Pseudomonas guariconensis Necrotizing Fasciitis, United Kingdom.

We describe a case of necrotizing fasciitis in the United Kingdom in which Pseudomonas guariconensis was isolated from multiple blood culture and tissue samples. The organism carried a Verona integron-encoded metallo-ß-lactamase gene and evidence of decreased susceptibility to ß-lactam antimicrobial agents. Clinicians should use caution when treating infection caused by this rare pathogen.

Self-expanding metal stents versus decompression tubes as a bridge to surgery for patients with obstruction caused by colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Using self-expanding metal stents (SEMS) and decompression tubes (DT) as a bridge-to-surgery (BTS) treatment may avoid emergency operations for patients with colorectal cancer-caused obstructions. This study aimed to evaluate the efficacy and safety of the two approaches. METHODS: We systematically retrieved literature from January 1, 2000, to May 30, 2023, from the PubMed, Embase, Web of Science, SinoMed, Wanfang Data, Chinese National Knowledge Infrastructure, and Cochrane Central Register of Clinical Trials databases. Randomized controlled trials (RCTs) or cohort studies of SEMS versus DT as BTS in colorectal cancer obstruction were selected. Risks of bias were assessed for RCTs and cohort studies using the Cochrane Risk of Bias tool version 2 and Risk of Bias in Nonrandomized Studies of Interventions. Certainty of evidence was determined using the Graded Recommendation Assessment. Odds ratio (OR), mean difference (MD), and 95% confidence interval (95% CI) were used to analyze measurement data. RESULTS: We included eight RCTs and eighteen cohort studies involving 2,061 patients (SEMS, 1,044; DT, 1,017). Pooled RCT and cohort data indicated the SEMS group had a significantly higher clinical success rate than the DT group (OR = 1.99, 95% CI 1.04, 3.81, P = 0.04), but no significant difference regarding technical success (OR = 1.29, 95% CI 0.56, 2.96, P = 0.55). SEMS had a shorter postoperative length of hospital stays (MD = - 4.47, 95% CI - 6.26, - 2.69, P < 0.00001), a lower rates of operation-related abdominal pain (OR = 0.16, 95% CI 0.05, 0.50, P = 0.002), intraoperative bleeding (MD = - 37.67, 95% CI - 62.73, - 12.60, P = 0.003), stoma creation (OR = 0.41, 95% CI 0.23, 0.73, P = 0.002) and long-term tumor recurrence rate than DT (OR = 0.47, 95% CI 0.22, 0.99, P = 0.05). CONCLUSION: SEMS and DT are both safe as BTS to avoid emergency surgery for patients with colorectal cancer obstruction. SEMS is preferable because of higher clinical success rates, lower rates of operation-related abdominal pain, intraoperative bleeding, stoma creation, and long-term tumor recurrence, as well as a shorter postoperative length of hospital stays. Trial registration CRD42022365951 .

An evaluation of the clinical efficacy of the application of 28mm cryoballoon for linear ablation of left atrial apex combined with enlarged pulmonary vein vestibule ablation for persistent atrial fibrillation.

OBJECTIVE: to retrospectively investigate the efficacy and safety of the application of 28 mm cryoballoon for pulmonary vein electrical isolation (PVI) combined with top left atrial linear ablation and pulmonary vein vestibular expansion ablation for persistent atrial fibrillation. METHODS: From July 2016 to December 2020, 413 patients diagnosed with persistent atrial fibrillation were evaluated, including 230 (55.7%) in the PVI group (PVI only) and 183 (44.3%) in the PVIPLUS group (PVI plus ablation of the left atrial apex and pulmonary vein vestibule). The safety and efficacy of the two groups were retrospectively analyzed. RESULTS: The AF/AT/AFL-free survival rates at 6, 12, 18, 24 and 30 months after procedure was 86.6%, 72.6%, 70.0%, 61.1% and 56.3% in the PVI group and 94.5%, 87.0%, 84.1%, 75.0% and 67.9% in the PVIPLUS group, respectively. At 30 months after procedure, the AF/AT/AFL-free survival rate was significantly higher in the PVIPLUS group than in the PVI group (P = 0.036; HR:0.63; 95% CI:0.42 to 0.95). CONCLUSION: The application of 28-mm cryoballoon for pulmonary vein electrical isolation combined with linear ablation of the left atrial apex and expanded ablation of the pulmonary vein vestibule improves the outcome of persistent atrial fibrillation.

