ventilation of the lungs and optimize global oxygenation for patients undergoing laparoscopic abdominal surgery.