Xueyin Shi

Role of mast cell activation in inducing microglial cells to release neurotrophin

The brain‐derived neurotrophic factor (BDNF) plays a critical role in pain hypersensitivity. BDNF is the ligand of P2X4 receptors (P2X4R) in the microglia. The causative factors involving the P2X4R over expression in the microglia remains unclear. Mast cell activation has a close relation with pain hypersensitivity. However, the underlying mechanism between mast cell activation and pain hypersensitivity is unknown. The present study aimed to elucidate the mechanism by which mast cell activation promoted the expression of P2X4R in the microglia. The results of present study showed that mast cell activation markedly promoted the expression of P2X4R and BDNF in microglial cells, which significantly enhanced the release of BDNF from microglial cells upon exposure to adenosine triphosphate. Mast cell‐derived tryptase activated PAR2 that resulted in promoting the expression of P2X4R in microglial cells. Pretreatment with antibodies against tryptase or PAR2, or using tryptase‐deficient HMC‐1 cells or PAR2‐deficient microglial cells abolished the increase in P2X4R expression and BDNF release. Increase in mitogen activated protein kinase phosphorylation was observed in the processes of mast cell‐induced BDNF release and P2X4R expression. We conclude that mast cell activation has the capacity to promote the expression of P2X4R and BDNF in microglial cells.

Hydrogen Sulfide Preconditioning Protects Rat Liver against Ischemia/Reperfusion Injury by Activating Akt-GSK-3β Signaling and Inhibiting Mitochondrial Permeability Transition

Hydrogen sulfide (H2S) is the third most common endogenously produced gaseous signaling molecule, but its impact on hepatic ischemia/reperfusion (I/R) injury, especially on mitochondrial function, remains unclear. In this study, rats were randomized into Sham, I/R, ischemia preconditioning (IPC) or sodium hydrosulfide (NaHS, an H2S donor) preconditioning groups. To establish a model of segmental (70%) warm hepatic ischemia, the hepatic artery, left portal vein and median liver lobes were occluded for 60 min and then unclamped to allow reperfusion. Preconditioning with 12.5, 25 or 50 μmol/kg NaHS prior to the I/R insult significantly increased serum H2S levels, and, similar to IPC, NaHS preconditioning decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the plasma and prevented hepatocytes from undergoing I/R-induced necrosis. Moreover, a sub-toxic dose of NaHS (25 μmol/kg) did not disrupt the systemic hemodynamics but dramatically inhibited mitochondrial permeability transition pore (MPTP) opening and thus prevented mitochondrial-related cell death and apoptosis. Mechanistic studies revealed that NaHS preconditioning markedly increased the expression of phosphorylated protein kinase B (p-Akt), phosphorylated glycogen synthase kinase-3 beta (p-GSK-3β) and B-cell lymphoma-2 (Bcl-2) and decreased the release of mitochondrial cytochrome c and cleaved caspase-3/9 levels. Therefore, NaHS administration prior to hepatic I/R ameliorates mitochondrial and hepatocellular damage through the inhibition of MPTP opening and the activation of Akt-GSK-3β signaling. Furthermore, this study provides experimental evidence for the clinical use of H2S to reduce liver damage after perioperative I/R injury.

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.

Antihypertensive Effects of Olmesartan Compared with Other Angiotensin Receptor Blockers

AbstractObjectives: Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been shown to be effective and well tolerated in hypertensive patients. Olmesartan is the seventh angiotensin receptor blocker licensed by the US Food and Drug Administration. The aim of this meta-analysis was to determine the efficacy and tolerability of olmesartan medoxomil in comparison with other ARBs. Data Sources: Reports of randomized controlled trials (RCTs) of olmesartan versus other ARBs were identified through a systematic search of PubMed (up to July 2010), EMBASE (1980 to July 2010), SinoMed (up to July 2010), and the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 7,2010). Review Methods: Pertinent studies were selected through extensive searches of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and SinoMed. Two of the authors abstracted data from the identified studies independently. Criteria for inclusion in our meta-analyses were randomized clinical trials in which patients were receiving an ARB and outcome data for blood pressure reduction or the incidence of adverse events were available. Quantitative and qualitative analyses of data from all RCTs meeting the criteria were performed. Our meta-analysis was undertaken according to the Quality of Reporting Meta-analyses (QUOROM) statement. Results: Twenty-two studies with data from 4892 patients were considered for analyses. Olmesartan provided greater diastolic blood pressure (DBP) and systolic blood pressure (SBP) reductions compared with losartan (DBP: 95% confidence interval [CI] 0.59, 2.62; SBP: 95% CI 0.46, 5.92). Olmesartan provided greater SBP reductions compared with valsartan (95% CI 0.29, 3.16). Similar blood pressure response rates and incidence of adverse events were found with losartan, valsartan, candesartan, and irbesartan. Conclusion: Olmesartan provides better antihypertensive efficacy than losartan and valsartan and has no association with an increased risk of adverse events in comparison with losartan, valsartan, candesartan, and irbesartan.

