Comparison Between the Protective Effect of Isoflurane and Propofol on Myocardium During Coronary Artery Bypass Grafting: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Intravenous non-volatile anaesthetics like propofol are commonly used in cardiac surgeries across several countries. Volatile anaesthetics like isoflurane may help in protecting the myocardium and minimize ischaemia-reperfusion injury. Hence, we did this review to compare the cardioprotective effect of isoflurane and propofol among patients undergoing coronary artery bypass grafting (CABG). METHODS: We conducted a search in the databases Medical Literature Analysis and Retrieval System Online (or MEDLINE), Embase, PubMed Central®, ScienceDirect, Google Scholar, and Cochrane Library from inception until April 2021. We carried out a meta-analysis with random-effects model and reported pooled risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI) depending on the type of outcome. RESULTS: We analysed 13 studies including 808 participants. Almost all were low-quality studies. For cardiac index, the pooled SMD was 0.14 (95% CI: -0.22 to 0.50); for cardiac troponin I, pooled SMD was 0.10 (95% CI: -0.28 to 0.48). For mortality, the RR was 3.00 (95% CI: 0.32 to 28.43); for MI, pooled RR was 1.58 (95% CI: 0.59 to 4.20); and for inotropic drug use, pooled RR was 1.04 (95% CI: 0.90 to 1.21). For length of intensive care unit stay, the pooled SMD was 0.13 (95% CI: -0.29 to 0.55), while pooled SMD for mechanical ventilation time was -0.02 (95% CI: -0.54 to 0.51). CONCLUSION: Isoflurane did not have significant cardioprotective effect compared to propofol following CABG. Hence, the anaesthetists need to check some viable alternatives to manage these patients and reduce the rate of postoperative complications.

Recent advances in the exploration and discovery of SARS-CoV-2 inhibitory peptides from edible animal proteins.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19), is spreading worldwide. Although the COVID-19 epidemic has passed its peak of transmission, the harm it has caused deserves our attention. Scientists are striving to develop medications that can effectively treat COVID-19 symptoms without causing any adverse reactions. SARS-CoV-2 inhibitory peptides derived from animal proteins have a wide range of functional activities in addition to safety. Identifying animal protein sources is crucial to obtaining SARS-CoV-2 inhibitory peptides from animal sources. This review aims to reveal the mechanisms of action of these peptides on SARS-CoV-2 and the possibility of animal proteins as a material source of SARS-CoV-2 inhibitory peptides. Also, it introduces the utilization of computer-aided design methods, phage display, and drug delivery strategies in the research on SARS-CoV-2 inhibitor peptides from animal proteins. In order to identify new antiviral peptides and boost their efficiency, we recommend investigating the interaction between SARS-CoV-2 inhibitory peptides from animal protein sources and non-structural proteins (Nsps) using a variety of technologies, including computer-aided drug approaches, phage display techniques, and drug delivery techniques. This article provides useful information for the development of novel anti-COVID-19 drugs.

Syndecan-4 is the key proteoglycan involved in mediating sepsis-associated lung injury.

Vascular endothelial cell dysfunction involving syndecan (SDC) proteoglycans contributes to acute sepsis-associated lung injury (ALI), but the exact SDC isoform involved is unclear. We aimed to clarify which SDCs are involved in ALI. A relevant gene expression dataset (GSE5883) was analysed for differentially expressed genes (DEGs) between lipopolysaccharide (LPS)-treated and control lung endothelial cells and for SDC isoform expression. Bioinformatic analyses to predict DEG function were conducted using R language, Gene Ontology, and the Kyoto Encyclopedia of Genes and Genomes. SDC2 and SDC4 expression profiles were examined under inflammatory conditions in human lung vascular endothelial cell and mouse sepsis-associated ALI models. Transcription factors regulating SDC2/4 were predicted to indirectly assess SDC involvement in septic inflammation. Of the DEGs, 224 and 102 genes were up- and downregulated, respectively. Functional analysis indicated that DEGs were involved in modulating receptor ligand and signalling receptor activator activities, cytokine receptor binding, responses to LPS and molecules of bacterial origin, regulation of cell adhesion, tumour necrosis factor signalling, and other functions. DEGs were also enriched for cytoplasmic ribonucleoprotein granules, transcription regulator complexes, and membrane raft cellular components. SDC4 gene expression was 4.5-fold higher in the LPS group than in the control group, while SDC2 levels were similar in both groups. SDC4 mRNA and protein expression was markedly upregulated in response to inflammatory injury, and SDC4 downregulation severely exacerbated inflammatory responses in both in vivo and in vitro models. Overall, our data demonstrate that SDC4, rather than SDC2, is involved in LPS-induced sepsis-associated ALI.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials.

