Chan Chen

Protective Effect of RNase on Unilateral Nephrectomy-Induced Postoperative Cognitive Dysfunction in Aged Mice

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially for elderly patients. Administration of RNase has been reported to exhibit neuroprotective effects in acute stroke. However, the potential role of RNase on POCD is unknown. Therefore, we sought to investigate whether RNase treatment could mitigate unilateral nephrectomy induced-cognitive deficit in aged mice. In the present study, twelve-month-old mice were administered RNase or an equal amount of normal saline perioperatively. All mice underwent Morris Water Maze (MWM) training 3 times per day for 7 days to acclimatize them to the water maze before surgical operation, and testing on days 1, 3 and 7 after surgery. We found that perioperative administration of RNase: 1) attenuated unilateral nephrectomy-induced cognitive impairment at day 3 after surgery; 2) reduced the hippocampal cytokines mRNA production and serum cytokines protein production at day 1 and day 7 (for MCP-1) after surgery, and; 3) inhibited hippocampal apoptosis as indicated by cleaved caspase-3 western blot and TUNEL staining at day 1 after surgery. In addition, a trend decrease of total serum RNA levels was detected in the RNase treated group after surgery compared with the untreated group. Further, our protocol of RNase administration had no impact on the arterial blood gas analysis right after surgery, kidney function and mortality rate at the observed days postoperatively. In conclusion, perioperative RNase treatment attenuated unilateral nephrectomy-induced cognitive impairment in aged mice.

Ventilation during cardiopulmonary bypass for prevention of respiratory insufficiency: A meta-analysis of randomized controlled trials

Background: Cardiopulmonary bypass (CPB) is necessary for most cardiac surgery, which may lead to postoperative lung injury. The objective of this paper is to systematically evaluate whether ventilation during CPB would benefit patients undergoing cardiac surgery. Methods: We searched randomized controlled trials (RCTs) through PubMed, Embase, and Cochrane Library from inception to October 2016. Eligible studies compared clinical outcomes of ventilation versus nonventilation during CPB in patients undergoing cardiac surgery. The primary outcome includes oxygenation index (PaO2/FiO2 ratio) or alveolar to arterial oxygen tension difference (AaDO2) immediately after weaning from bypass. The secondary outcomes include postoperative pulmonary complications (PPCs), shunt fraction (Qs/Qt), hospital stay, and AaDO2 4 hours after CPB. Results: Seventeen trials with 1162 patients were included in this meta-analysis. Ventilation during CPB significantly increased post-CPB PaO2/FiO2 ratio (mean difference [MD] = 21.84; 95% confidence interval [CI] = 1.30 to 42.37; P = 0.04; I2 = 75%) and reduced post-CPB AaDO2 (MD = –50.17; 95% CI = –71.36 to –28.99; P <0.00001; I2 = 74%). Qs/Qt immediately after weaning from CPB showed a significant difference between groups (MD = –3.24; 95% CI = –4.48 to –2.01; P <0.00001; I2 = 0%). Incidence of PPCs (odds ratio [OR] = 0.79; 95% CI = 0.42 to 1.48; P = 0.46; I2 = 37%) and hospital stay (MD = 0.09; 95% CI = –23 to 0.41; P = 0.58; I2 = 37%) did not differ significantly between groups. Conclusion: Ventilation during CPB might improve post-CPB oxygenation and gas exchange in patients who underwent cardiac surgery. However, there is no sufficient evidence to show that ventilation during CPB could influence long-term prognosis of these patients. The beneficial effects of ventilation during CPB are requisite to be evaluated in powerful and well-designed RCTs.