Efficacy of extended antrum ablation based on substrate mapping plus pulmonary vein isolation in the treatment of atrial fibrillation.

INTRODUCTION AND OBJECTIVES: Pulmonary vein isolation (PVI) technique has become the cornerstone of atrial fibrillation (AF) catheter ablation. The objective of this study was to assess the efficacy and safety of extended antrum ablation based on electrophysiological substrate mapping plus PVI in AF patients who underwent cryoballoon ablation. METHODS: In this observational study, a total of 121 paroxysmal AF patients and 80 persistent AF patients who did not achieve the procedure endpoint after cryoballoon ablation received extra extended antrum ablation (EAA) based on electrophysiological substrate mapping via radiofrequency ablation (EAA group). As a control group (PVI group), among paroxysmal AF and persistent AF patients, we conducted a propensity score-matched cohort, in whom only PVI was completed. RESULTS: The average follow-up time was 15.27±7.34 months. Compared with PVI group, paroxysmal AF patients in the EAA group had a significantly higher rate of AF-free survival (90.1% vs. 80.2%, p=0.027) and AF, atrial flutter, or atrial tachycardia (AFLAT) -free rate survival (89.3% vs. 79.3%, p=0.031). Persistent AF patients in the EAA group also had a significantly higher rate of AF-free survival (90.0% vs. 75.0%, p=0.016) and AFLAT-free survival (88.8% vs. 75.0%, p=0.029) than PVI group. Complication rates did not significantly differ between both groups, in either paroxysmal AF or persistent AF patients. CONCLUSION: Our findings demonstrate that extra extended antrum ablation based on electrophysiological substrate mapping is effective and safe. Moreover, the strategy can improve the outcome of AF cryoablation.

Is bivalirudin an alternative anticoagulant for extracorporeal membrane oxygenation (ECMO) patients? A systematic review and meta-analysis.

BACKGROUND: Anticoagulation is important for extracorporeal membrane oxygenation (ECMO). Heparin is widely used; however, in some cases, it is not suitable for patients. Bivalirudin has been recently proposed for ECMO patients, and there is no evidence regarding its effectiveness and safety. OBJECTIVE: We aimed to systematically review the effectiveness and safety of bivalirudin in ECMO patients. STUDY DESIGN AND METHODS: PubMed, Web of Science, Cochrane Library, and EMBASE were searched to find relevant research on the use of bivalirudin versus heparin for anticoagulation in ECMO patients. Outcomes included in-hospital mortality, ECMO duration, major bleeding events, thrombosis events and circuit intervention events. Types of studies included randomized control trials (RCTs), cohort studies, and case-control studies. Case reports, studies lacking comparison with heparin, and where patients transitioned between heparin and bivalirudin, were excluded. Publication bias was evaluated when the number of included studies was more than ten. Sensitivity analysis was performed to examine the stability of the results. RESULTS: Ten articles were selected, and nine articles were included in the meta-analysis. The results of the meta-analysis showed hospital mortality [OR = 0.65, 95%CI (0.44, 0.95), P = 0.03] and thrombosis events decreased (OR = 0.55, 95%CI [0.37, 0.83], P = 0.004) in bivalirudin group compared with heparin in adult patients. Major bleeding events (OR = 0.66, 95%CI [0.17, 2.55], P = 0.55), ECMO duration (MD = 18.92, 95%CI [-29.33, 67.17], P = 0.44) and circuit intervention events (OR = 1.67, 95%CI [0.54, 5.18], P = 0.37) in the bivalirudin group was not statistically significant compared with the heparin group. CONCLUSION: Bivalirudin may provide survival benefits and reduce thrombosis in adult patients on ECMO compared with heparin. There is no difference in treating major bleeding events between bivalirudin and heparin group. However, because all included studies were retrospective observational studies, the evidence level of this systematic review is low and heterogeneity could not be avoided. More high-quality clinical studies are urgently needed to confirm these benefits.