BACKGROUND: Elevated levels of inflammatory factors are associated with poor prognosis in coronavirus disease-19 (COVID-19). However, mesenchymal stem cells (MSCs) have immunomodulatory functions. Accordingly, this meta-analysis aimed to determine the efficacy and safety of MSC-based therapy in patients with COVID-19 pneumonia. METHODS: Online global databases were used to find relevant studies. Two independent researchers then selected and evaluated the studies for suitability while the Cochrane risk of bias tool determined the quality of all articles and Cochran's Q test and I2 index assessed the degree of heterogeneity in the principal studies. Statistical analysis was performed using Review Manager software, and the effect of each study on the overall estimate was evaluated by sensitivity analysis. RESULTS: Seven studies were included in the meta-analysis, and all MSCs used in the trials were acquired from the umbilical cord. The results of these studies (n = 328) indicated that patients with COVID-19 pneumonia who received MSCs had a 0.58 risk of death compared with controls (95% CI = 0.38, 0.87; P = 0.53; I2 = 0%). In terms of inflammatory biomarkers, MSCs reduced the levels of C-reactive protein (n = 88; MD = - 32.49; 95% CI = - 48.43, - 16.56; P = 0.46; I2 = 0%) and interferon-gamma (n = 44; SMD = - 1.23; 95% CI = - 1.89, - 0.57; P = 0.37; I2 = 0%) in severe COVID-19 patients but had no significant effect on interleukin-6 (n = 185; MD = - 0.75; 95% CI = - 7.76, 6.27; P = 0.57; I2 = 0%). A summary of the data revealed no significant differences in adverse events (n = 287) or serious adverse events (n = 229) between the MSC and control groups. CONCLUSIONS: Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.

Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-Dependent Manner.

Mesenchymal stem cells (MSCs) have been demonstrated to attenuate acute lung injury (ALI). We also found that they can suppress the activation of alveolar macrophages (AMs), which can partly account for their therapeutic effects. MSCs do not inherently own immunosuppressive effects, when co-cultured with inflammatory immune cells, MSCs can be activated by inflammatory cytokines and meanwhile exert immunosuppressive effects. In order to further research, RNA sequencing (RNA-seq) of MSCs cultured before and after co-culturing with activated macrophages was performed. The data suggested a total of 5268 differentially expressed genes (DEGs) along the process. We used the data of 2754 upregulated DEGs to develop a signaling network of genes and the transcription factors targeting them in order to predict the altered functions of MSCs after exposure to inflammatory stimuli. This constructed network revealed some critical target genes and potential roles of MSCs under inflammatory conditions. According to the network, Ptgs2 was assumed to be an important gene participating in the immunosuppressive effects of MSCs. We also identified significant increases in the expression of COX2 protein and the secretion of PGE2 from MSCs. The use of the COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppression of macrophage activation by MSCs in vitro. In addition, a selective antagonist of PGE2 binding receptor (EP4 receptor), GW627368X, also reversed the inhibitory effects of MSCs on AMs and the protective effects in ALI mouse. In summary, the therapeutic effects of MSCs on ALI partly occur through suppressing AM activation via PGE2 binding to EP4 receptor.

Effect of Intraoperative Ventilation Strategies on Postoperative Pulmonary Complications: A Meta-Analysis.