Role of Toll-like Receptor 3 in Lung Ischemia-reperfusion Injury

ABSTRACT Lung ischemia-reperfusion injury (LIRI) occurs in various clinical situations, such as transplantation, cardio pulmonary bypass, cardiac arrest, and major trauma, leading to significant morbidity and mortality. Despite researchers having spent years of effort to investigate the pathogenesis of pulmonary ischemic injury, the concrete cellular and molecular mechanisms are still unknown. We hypothesized that toll-like receptor (TLR) 3 signaling may play a vital role in inflammation responses, apoptosis, and pulmonary dysfunction during LIRI. Lung ischemia-reperfusion (I/R) mouse model was established by the occlusion of the left pulmonary hilum of adult male C57BL/6J wild-type (WT) and TLR3 deficient (TLR3−/−) mice for 1 h, followed by reperfusion for 2 h. Blood serum and lung tissues of the mice were collected after lung I/R for subsequent experiments. Compared with WT mice, TLR3−/− mice had better preserved pulmonary function, and significantly attenuated pulmonary cytokines mRNA and protein production after I/R. Pulmonary apoptosis was also inhibited after TLR3 knockout, as indicated by cleaved caspase-3 western blot and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Levels of serum microRNAs (miRNAs), especially miRNA155, were decreased in the TLR3−/− I/R group compared with that of the WT I/R group. In conclusion, these data suggest that TLR3 signaling pathway may be a promising target for the treatment of lung I/R injury.

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery

Objective. Ischemia/reperfusion (I/R) injury is an unavoidable event for patients in cardiac surgery under cardiopulmonary bypass (CPB). This study was designed to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb), a hemoglobin-based oxygen carrier (HBOC), can protect heart against CPB-induced I/R injury or not and to elucidate the underlying mechanism. Methods and Results. A standard dog CPB model with 2-hour cardiac arrest and 2-hour reperfusion was established. The results demonstrated that a low-dose PolyPHb (0.1%, w/v) provided a significant protection on the I/R heart, whereas the high-dose PolyPHb (3%, w/v) did not exhibit cardioprotective effect, as evidenced by the impaired cardiac function, decreased myocardial oxygen utilization, and elevated enzymes release and pathological changes. Further study indicated that exposure of isolated coronary arteries or human umbilical vein endothelial cells (HUVECs) to a high-dose PolyPHb caused impaired endothelium-dependent relaxation, which was companied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, and elevated malonaldehyde (MDA) formation. Consistent with the increased oxidative stress, the NAD(P)H oxidase activity and subunits expression, including gp91phox, p47phox, p67phox, and Nox1, were greatly upregulated. Conclusion. The high-dose PolyPHb fails to protect heart from CPB-induced I/R injury, which was due to overproduction of NAD(P)H oxidase-induced ROS and resultant endothelial dysfunction.

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

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSION 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.

RNase attenuates acute lung injury induced by ischemia–reperfusion in mice

Treatment with ribonuclease (RNase) reportedly protects the heart after myocardial ischemia-reperfusion (I/R), but its potential effect on lung I/R injury (LIRI) is unknown. Thus, we aim to explore whether RNase treatment would relieve LIRI. Thirty-six C57BL/6J adult male wild-type mice were evenly divided into I/R+RNase (I/R+R) group, I/R group, and sham group. Lung I/R was induced by left pulmonary hilum occlusion for 1h and reperfusion for 2h. All mice were treated with RNase or same dosage of normal saline in advance. After I/R, blood and lung tissues were collected for analysis. The results showed that lung injury scores, wet/dry ratio, expressions of inflammatory cytokines, pulmonary apoptosis, and levels of serum extracellular RNA (exRNA), including microRNAs, were markedly elevated after I/R. However, RNase treatment significantly attenuated cytokine production in both lung tissue and serum and also suppressed pulmonary apoptosis as reflected by TUNEL staining and activated caspase-3. In addition, total serum exRNA levels in the I/R+R group had a downward trend versus the I/R group. In conclusion, the increase of circulating exRNA levels contributed to LIRI in adult mice, which could be relieved by injection of RNase during perioperative window. The potential mechanism is the decrease of serum exRNA level and the suppression of pulmonary inflammation and apoptosis.