Pseudomonas laoshanensis sp. nov., isolated from peanut field soil.

A novel Gram-stain-negative, aerobic strain, designated Y22T, was isolated from peanut field soil in Laoshan Mountain in China. Cells of strain Y22T were rod-shaped and motile by a single flagellum. The strain was found to be oxidase- and catalase-positive. 16S rRNA gene sequence based on phylogenetic analysis indicated that strain Y22T belonged to the genus Pseudomonas, and showed the highest 16S rRNA gene sequence similarity of 99.0% to Pseudomonas pelagia JCM 15562T, followed by Pseudomonas salina JCM 19469T (98.4%), Pseudomonas sabulinigri JCM 14963T (97.9%), Pseudomonas bauzanensis CGMCC 1.9095T (97.6%) and Pseudomonas litoralis KCTC23093T (97.5%). The phylogenetic analysis based on multilocus sequence analyses with concatenated 16S rRNA, gyrB, rpoD and rpoB genes indicated that strain Y22T belonged to Pseudomonas pertucinogena lineage. The average nucleotide identity scores between strain Y22T and closely related species were 74.6-82.8%, and the Genome-to-Genome Distance Calculator scores were 16.4-44.9%. The predominant cellular fatty acids of strain Y22T were C18:1ω7c (29.6%), C17:0 cyclo (17.5%) and summed feature 3 (C16:1ω7c and/or C16:1ω6c) (17.4%). The genomic DNA G+C content was 57.9 mol%. On the basis of phenotypic characteristics, phylogenetic analyses and in silico DNA-DNA relatedness, a novel species, Pseudomonas laoshanensis sp. nov. is proposed. The type strain is Y22T (= JCM 32580T = KCTC 62385T = CGMCC 1.16552T).

The effect of forskolin on membrane clock and calcium clock in the hypoxic/reoxygenation of sinoatrial node cells and its mechanism.

BACKGROUND: In this study, we investigated the effect of forskolin (FSK, a selective adenylate cyclase agonist) on the automatic diastolic depolarization of sinus node cells (SNC) with hypoxia/reoxygenation (H/R) injury. METHODS: The SNC of the newborn rat was randomly assigned into the control group, the H/R (H/R injury) group, or the H/R + FSK (H/R injury + FSK treatment) group. Patch-clamp was performed to record the action potential and electrophysiological changes. The cellular distribution of intracellular calcium concentration was analyzed by fluorescence staining. RESULTS: Compared with the control cells, spontaneous pulsation frequency (SPF) and diastolic depolarization rate (DDR) of H/R cells were reduced from 244.3 ± 10.6 times/min and 108.7 ± 7.8 mV/s to 130.5 ± 7.6 times/min and 53.4 ± 6.5 mV/s, respectively. FSK significantly increased SPF and DDR of H/R cells to 208.3 ± 8.3 times/min and 93.2 ± 8.9 mV/s (n = 15, both p < 0.01), respectively. H/R reduced the current densities of If, ICa,T and inward INCX, which were significantly increased by 10 µM FSK treatment (n = 15, p < 0.01). Furthermore, reduced expression of HCN4 and NCX1.1 channel protein were significantly increased by FSK. Inhibitor studies showed that both SQ22536 (a selective adenylate cyclase inhibitor) and H89 (a selective protein kinases A [PKA] inhibitor) blocked the effects of FSK on SPF and DDR. CONCLUSIONS: H/R causes pacemaker dysfunction in newborn rat sinoatrial node cells leading to divergence of the DD and the slow of spontaneous APs, which change can be dramatically reversed by FSK through increasing INCX and If current in H/R injury.