Introduction: The role of intraoperative ventilation strategies in subjects undergoing surgery is still contested. This meta-analysis study was performed to assess the relationship between the low tidal volumes strategy and conventional mechanical ventilation in subjects undergoing surgery. Methods: A systematic literature search up to December 2020 was performed in OVID, Embase, Cochrane Library, PubMed, and Google scholar, and 28 studies including 11,846 subjects undergoing surgery at baseline and reporting a total of 2,638 receiving the low tidal volumes strategy and 3,632 receiving conventional mechanical ventilation, were found recording relationships between low tidal volumes strategy and conventional mechanical ventilation in subjects undergoing surgery. Odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CIs) were calculated between the low tidal volumes strategy vs. conventional mechanical ventilation using dichotomous and continuous methods with a random or fixed-effect model. Results: The low tidal volumes strategy during surgery was significantly related to a lower rate of postoperative pulmonary complications (OR, 0.60; 95% CI, 0.44-0.83, p < 0.001), aspiration pneumonitis (OR, 0.63; 95% CI, 0.46-0.86, p < 0.001), and pleural effusion (OR, 0.72; 95% CI, 0.56-0.92, p < 0.001) compared to conventional mechanical ventilation. However, the low tidal volumes strategy during surgery was not significantly correlated with length of hospital stay (MD, -0.48; 95% CI, -0.99-0.02, p = 0.06), short-term mortality (OR, 0.88; 95% CI, 0.70-1.10, p = 0.25), atelectasis (OR, 0.76; 95% CI, 0.57-1.01, p = 0.06), acute respiratory distress (OR, 1.06; 95% CI, 0.67-1.66, p = 0.81), pneumothorax (OR, 1.37; 95% CI, 0.88-2.15, p = 0.17), pulmonary edema (OR, 0.70; 95% CI, 0.38-1.26, p = 0.23), and pulmonary embolism (OR, 0.65; 95% CI, 0.26-1.60, p = 0.35) compared to conventional mechanical ventilation. Conclusions: The low tidal volumes strategy during surgery may have an independent relationship with lower postoperative pulmonary complications, aspiration pneumonitis, and pleural effusion compared to conventional mechanical ventilation. This relationship encouraged us to recommend the low tidal volumes strategy during surgery to avoid any possible complications.

Efficacy of Perioperative Intercostal Analgesia via a Multimodal Analgesic Regimen for Chronic Post-Thoracotomy Pain During Postoperative Follow-Up: A Big-Data, Intelligence Platform-Based Analysis.

BACKGROUND: Chronic post-thoracotomy pain is still an obstacle for lung-cancer patients even after less invasive surgical procedures. It is unclear whether intercostal analgesia is as useful in the prevention of postoperative chronic pain as it is for acute pain for video-assisted thoracoscopic surgery (VATS). The purpose of this study was to evaluate the efficacy of perioperative intercostal analgesia for chronic pain via a multimodal analgesic regimen for VATS during 6 months of postoperative follow-up. METHODS: We identified 837 cases of VATS from August 2016 to August 2018. Patients were treated by perioperative intercostal analgesia with 0.75% ropivacaine 50 mg through the intercostal catheter every 8 hours until chest tube extubation (INA group) or conventional analgesia with preoperative 0.75% ropivacaine 50 mg at incision once (CON group). Numerical rating scale (NRS) and neuropathic pain were evaluated in 6 months of post-surgery follow-up. Postoperative adverse effects were recorded. RESULTS: In total, there were 419 patients in INA group and 418 patients in CON group. Scores of NRS with motion was lower in INA group at 3 postoperative days (P = 0.032). Occurrence of chronic pain was 28.4% in INA group and 32.8% in CON group at 6 postoperative months, 10.6% of patients experienced increasing pain from 3 to 6 months. Occurrence of considerable neuropathic pain (ID pain score ≥ 2) was 2.1% in INA group and 3.1% in CON group at 6 postoperative months. No differences were found between the two groups. Occurrence of numbness was lower in INA group (6.7% vs 10.5%, P = 0.031), and other pain symptoms did not differ between the groups. The incidence of dizziness, nausea, vomiting and atelectasis was not different between the two groups. CONCLUSION: In a multimodal analgesic regimen of VATS, perioperative intercostal analgesia with 0.75% ropivacaine infusion 50 mg three times in a day does not have an obvious effect on chronic post-thoracotomy pain.

Protective mechanical ventilation with optimal PEEP during RARP improves oxygenation and pulmonary indexes.