Propofol post-conditioning protects against cardiomyocyte apoptosis in hypoxia/reoxygenation injury by suppressing nuclear factor-kappa B translocation via extracellular signal-regulated kinase mitogen-activated protein kinase pathway.

Background and objective Perioperative myocardial ischaemia leads to an exceedingly high mortality. Previous studies have indicated that propofol pre-conditioning could mimic the cardioprotective effects of ischaemic pre-conditioning. The purpose of this study was to determine whether propofol post-conditioning is cardioprotective and to explore the possible molecular mechanism of propofol post-conditioning. Methods Primary cultured neonatal rat cardiomyocytes were exposed to 12 h of hypoxia followed by 4 h of reoxygenation (H/R) and post-conditioned by different concentrations of propofol at the onset of reperfusion with and without a specific inhibitor of extracellular signal-regulated kinases (ERKs). Cell apoptosis and the generation of intracellular reactive oxygen species were measured using FACScalibur flow cytometric analysis. ERK1/2 phosphorylation and nuclear factor-kappa B (NF-κB) translocation were determined by western blot and immunofluorescence, respectively. Results Propofol post-conditioning enhanced cell viability (86.6 ± 6.5 versus 64.1 ± 3.4%) and reduced apoptosis (3.6 ± 0.4 versus 12.5 ± 2.1%) to protect cardiomyocytes against H/R injury. Meanwhile, propofol post-conditioning stimulated expression of phosphor-ERKs. H/R markedly induced p65 NF-κB nuclear translocation in cardiomyocytes, whereas propofol post-conditioning significantly suppressed H/R-primed NF-κB translocation. Moreover, addition of the mitogen-activated protein kinase kinase 1 inhibitor U0126 into cardiomyocytes 30 min before H/R eliminated the cardioprotection of propofol post-conditioning. Conclusion Propofol exerts cardioprotection when administered at the early phase of reperfusion. The effect is mediated through decrease in cardiomyocyte apoptosis and NF-κB nucleus translocation potentially via ERK signalling pathways.

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.

Antihypertensive effects of olmesartan compared with other angiotensin receptor blockers: a meta-analysis.

OBJECTIVES Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) have been shown to be effective and well tolerated in hypertensive patients. Olmesartan is the seventh angiotensin receptor blocker licensed by the US Food and Drug Administration. The aim of this meta-analysis was to determine the efficacy and tolerability of olmesartan medoxomil in comparison with other ARBs. DATA SOURCES Reports of randomized controlled trials (RCTs) of olmesartan versus other ARBs were identified through a systematic search of PubMed (up to July 2010), EMBASE (1980 to July 2010), SinoMed (up to July 2010), and the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 7, 2010). REVIEW METHODS Pertinent studies were selected through extensive searches of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and SinoMed. Two of the authors abstracted data from the identified studies independently. Criteria for inclusion in our meta-analyses were randomized clinical trials in which patients were receiving an ARB and outcome data for blood pressure reduction or the incidence of adverse events were available. Quantitative and qualitative analyses of data from all RCTs meeting the criteria were performed. Our meta-analysis was undertaken according to the Quality of Reporting Meta-analyses (QUOROM) statement. RESULTS Twenty-two studies with data from 4892 patients were considered for analyses. Olmesartan provided greater diastolic blood pressure (DBP) and systolic blood pressure (SBP) reductions compared with losartan (DBP: 95% confidence interval [CI] 0.59, 2.62; SBP: 95% CI 0.46, 5.92). Olmesartan provided greater SBP reductions compared with valsartan (95% CI 0.29, 3.16). Similar blood pressure response rates and incidence of adverse events were found with losartan, valsartan, candesartan, and irbesartan. CONCLUSION Olmesartan provides better antihypertensive efficacy than losartan and valsartan and has no association with an increased risk of adverse events in comparison with losartan, valsartan, candesartan, and irbesartan.