Comment on: “Effect of High-Intensity Interval Training on Total, Abdominal and Visceral Fat Mass: A Meta-Analysis”

We read with great interest the recent meta-analysis written by Maillard et al. [1] that investigated the effect of highintensity interval training (HIIT) on total, abdominal and visceral fat mass. The authors concluded that HIIT was a time-efficient strategy to decrease fat-mass deposits, including those of abdominal and visceral fat mass. Furthermore, the authors found that HIIT running may be more effective than HIIT cycling. We appreciate the authors’ thorough analysis, however some important limitations of the findings of this review should be noted. First, the authors limited their search to the PubMed and Google Scholar electronic databases. Unfortunately, other large databases such as Web of Science and the Cochrane Library interface for searching CENTRAL (Cochrane Central Register of Controlled Trials) were not explored. Additionally, the information regarding the search strategy was poorly depicted. A combination of only three search terms was used, and the search strategy may have resulted in the potential for selection bias and may have influenced the generalizability of the study findings. Thus, for an elaborate search of the literature, an optimal search strategy is necessary. Second, it is critical to assess the quality of each included trial because this is directly linked to the reliability of the results. In addition, reporting methodological quality helps clinicians determine whether and how the results of clinical trials will affect their clinical practice [2]. As has been reported in a large number of publications, study quality assessment is an essential step in a meta-analysis [3, 4]; however, in this review important detailed information about quality assessment was not provided. Accordingly, it is difficult for readers to determine the reliability of the study findings. Third, to achieve the targeted intensity level, HIIT requires a high degree of motivation; therefore, a significant concern is the safety of HIIT for patients. Although the HIIT modality may be a tolerated and time-efficient strategy for improving patient health, adverse events during training (e.g. fall, ankle sprain, or angina) cannot be ignored. Both safety and efficacy need to be considered to guide clinical judgment and treatment. Maillard et al. [1] should have therefore taken the adverse events of HIIT into account and made it one of the indicators of outcome measures in their review. In conclusion, Maillard et al. [1] analyzed an important issue regarding the effect of HIIT on total, abdominal and visceral fat mass; however, the results of this meta-analysis should be interpreted with caution due to the limitations mentioned above. We believe that our remarks will contribute to a more accurate elaboration of the results presented by Maillard et al. [1].

Treatment with placental growth factor attenuates myocardial ischemia/reperfusion injury

Studies have established that oxidative stress plays an important role in the pathology of myocardial ischemia/reperfusion injury (MIRI). Vascular endothelial growth factor receptor 1 (VEGFR1) activation was reported to reduce oxidative stress and apoptosis. In the present study, we tested the hypothesis that the activation of VEGFR1 by placental growth factor (PlGF) could reduce MIRI by regulating oxidative stress. Mouse hearts and neonatal mouse cardiomyocytes were subjected to ischemia/reperfusion (I/R) and oxygen glucose deprivation (OGD), respectively. PlGF pretreatment markedly ameliorated I/R injury, as demonstrated by reduced infarct size and improved cardiac function. The protection was associated with a reduction of cardiomyocyte apoptosis. Similarly, our in vitro study showed that PlGF treatment improved cell viability and reduced cardiomyocyte apoptosis. Also, activation of VEGFR1 by PlGF suppressed intracellular and mitochondrial reactive oxygen species (ROS) generation. However, VEGFR1 neutralizing monoclonal antibody, which preventing PlGF binding, totally blocked this protective effect. In conclusion, activation of VEGFR1 could protect heart from I/R injury by suppression of oxidative stress and apoptosis.