BACKGROUND: This trial aimed to evaluate the effects of a protective ventilation strategy on oxygenation/pulmonary indexes in patients undergoing robot-assisted radical prostatectomy (RARP) in the steep Trendelenburg position. METHODS: In phase 1, the most optimal positive end-expiratory pressure (PEEP) was determined in 25 patients at 11 cmH2O. In phase 2, 64 patients were randomized to the traditional ventilation group with tidal volume (VT) of 9 ml/kg of predicted body weight (PBW) and the protective ventilation group with VT of 7 ml/kg of PBW with optimal PEEP and recruitment maneuvers (RMs). The primary endpoint was the intraoperative and postoperative PaO2/FiO2. The secondary endpoints were the PaCO2, SpO2, modified clinical pulmonary infection score (mCPIS), and the rate of complications in the postoperative period. RESULTS: Compared with controls, PaO2/FiO2 in the protective group increased after the second RM (P=0.018), and the difference remained until postoperative day 3 (P=0.043). PaCO2 showed transient accumulation in the protective group after the first RM (T2), but this phenomenon disappeared with time. SpO2 in the protective group was significantly higher during the first three postoperative days. Lung compliance was significantly improved after the second RM in the protective group (P=0.025). The mCPIS was lower in the protective group on postoperative day 3 (0.59 (1.09) vs. 1.46 (1.27), P=0.010). CONCLUSION: A protective ventilation strategy with lower VT combined with optimal PEEP and RMs could improve oxygenation and reduce mCPIS in patients undergoing RARP. TRIAL REGISTRATION: ChiCTR ChiCTR1800015626 . Registered on 12 April 2018.

JNK­IN­8 treatment alleviates lipopolysaccharide­induced acute lung injury via suppression of inflammation and oxidative stress regulated by JNK/NF­κB signaling.

JNK serves critical roles in numerous types of inflammation­ and oxidative stress­induced disease, including acute lung injury (ALI). JNK­IN­8 is the first irreversible JNK inhibitor that has been described. However, whether JNK­IN­8 can prevent lipopolysaccharide (LPS)­induced ALI by inhibiting JNK activation and its downstream signaling is poorly understood. The objective of the present study was to investigate the specific therapeutic effects of JNK­IN­8 on LPS­induced ALI and the molecular mechanisms involved. JNK­IN­8 attenuated myeloperoxidase activity, malondialdehyde and superoxide dismutase content and the lung wet/dry ratio, and improved the survival rate following lethal injection of LPS. Additionally, JNK­IN­8 decreased bronchoalveolar lavage fluid protein levels, lactate dehydrogenase activity, neutrophil infiltration and the number of macrophages (as demonstrated by flow cytometry), as well as the production of TNF­α, IL­6 and IL­1ß (as evaluated via ELISA). In addition, reverse transcription­quantitative PCR and ELISA showed that JNK­IN­8 attenuated LPS­induced inflammatory cytokine production and oxidative stress in primary murine peritoneal macrophages and RAW264.7 cells in vitro. Furthermore, the present study demonstrated that the JNK/NF­κB signaling pathway was involved in the therapeutic effect of JNK­IN­8 against LPS­induced injury both in vivo and in vitro. In conclusion, these findings indicated that JNK­IN­8 had a therapeutic effect on LPS­induced ALI in mice. The mechanism may be associated with inhibition of the JNK/NF­κB signaling pathway. JNK­IN­8 may be a potential therapeutic agent for the treatment of ALI.

Pretreatment with AM1241 Enhances the Analgesic Effect of Intrathecally Administrated Mesenchymal Stem Cells.