Inhibitory Effects of Cyclopiazonic Acid on the Pacemaker Current in Sinoatrial Nodal Cells.

OBJECTIVE: The spontaneous action potential of isolated sinoatrial node (SAN) cells is regulated by a coupled-clock system of two clocks: the calcium clock and membrane clock. However, it remains unclear whether calcium clock inhibitors have a direct effect on the membrane clock. The purpose of this study was to investigate the direct effect of cyclopiazonic acid (CPA), a selective calcium clock inhibitor, on the function of the membrane clock of SAN cells. METHODS: at SAN cells were isolated by trypsinization and identified based on morphology and electrophysiology. If and HCN currents were recorded via patch clamp technique. The expression of the HCN channel protein was determined by Western blotting analysis. RESULTS: The diastolic depolarization rate of spontaneous action potentials and the current densities of If were reduced by exposure to 10 µM CPA. The inhibitory effect of CPA was concentration-dependent with an IC50 value of 16.3 µM and a Hill coefficient of 0.98. The effect of CPA on If current was also time-dependent, and the If current amplitude was partially restored after washout. Furthermore, the steady-state activation curve of the If current was shifted to a negative potential, indicating that channel activation slowed down. Finally, the protein expression of HCN4 in HEK293 cells was markedly downregulated by CPA. CONCLUSIONS: These results indicate that the direct inhibition effect of CPA on the If current in SAN cells is both concentration- and time-dependent. The underlying mechanisms may involve slowing down steady-state activation and the downregulation of pacemaker channel protein expression.

Gut, metabolism and nutritional Support for COVID-19: Experiences from China.

There is little research that focuses on the relationship between the gut, metabolism, nutritional support and COVID-19. As a group of Chinese physicians, nutritionists and scientists working on the frontline treating COVID-19 patients, we aim to integrate our experiences and the current clinical evidence to address this pressing issue in this article. Based on our clinical observations and available evidence, we recommend the following practice. Firstly, the Nutritional Risk Screening 2002 tool should be used routinely and periodically; for patients with a score ≥3, oral nutritional supplements should be given immediately. Secondly, for patients receiving the antiviral agents lopinavir/ritonavir, gastrointestinal side effects should be monitored for and timely intervention provided. Thirdly, for feeding, the enteral route should be the first choice. In patients undergoing mechanical ventilation, establishing a jejunal route as early as possible can guarantee the feeding target being achieved if gastric dilatation occurs. Fourthly, we suggest a permissive underfeeding strategy for severe/critical patients admitted to the intensive care unit during the first week of admission, with the energy target no more than 20 kcal/kg/day (for those on mechanical ventilation, this target may be lowered to 10-15 kcal/kg/day) and the protein target around 1.0-1.2 g/kg/day. If the inflammatory condition is significantly alleviated, the energy target may be gradually increased to 25-30 kcal/kg/day and the protein target to 1.2-1.5 g/kg/day. Fifthly, supplemental parenteral nutrition should be used with caution. Lastly, omega-3 fatty acids may be used as immunoregulators, intravenous administration of omega-3 fatty emulsion (10 g/day) at an early stage may help to reduce the inflammatory reaction.

Change in late sodium current of atrial myocytes in spontaneously hypertensive rats with allocryptopine treatment.