Effect of intralipid on myocardial injury during valve replacement surgery with concomitant radiofrequency ablation: A randomized controlled trial

Background: This study aimed to evaluate the effect of intralipid postconditioning (ILPC) on myocardial damage in patients undergoing valve replacement surgery with concomitant radiofrequency ablation (RFA) for atrial fibrillation (AF). Methods: Randomized patient and assessor-blind controlled trial conducted in adult patients undergoing valve replacement surgery with concomitant RFA. Sixty-nine patients were randomly assigned to ILPC group (n = 34) or control group (n = 35): ILPC group received an intravenous infusion of 20% intralipid (2 mL/kg) just 10 minutes before aortic cross-unclamping, and control group received an equivalent volume of normal saline. Serum cardiac troponin-T (cTnT) and creatine kinase-MB (CK-MB) was measured before surgery and at 4, 12, 24, 48, and 72 hours after surgery. The primary endpoints were the 72-hour area under the curve (AUC) for cTnT and CK-MB. Results: The total 72-hour AUC of cTnT (P = .33) and CK-MB (P = .52) were comparable between 2 groups. The left ventricle ejection fraction at discharge (P = .011) was higher in the ILPC group than that in the control group, while the AF recurrence did not differ significantly between 2 groups. Conclusions: There was no observed beneficial effect of ILPC on myocardial injury documented by the cardiac biomarkers in patients undergoing valve replacement surgery with concomitant RFA, and the effect of intralipid against myocardial I/R injury is undetectable within the background of massive biomarker release following ablation owing to localized myocardial necrosis. Besides, there are no other published data about the cardioprotective role of intralipid in patients undergoing this procedure and benefits of this protection need further studies to validate.

RNase alleviates neurological dysfunction in mice undergoing cardiac arrest and cardiopulmonary resuscitation

Cardiac arrest (CA) is one of the leading lethal factors. Despite cardiopulmonary resuscitation (CPR) procedure has been consecutively improved and lots of new strategies have been developed, neurological outcome of the patients experienced CPR is still disappointing. Ribonuclease (RNase) has been demonstrated to have neuroprotective effects in acute stroke and postoperative cognitive impairment, possibly through acting against endogenous RNA that released from damaged tissue. However, the role of RNase in post-cardiac arrest cerebral injury is unknown. In the present study, we investigated the role of RNase in neurological outcome of mice undergoing 5 minutes of CA and followed by CPR. RNase or the same dosage of normal saline was administrated. We found that RNase administration could: 1) improve neurologic score on day 1 and day 3 after CA/CPR performance; 2) improve memory and learning ability on day 3 after training in contextual fear-conditioning test; 3) reduce extracellular RNA (exRNA) level in plasma and hippocampus tissue, and hippocampal cytokines mRNA production on day 3 after CA/CPR procedure; 4) attenuate autophagy levels in hippocampus tissue on day 3 after CA/CPR procedure. In conclusion, RNase could improve neurological function by reducing inflammation response and autophagy in mice undergoing CA/CPR.Cardiac arrest (CA) is one of the leading lethal factors. Despite cardiopulmonary resuscitation (CPR) procedure has been consecutively improved and lots of new strategies have been developed, neurological outcome of the patients experienced CPR is still disappointing. Ribonuclease (RNase) has been demonstrated to have neuroprotective effects in acute stroke and postoperative cognitive impairment, possibly through acting against endogenous RNA that released from damaged tissue. However, the role of RNase in post-cardiac arrest cerebral injury is unknown. In the present study, we investigated the role of RNase in neurological outcome of mice undergoing 5 minutes of CA and followed by CPR. RNase or the same dosage of normal saline was administrated. We found that RNase administration could: 1) improve neurologic score on day 1 and day 3 after CA/CPR performance; 2) improve memory and learning ability on day 3 after training in contextual fear-conditioning test; 3) reduce extracellular RNA (exRNA) level in plasma and hippocampus tissue, and hippocampal cytokines mRNA production on day 3 after CA/CPR procedure; 4) attenuate autophagy levels in hippocampus tissue on day 3 after CA/CPR procedure. In conclusion, RNase could improve neurological function by reducing inflammation response and autophagy in mice undergoing CA/CPR.