Mesenchymal stem cells have cannabinoid (CB) receptors type 1 and type 2 and can alleviate a variety of neuropathic pains, including chronic constriction injury (CCI). A selective CB2 receptor agonist is AM1241. In the present study, it was found that mice with CCI displayed a longer duration of mechanical and thermal analgesia when intrathecally (i.t.) injected with AM1241-treated mesenchymal stem cells, compared to those injected with untreated mesenchymal stem cells or AM1241 alone. Moreover, CCI-induced upregulation of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (p-ERK1/2) was inhibited following i.t. injection of AM1241-treated mesenchymal stem cells and this inhibition was noticeably higher compared to injection with untreated mesenchymal stem cells. The expression of transforming growth factor-ß1 (TGF-ß1) was also analyzed in the dorsal root ganglion (DRGs) and spinal cord of CCI mice. In untreated CCI mice, expression of TGF-ß1 was increased, whereas pretreatment with AM1241-treated mesenchymal stem cells regulated the expression of TGF-ß1 on 10 days and 19 days after surgery. In addition, i.t. injection of exogenous TGF-ß1 slightly alleviated neuropathic pain whilst neutralization of TGF-ß1 potently blocked the effect of AM1241-treated mesenchymal stem cells on thermal hyperalgesia and mechanical allodynia of CCI mice. In an in vitro experiment, AM1241 could enhance the release of TGF-ß1 in the supernatant of BMSCs after lipopolysaccharide (LPS) simulation. Taken together, the findings of the current study show that i.t. administration of AM1241-treated mesenchymal stem cells has a positive effect on analgesia and that TGF-ß1 and p-ERK1/2 may be the molecular signaling pathway involved in this process.

Effect of intraoperative lung-protective mechanical ventilation on pulmonary oxygenation function and postoperative pulmonary complications after laparoscopic radical gastrectomy.

This study aimed to observe the effects of lung-protective ventilation (LPV) on oxygenation index (OI) and postoperative pulmonary complications (PPCs) after laparoscopic radical gastrectomy in middle-aged and elderly patients. A total of 120 patients who were scheduled to undergo laparoscopic radical gastrectomy with an expected time of >3 h were randomly divided into conventional ventilation (CV group) with tidal volume (TV) of 10 mL/kg without positive end-expiratory pressure (PEEP), and lung-protective ventilation (PV group) with 7 mL/kg TV and personal level of PEEP with regular recruitment maneuver every 30 min. Measurements of OI, modified clinical pulmonary infection score (mCPIS), and PPCs were assessed during the perioperative period. Fifty-seven patients in the CV group and 58 in the PV group participated in the data analysis. Patients in the PV group showed better pulmonary dynamic compliance, OI, and peripheral capillary oxygen saturation during and after surgery. The mCPIS was significantly lower in the PV group than in the CV group after surgery. The incidence rate of PPCs was lower in the PV group than in the CV group and the difference was significant in patients whose ventilation time was longer than 6 h in both groups. LPV during laparoscopic radical gastrectomy significantly improved pulmonary oxygenation function and reduced postoperative mCPIS and the incidence of PPCs during the early period after surgery of middle-aged and elderly patients, especially patients whose mechanical ventilation time was longer than 6 h.

The efficacy of pregabalin for the management of acute and chronic postoperative pain in thoracotomy: a meta-analysis with trial sequential analysis of randomized-controlled trials.

PURPOSE: Pregabalin is commonly used as an analgesic for neuropathic pain. But pregabalin as an adjunct to a multimodal analgesic regimen - although standard clinical protocol in some settings - has remained controversial. This meta-analysis was conducted to identify the efficacy of pregabalin for management of postoperative pain in thoracotomy. MATERIALS AND METHODS: Pubmed, Embase, Cochrane, Web of Science, Springer, and Clinical Trial Register database were searched for randomized controlled trials (RCTs) of pregabalin in preventing postoperative pain in thoracotomy. Review Manager 5.3 and STATA 12.0 were selected to conduct the meta-analysis. Trial sequential analysis was used to control random errors and calculate the required information size. RESULTS: Nine RCTs with 684 patients were included in our meta-analysis. Outcomes favoring pregabalin included less pain on a 0-10 scale on 1 day [mean difference (MD): -0.87; 95% CI: -1.55 to -0.19; P=0.01], 3 days (MD: -1.55; 95% CI: -1.93 to -1.18; P<0.00001), 1 month (MD: -1.58; 95% CI: -2.75 to -0.42; P=0.008), 3 months (MD: -1.69; 95% CI: -2.71 to -0.66; P=0.001) postoperatively, and less incidence of neuropathic pain (OR: 0.20; 95% CI: 0.05-0.91; P=0.04), less mean morphine consumption (MD: -5.03; 95% CI: -8.06 to -1.99; P=0.001), but more dizziness (OR: 3.33; 95% CI: 1.36-8.17; P=0.009), more drowsiness (OR: 8.61; 95% CI: 2.23-33.20; P=0.002), and less constipation (OR: 0.23; 95% CI: 0.09-0.59; P=0.002). There was no statistical differences in pain score on 7 days (MD:-0.77; 95% CI: -2.38 to 0.84; P=0.35), nausea (OR: 0.73; 95% CI: 0.42-1.26; P=0.26), and vomiting (OR: 0.83; 95% CI: 0.36-1.90; P=0.65). CONCLUSION: Pregabalin can prevent postoperative pain in thoracotomy and decrease incidence of neuropathic pain and morphine consumption. Pregabalin may be a valuable asset in management of acute and persistent postoperative pain in thoracotomy.