AIM: We aimed to study the effect of allocryptopine (All) on the late sodium current (INa,Late) of atrial myocytes in spontaneously hypertensive rats (SHR). METHODS: The enzyme digestion method was used to separate single atrial myocytes from SHR and Wistar-Kyoto (WKY) rats. INa,Late was recorded using the patch-clamp technique, and the effect of All was evaluated on the current. RESULTS: Compared with WKY rat cells, an increase in the INa,Late current in SHR myocytes was found. After treatment with 30 µM All, the current densities were markedly decreased; the ratio of INa,Late/INa,peak of SHR was reduced by 30 µM All. All reduced INa,Late by alleviating inactivation of the channel and increasing the window current of the sodium channel. Furthermore, INa,Late densities of three SCN5A mutations declined substantially with 30 µM All in a concentration-dependent manner. CONCLUSIONS: The results clearly show that an increase in INa,Late in SHR atrial myocytes was inhibited by All derived from Chinese herbal medicine.

A gene signature associated with prognosis and immune processes in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) has a poor prognosis that has not significantly improved in the past several decades. A prognostic-related signature was needed. METHODS: The Cancer Genome Atlas and GSE41613 databases were downloaded as a training and validation set, respectively. We identified 12 genes that demonstrated progression and prognostic value, and then, a gene signature was constructed. RESULTS: This classification could reflect distinct characteristics, phenotypically and molecularly, among HNSCC tumors. It could stratify patients with significantly different survival rates (median survival: 2083 days vs 927 days; P = 3.85E-08) in the training cohort and validation cohort (P = 0.007) and was significantly involved in immune/inflammatory response and tumor progression processes. CONCLUSIONS: This bioinformatics-based signature suggested the presence of two distinct populations of patients with HNSCC with distinguishable phenotypic characteristics and clinical outcomes and might provide insight for new types of immune therapy.

TGFß1 and HGF regulate CTGF expression in human atrial fibroblasts and are involved in atrial remodelling in patients with rheumatic heart disease.

OBJECTIVE: This study aimed to investigate the effects of transforming growth factor ß1 (TGF ß1) and hepatocyte growth factor (HGF) on the expression of connective tissue growth factor (CTGF) in human atrial fibroblasts, and to explore the relationship of these factors in atrial fibrosis and atrial anatomical remodelling (AAR) of patients with atrial fibrillation (AF). METHODS: Fresh right auricular appendix tissue of 20 patients with rheumatic heart disease undergoing valve replacement surgery was collected during surgeries, 10 patients had sinus rhythm(SR), and 10 patients had chronic atrial fibrillation (CAF). Atrial fibroblasts were then cultured from the tissues with differential attachment technique and treated with either TGFß1 (10 ng/mL) or HGF (100 ng/mL). CTGF mRNA levels were measured by RT-PCR, and CTGF protein content was determined using immunofluorescence and Western blotting assays. RESULTS: CAF group had higher left atrial diameters (LADs) and higher CTGF mRNA expression in atrial fibroblasts compared with SR group. The CTGF protein content in CAF group was higher than that of SR group and positively correlated with LAD and AF duration. After CAF group was treated with TGFß1, CTGF mRNA and protein expression were significantly down-regulated, whereas when treated with HGF, expression was up-regulated compared with SR group. CONCLUSIONS: Increased CTGF expression was associated with enlarged LAD, atrial fibrosis and AAR in patients with AF. TGFß1 and HGF regulate CTGF expression in human atrial fibroblasts with up-regulation of mRNA and down-regulation of protein, therefore, either promote or inhibit atrial fibrosis, which could be related to the incidence and persistence of AF.

Hyperforin improves post-stroke social isolation­induced exaggeration of PSD and PSA via TGF-ß.