Effect of intraoperative lung-protective mechanical ventilation on pulmonary oxygenation function and postoperative pulmonary complications after laparoscopic radical gastrectomy

This study aimed to observe the effects of lung-protective ventilation (LPV) on oxygenation index (OI) and postoperative pulmonary complications (PPCs) after laparoscopic radical gastrectomy in middle-aged and elderly patients. A total of 120 patients who were scheduled to undergo laparoscopic radical gastrectomy with an expected time of >3 h were randomly divided into conventional ventilation (CV group) with tidal volume (TV) of 10 mL/kg without positive end-expiratory pressure (PEEP), and lung-protective ventilation (PV group) with 7 mL/kg TV and personal level of PEEP with regular recruitment maneuver every 30 min. Measurements of OI, modified clinical pulmonary infection score (mCPIS), and PPCs were assessed during the perioperative period. Fifty-seven patients in the CV group and 58 in the PV group participated in the data analysis. Patients in the PV group showed better pulmonary dynamic compliance, OI, and peripheral capillary oxygen saturation during and after surgery. The mCPIS was significantly lower in the PV group than in the CV group after surgery. The incidence rate of PPCs was lower in the PV group than in the CV group and the difference was significant in patients whose ventilation time was longer than 6 h in both groups. LPV during laparoscopic radical gastrectomy significantly improved pulmonary oxygenation function and reduced postoperative mCPIS and the incidence of PPCs during the early period after surgery of middle-aged and elderly patients, especially patients whose mechanical ventilation time was longer than 6 h.

IL-33 Attenuates Sepsis by Inhibiting IL-17 Receptor Signaling through Upregulation of SOCS3.

BACKGROUND/AIMS: Sepsis is a systemic inflammatory response during infection. There are limited therapeutic options for sepsis patients. Interleukin (IL)-33 has been reported recently with a beneficial effect in mouse sepsis. METHODS: In this study, we initiated a clinical study to measure serum levels of pro-inflammatory cytokines including IL-33 in sepsis patients. Next, we employed cecal ligation and puncture (CLP) to study the role of IL-33 during sepsis. To further dissect the molecular mechanism, we used in vivo knockout models and in vitro knockdown murine embryonic fibroblasts (MEFs) to investigate the cross-talk between IL-33 and IL-17 signaling, and to identify the potential downstream mediators. RESULTS: IL-33 and IL-17 were upregulated in both clinical and experimental sepsis. In CLP, IL-33 (-/-) mice showed higher mortality rate, and IL-33 treatment improved the survival rate. Elevated proinflammatory cytokines in sepsis were related to IL-17 from γδT cells. IL-33 treatment suppressed production of these cytokines by targeting IL-17 signaling both in vivo and in vitro. Finally, IL-33 was shown to inhibit the IL-17 pathway via activating suppressor of cytokine signaling (SOCS)-3. CONCLUSION: Collectively, the results suggest that IL-33 plays a negative regulatory role in sepsis progression by inhibiting IL-17 pathway through activating SOCS3. This finding would inspire a new therapeutic strategy for treating sepsis.

The Role of IL-33 on LPS-Induced Acute Lung Injury in Mice.

The objective of the study is to investigate the role and specific molecular mechanism of interleukin-33 (IL-33) acted on acute lung injury (ALI) induced by lipopolysaccharide (LPS). C57BL/6 mice intratracheally instilled LPS to induce ALI model. The mice were randomly divided into three groups: the sham operation group (Sham), ALI group (ALI), and pretreatment with IL-33 of ALI group (IL-33). By observing the survival rate, inflammatory cytokines in bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) levels in lung tissue, lung histopathological examination, pulmonary capillary leakage, lung wet/dry (W/D) weight ratio, fibrosis levels in lung tissue, and associated pathways changes among the different groups, comparing to explore the role of IL-33 pretreatment on ALI mice and the possible molecular mechanisms. IL-33 pretreatment overall decreased the survival rate of ALI mice. IL-33 aggravated inflammation reaction showing as increasing the release of proinflammatory cytokines TNF-α and IL-6, increasing MPO levels in lung tissue, and aggravating lung pathology injury. In addition, IL-33 pretreatment further destroyed adherens junctions (AJs) by increasing the phosphorylation of VE-cadherin, resulting in the concomitantly pulmonary capillary barrier damage and pulmonary edema. During this process, mitogen-activated protein kinase (MAPK) pathways further activated. However, IL-33 pretreatment had no significant impact on collagen content of lung tissue. Our results indicated that IL-33 aggravated inflammatory reaction and increased microvascular permeability, but had little effect on pulmonary fibrosis, associated with the further activation of MAPK family proteins in the process. To sum up, IL-33 decreased survival rate and aggravated LPS-induced ALI.

Mesoporous Silica Particles as a Multifunctional Delivery System for Pain Relief in Experimental Neuropathy.

The long-term use of potent analgesics is often needed to treat chronic pain. However, it has been greatly hindered by their side effects such as addiction and withdrawal reactions. The study seeks to circumvent these drawbacks by taking advantage of a multifunctional delivery system based on nanoparticles to target on pathological neuroinflammation. A drug delivery system is designed and generated using mesoporous silica nanoparticles (MSNs) that are loaded with Δ9-THC (Δ9-tetrahydrocannabinol, a cannabinoid) and ARA290 (an erythropoietin-derived polypeptide), both of which possess analgesic and anti-inflammatory functions. The actions of such THC-MSN-ARA290 nanocomplexes depend on the enhanced permeability and retention of THC through nanosized carriers, and a redox-sensitive release of conjugated ARA290 peptide into the local inflammatory milieu. The biosafety and anti-inflammatory effects of the nanocomplexes are first evaluated in primary microglia in vitro, and further in a mouse model of chronic constriction injury. It is found that the nanocomplexes attenuate in vitro and in vivo inflammation, and achieve a sustained relief of neuropathic pain in injured animals induced by both thermal hyperalgesia and mechanical allodynia. Thus, a nanoparticle-based carrier system can be useful for the amelioration of chronic neuropathic pain through combinatorial drug delivery.

Up-regulation of immunomodulatory effects of mouse bone-marrow derived mesenchymal stem cells by tetrahydrocannabinol pre-treatment involving cannabinoid receptor CB2.

Chronic pain is commonly and closely correlated with inflammation. Both cannabinoid signaling and mesenchymal stem cells (MSCs) have been demonstrated to reduce inflammatory pain. Although cannabinoid signaling is essential for mesenchymal stem cell survival and differentiation, little is known about its role in modulatory effect of MSCs on inflammation and pain sensitivity. Here we showed that mouse bone-marrow derived MSCs (BM-MSCs) expressed both cannabinoid receptor type 1 and 2 (CB1 and CB2). CB2 expression level in BM-MSCs increased with their maturation. In addition, we found that tetrahydrocannabinol (THC) activated CB2 receptor and ERK signaling, consequently enhancing the modulation of MSCs on inflammation-associated cytokine release from lipopolysaccharides-stimulated microglia. Consistent with in vitro data, THC pretreatment enhanced the immunomodulatory effects of BM-MSC on thermal hyperalgesia and mechanical allodynia in chronic constriction injury model, by decreasing the release of pro-inflammation cytokines. Our study revealed the crucial role of THC in promoting the immunomodulatory effects of MSCs and proposed a new strategy to alleviate pain based on stem cells therapy.