Stroke survivors often experience social isolation, which can lead to post­stroke depression (PSD) and post­stroke anxiety (PSA) that can compromise neurogenesis and impede functional recovery following the stroke. The present study aimed to investigate the effects and mechanisms of post­stroke social isolation­mediated PSD and PSA on hippocampal neurogenesis and cognitive function. The effects of the natural antidepressant hyperforin on post­stroke social isolation­mediated PSD and PSA were also investigated. In the present study, a model of PSD and PSA using C57BL/6J male mice was successfully established using middle cerebral artery occlusion combined with post­stroke isolated housing conditions. It was observed that PSD and PSA were more prominent in the isolated mice compared with the pair­housed mice at 14 days post­ischemia (dpi). Mice isolated 3 dpi exhibited decreased transforming growth factor­ß (TGF­ß) levels and impairment of hippocampal neurogenesis and memory function at 14 dpi. Intracerebroventricular administration of recombinant TGF­ß for 7 consecutive days, starting at 7 dpi, restored the reduced hippocampal neurogenesis and memory function induced by social isolation. Furthermore, intranasal administration of hyperforin for 7 consecutive days starting at 7 dpi improved PSD and PSA and promoted hippocampal neurogenesis and memory function in the isolated mice at 14 dpi. The inhibition of TGF­ß with a neutralizing antibody prevented the effects of hyperforin. In conclusion, the results revealed a previously uncharacterized role of hyperforin in improving post­stroke social isolation­induced exaggeration of PSD and PSA and, in turn, promoting hippocampal neurogenesis and cognitive function via TGF­ß.

Calcium-Mediated Oscillation in Membrane Potentials and Atrial-Triggered Activity in Atrial Cells of Casq2R33Q/R33Q Mutation Mice.

Aim: We investigated the underlying mechanisms in atrial fibrillation (AF) associated with R33Q mutation and Ca2+-triggered activity. Methods and Results: We examined AF susceptibility with intraesophageal burst pacing in the sarcoplasmic reticulum (SR) Ca2+ leak model calsequestrin 2 R33Q (Casq2R33Q/R33Q) mice. Atrial trigger appeared in R33Q mice but not WT mice (17.24%, 5/29 vs. 0.00%, 0/32, P < 0.05). AF was induced by 25 Hz pacing in R33Q mice (48.27%, 14/29 vs. 6.25%, 2/32, P < 0.01). The mice were given 1.5 mg/kg isoproterenol (Iso), and the incidences of AF increased (65.51%, 19/29 vs. 9.21%, 3/32, P < 0.01). Electrophysiology experiments and the recording of intracellular Ca2+ indicated significant increases in the Ca2+ sparks (5.24 ± 0.75 100 µM-1.s-1 vs. 0.29 ± 0.04 100 µM-1.s-1, n = 20, P < 0.05), intracellular free Ca2+ (0.238 ± 0.009 µM vs. 0.172 ± 0.006 µM, n = 20, P < 0.05), Ca2+ wave (11.74% vs. 2.24%, n = 20, P < 0.05), transient inward current (ITi) (-0.56 ± 0.02 pA/pF vs. -0.42 ± 0.01 pA/pF, n = 10, P < 0.05), and oscillation in membrane potentials (10.71%, 3/28 vs. 4.16%, 1/24, P < 0.05) in the R33Q group, but there was no significant difference in the L-type calcium current. These effects were enhanced by Iso, and the inhibition of calmodulin-dependent protein kinase II (CaMKII) by 1 µM KN93 reversed the effects of Iso on Ca2+ sparks (5.01 ± 0.66 100 µm-1.s-1 vs. 11.33 ± 1.63 100 µm-1.s-1, P < 0.05), intracellular Ca2+ (0.245 ± 0.005 µM vs. 0.324 ± 0.008 µM, P < 0.05), Ca2+ wave (12.35% vs. 17.83%, P < 0.05), ITi (-0.61 ± 0.02 pA/pF vs. -0.78 ± 0.03 pA/pF, n = 10, P < 0.05), and oscillation in membrane potential (17.85% 5/28 vs. 32.17% 9/28, P < 0.05). The reduction of ryanodine receptor 2 (RyR2) stable subunits (Casq2, triadin, and junctin) rather than RYR2 and the increase in CaMKII, phosphor-CaMKII, phosphor-RyR2 (Ser 2814), SERCA, and NCX1.1 was reflected in the R33Q group. Conclusion: This study demonstrates that the increase in spontaneous calcium elevations corresponding to ITi that may trigger the oscillation in membrane potentials in the R33Q group, thereby increasing the risk of AF. The occurrence of spontaneous calcium elevations in R33Q atrial myocytes is due to the dysfunction of RyR2 stable subunits, CaMKII hyperactivity, and CaMKII-mediated RyR phosphorylation. An effective therapeutic strategy to intervene in Ca2+-induced AF associated with the R33Q mutation may be through CaMKII inhibition.