Norcantharidin inhibits Wnt signal pathway via promoter demethylation of WIF-1 in human non-small cell lung cancer.

Wingless-type (Wnt) family of secreted glycoproteins is a group of signal molecules implicated in oncogenesis. Abnormal activation of Wnt signal pathway is associated with a variety of human cancers, including non-small cell lung cancer (NSCLC). Wnt antagonists, such as the secreted frizzled-related protein (SFRP) family, Wnt inhibitory factor-1 (WIF-1) and cerberus, inhibit Wnt signal pathway by directly binding to Wnt molecules. Norcantharidin (NCTD) is known to possess anticancer activity but less nephrotoxicity than cantharidin. In this study, we found that NCTD inhibited cell proliferation, induced apoptosis, arrested cell cycle and suppressed cell invasion/migration in vitro. Additionally, Wnt signal pathway transcription was also suppressed. NCTD treatment blocked cytoplasmic translocation of beta-catenin into the nucleus. Alterations of apoptosis-related proteins, such as Bax, cleaved caspase-3 (pro-apoptotic) and Bcl-2 (anti-apoptotic), had been detected. Furthermore, the expression levels of WIF-1 and SFRP1 were significantly increased in NCTD-treated groups compared with negative control (NC) groups. Abnormal methylation was observed in NC groups, while NCTD treatment promoted WIF-1 demethylation. The present study revealed that NCTD activated WIF-1 via promoter demethylation, inhibiting the canonical Wnt signal pathway in NSCLC, which may present a new therapeutic target in vivo.

Efficacy and safety of remifentanil and sulfentanyl in painless gastroscopic examination: a prospective study.

We aim to assess efficacy and safety of remifentanil or sulfentanyl combined with propofol during painless gastroscopic examination in patients. In this study, 270 patients were randomly divided into 3 groups: propofol was given only in group P; propofol and remifentanil in group PR; propofol and sulfentanyl in group PS during the gastroscopic examination. Efficiency of group P was significantly higher than that of group PR and PS (P<0.01) [corrected]. Efficiency of group PR was lower than that of group PS (P<0.05). Incidence of chest wall rigidity and oxygen desaturation in group PR were higher than group P and PS (P<0.05), whereas there was no difference between groups P and PS (P>0.05). Propofol combined with remifentanil could provide satisfying anesthesia and more respiratory depression, whereas sulfentanyl at equivalent dose combined with propofol could also provide with satisfying anesthesia and less respiratory depression. Combined sufentanyl with propofol would be an effective anesthesia technique in the daytime procedure.

Hydroxyethyl starch 130/0.4 exerts its anti-inflammatory effect in endotoxemic rats by inhibiting the TLR4/NF-kappaB signaling pathway.

Previous studies demonstrated that hydroxyethyl starch (HES) down-regulates the inflammatory response, but the mechanism is controversial. The present study measured the effects of HES130/0.4 on plasma proinflammatory cytokines levels and the Toll-like receptor-4 (TLR4)/nuclear factor-kappa B (NF-kappaB) signaling pathway in lipopolysaccharide (LPS)-treated rats. Endotoxemia was induced in rats by injection of LPS (5 mg/kg, via tail vein) and the rats were infused with different doses of HES130/0.4 (7.5, 15, or 30 ml/kg, via jugular vein). At 2 hr after the injection of LPS, plasma and peripheral monocytes were collected to determine tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta concentrations (enzyme-linked immunosorbent assay), NF-kappaB activities (electrophoretic mobility shift assay), TLR4 mRNA expression (reverse transcription-polymerase chain reaction), and TLR4 protein levels (Western blotting). The infusion of HES130/0.4 in endotoxemic rats, especially 15 ml/kg, significantly reduced the release of plasma TNF-alpha and IL-1beta, which was consistent with the observed inhibitory effects of HES130/0.4 on NF-kappaB activation, TLR4 mRNA expression, and TLR4 protein level in monocytes. Thus, HES130/0.4 evidently exerts its anti-inflammatory effect in endotoxemic rats by inhibiting the TLR4/NF-kappaB signaling pathway, which suggests that HES130/0.4 may useful for treating early Gram-negative sepsis.