Multi-objective optimization of asymmetric acoustic transmission with periodical structure.

Asymmetric acoustic wave propagation is important for control and manipulation of the acoustic wave signals in various devices. However, previous approach to find optimal asymmetric acoustic transmission (AAT) is through repeatedly adjusting the geometrical parameters, thus causing time-consuming. Here we propose a study on the multi-objective optimization of the AAT, aiming to achieve the widest working frequency range (fr) and the highest transmittance peak (η) with regard to the design variables. For this purpose, the Radial Basis Function (RBF) neural work and finite element (FE) method are applied to obtain the valuable data in the procedure. Furthermore, local sensitivity analysis of design parameters on the fr and η are analyzed. Ultimately, the Non-Dominated Sorting Genetic Algorithm II (NSGA-II) is adapted for getting the Pareto-optimal solutions. The optimization results show great improvement for the overall performance of the AAT, which could be potentially significant in designing various sound devices.

Soluble interleukin­2 receptor as a factor associated with angiogenesis in gastric cancer.

Angiogenesis serves a role in the growth, metastasis and prognosis of tumors. The aim of the present study was to evaluate the angiogenic ability and clinical significance of the immune biomarker soluble interleukin­2 receptor (sIL­2R) in gastric cancer (GC) patients. Serum levels of sIL­2R were measured in 35 GC patients with different stages of disease and 32 healthy individuals, and it was investigated whether the levels were associated with angiogenesis factors, including vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)­ß1. Human umbilical vein endothelial cells (HUVECs) were pretreated with or without recombinant human (rh)sIL­2R, VEGF and TGF­ß1 for 24 h, and then the HUVECSs were harvested to determine the degree of angiogenesis. The supernatants were also collected for VEGF and TGF­ß1 testing. Serum levels of sIL­2R were higher in GC patients than in healthy individuals, as were the levels of VEGF and TGF­ß1. In addition, serum levels of sIL­2R were positively associated with the levels of VEGF and TGF­ß1. Angiogenesis of HUVECs was also increased by rhsIL­2R pretreatment. VEGF and TGF­ß1 secretion were also incre-ased in supernatants that were pretreated with rhsIL­2R. The results of the present study suggested that serum levels of sIL­2R contributes to the pathophysiology of GC progression and may be used as a prognostic biomarker for GC.

Enriched housing promotes post-stroke functional recovery through astrocytic HMGB1-IL-6-mediated angiogenesis.

Enriched environment (EE) is shown to promote angiogenesis, neurogenesis and functional recovery after ischemic stroke. However, the underlying mechanisms remain unclear. C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion, after which mice were housed in either standard environment (SE) or EE. Here we found that post-ischemic EE exhibited decreased depression and anxiety-like behavior, and promoted angiogenesis and functional recovery compared to SE mice. EE mice treated with high-mobility group box-1 (HMGB1) inhibitor glycyrrhizin had an increased post-stroke depression and anxiety-like behavior, and the angiogenesis and functional recovery were decreased. HMGB1 and interleukin-6 (IL-6) expression in astrocyte were increased in EE mice. EE mice treated with glycyrrhizin decreased, whereas EE mice treated with recombinant HMGB1 (rHMGB1) increased the levels of IL-6 and p-AKT. Blockade of IL-6 with anti-IL-6-neutralizing antibody in EE mice attenuated EE-mediated angiogenesis and functional recovery. Furthermore, our in vitro data revealed that in primary astrocyte cultures rHMGB1 promoted the expression of IL-6 in activated astrocytes. PI3K/AKT signaling pathway was involved in HMGB1-mediated expression of astrocytic IL-6. Thus, our results reveal a previously uncharacterized property of HMGB1/IL-6 signaling pathway in EE-mediated angiogenesis and functional recovery after ischemic stroke.

Proinflammatory effects of S100A8/A9 via TLR4 and RAGE signaling pathways in BV-2 microglial cells.

S100A8/A9, a heterodimer of the two calcium-binding proteins S100A8 and S100A9, has emerged as an important proinflammatory mediator in acute and chronic inflammation. However, whether S100A8/A9 is implicated in microglial­induced neuroinflammatory response remains unclear. Here, we found that S100A8/A9 significantly increased the secretion of proinflammatory cytokines inclu-ding tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in cultured BV-2 microglial cells. Inhibition of the Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) with C225 and a RAGE-blocking antibody, respectively significantly reduced the secretion of TNF-α and IL-6 from S100A8/A9-stimulated BV-2 microglial cells. Furthermore, S100A8/A9 markedly enhanced the nuclear translocation of NF-κB p65 and the DNA-binding activities of NF-κB in BV-2 microglial cells, and suppression of ERK and JNK/MAPK signaling pathways by PD98059 or SP600125 significantly inhibited NF-κB activity and the release of TNF-α and IL-6 in the S100A8/A9-treated BV-2 microglial cells. Our data also showed that inhibition of NF-κB with pyrrolidine dithiocarbamate (PDTC) significantly reduced the secretion of TNF-α and IL-6 from BV-2 microglial cells treated with S100A8/A9. Taken together, our data suggest that S100A8/A9 acts directly on BV-2 microglial cells via binding to TLR4 and RAGE on the membrane and then stimulates the secretion of proinflammatory cytokines through ERK and JNK-mediated NF-κB activity in BV-2 microglial cells. Targeting S100A8/A9 may provide a novel therapeutic strategy in microglial-induced neuroinflammatory diseases.

Delayed Treatment with Green Tea Polyphenol EGCG Promotes Neurogenesis After Ischemic Stroke in Adult Mice.

(-)-Epigallocatechin-3­gallate (EGCG), the predominant constituent of green tea, has been demonstrated to be neuroprotective against acute ischemic stroke. However, the long-term actions of EGCG on neurogenesis and functional recovery after ischemic stroke have not been identified. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 28 days. Neural progenitor cells (NPCs) were isolated from ipsilateral subventricular zone (SVZ) at 14 days post-ischemia (dpi). The effects of EGCG on the proliferation and differentiation of NPCs were examined in vivo and in vitro. Behavioral assessments were made 3 days before MCAO and at 28 dpi. SVZ NPCs were stimulated with lipopolysaccharide (LPS) in vitro to mimic the inflammatory response after ischemic stroke. We found that 14 days treatment with EGCG significantly increased the proliferation of SVZ NPCs and the migration of SVZ neuroblasts, as well as functional recovery, perhaps through M2 phenotype induction in microglia. LPS stimulation promoted the neuronal differentiation in cultured NPCs from the ischemic SVZ. EGCG treatment (20 or 40 µM) further significantly increased the neuronal differentiation of LPS-stimulated SVZ NPCs. After screening for multiple signaling pathways, the AKT signaling pathway was found to be involved in EGCG-mediated proliferation and neuronal differentiation of NPCs in vitro. Taken together, our results reveal a previously uncharacterized role of EGCG in the augment of proliferation and neuronal differentiation of SVZ NPCs and subsequent spontaneous recovery after ischemic stroke. Thus, the beneficial effects of EGCG on neurogenesis and stroke recovery should be considered in developing therapeutic approaches.