Citrus pectin protects mice from burn injury by modulating intestinal microbiota, GLP-1 secretion and immune response.

Water-soluble rhamnogalacturonan-I enriched citrus pectin (WRP) has promising effect on antimicrobial defense. We aim to determine whether the modified acidic (A) or neutral (B) WRP solutions can improve intestinal microbial dysbiosis in burn-injured mice. Male Balb/c mice were gavaged with WRPs at 80, 160, 320 mg/kg. Body weight daily for 21 days before exposed to thermal injury of 15 % total body surface area and mortality was monitored. Mice with 80 mg/kg WRPs were also subjected to fecal DNAs and T cell metabonomics analysis, intestinal and plasma glucagon-like peptide 1 (GLP-1) detection, plasma defensin, immunoglobin and intestinal barrier examinations at 1 and 3d postburn (p.b.). Burn-induced mortality was only improved by low dose WRP-A (P = 0.039). Both WRPs could prevent the dysbiosis of gut microbiota in burn injury by reducing the expansion of inflammation-promoting bacteria. Both WRPs suppressed ileum GLP-1 production at 1d p.b. (P = 0.002) and plasma GLP-1 levels at 3d p.b. (P = 0.013). Plasma GLP-1 level correlated closely with ileum GLP-1 production (P = 0.019) but negatively with microbiota diversity at 1d p.b. (P = 0.003). Intestinal T cell number was increased by both WRPs in jejunum at 3d p.b. However, the exaggerated splenic T cell metabolism in burn injury was reversed by both WRPs at 1d p.b. The burn-increased plasma defensin ß1 level was only reduced by WRP-B. Similarly, the intestinal barrier permeability was only rescued by WRP-B at 1d p.b. WRP-A rather than WRP-B could reduce burn-induced mortality in mice by suppressing intestinal GLP-1 secretion, restoring gut microbiota dysbiosis and improving adaptive immune response.

Distinctive biochemistry profiles associated with hyperuricemia between Tibetans and Hans in China.

Purpose: We sought to identify distinct risk factors for hyperuricemia in native Tibetan and immigrant Han populations in Tibet, China. Methods: Three cohorts of male participants aged between 20 and 40 years were enrolled in this study. Biochemical parameters including serum uric acid (UA), fasting plasma glucose, insulin, lactate dehydrogenase (LDH), thyroxin, blood cell count, aminotransferase, and lipid profiles were analyzed. The association of risk factors with UA levels was evaluated using a multivariable line regression model. The effect of UA level on the biochemical parameters between the Hans and Tibetans was evaluated by two-way ANOVA. Results: The prevalence of hyperuricemia (≥420 µmol/L) was 24.8% (62/250) in the Hans, similar to 23.8% (29/136) in the Tibetans. In the regression analysis, the risk factors that were significantly associated with UA in Hans did not apply to Tibetans. Tibetans had higher fasting insulin (P<0.05) and LDH (P<0.01) levels, in contrast with lower levels of triglycerides (P<0.05), total cholesterol (P<0.01), and low-density lipoprotein-cholesterol (P<0.01) than Hans in normal UA populations. Biochemistry analysis revealed lower albumin levels (P<0.001) and higher levels of all aminotransaminase and especially alkaline phosphatase (P<0.01) in Tibetans than in Hans in both populations. Compared with Hans, Tibetans had lower serum levels of urea, creatinine, and electrolytes in the normal UA population, which were further exacerbated in the high UA population. Tibetans had comparable white blood cell counts as Hans in both normal and high UA populations. In contrast, the red blood cell count and hemoglobin concentration were much lower in Tibetans than in Hans under high UA conditions. Conclusions: The distinctive biochemistry between Tibetans and Hans may underlie the different etiologies of hyperuricemia in Tibet, China.

Differentiated expressed miRNAs in splenic monocyte induced by burn injury in mice.

To find potential biomarkers based on miRNA and their potential targets in splenic monocytes in burn-injured mice. Male Balb/c mice were subjected to sham or scalding injury of 15% total body surface area. Spenic CD11b+ monocytes were purified with magnetic beads. The monocytes were cultured in the presence of lipopolysaccharide. The proliferation of monocytes was detected by MTT assay, and the cytokines in the supernatant were examined by enzyme linked immunosorbent assay. The purified monocytes were also under total RNA extraction. The differential monocytic miRNAs expression between the sham and burn-injured mice was analysed by miRNA microarray. The activity of monocytes was comparable between the two groups (p > 0.05). However, monocytes from burn-injured mice secreted higher levels of tumour necrosis factor (TNF)-α and transforming growth factor-ß, but lower level of monocyte chemoattratctant protein-1. A total of 54 miRNAs were differentially expressed in monocytes from burn relative to sham-injured mice (fold >3). Further quantitative reverse transcription polymerase chain reaction confirmed that the expression of miR-146a was significantly down-regulated, while miR-3091-6p was up-regulated after burn injury. Using the combination of Miranda and TargetScan softwares, we found that mir-146a may regulate 180 potential target genes including TNF receptor related factor 6 (TRAF6), interleukin-1 receptor related kinase 1 (IRAK1) and CD28. Mir-3091-6p may regulate 39 potential targets, including SOCS7 (cytokine signal transduction inhibitor 7) and ARRB2 (arrestin, ß 2). The miRNAs expressed by monocytes after burn injury may be involved in the regulation of innate immune response in burn injury.

Central GLP-1 Resistance Induced by Severe Traumatic Brain Injury Was Associated with Persistent Hyperglycemia in Humans.

INTRODUCTION: Whether central glucagon-like peptide 1 (GLP-1)/GLP-1 receptor system mediated peripheral glucose homeostasis in patients with traumatic brain injury (TBI) is not clear. We aim to determine if plasma GLP-1 level could distinguish the non-survivors from the survivors during the first 14 days after TBI that could prognose 6 months mortality. METHODS: Metabolic, inflammatory, and hematologic profiles were examined in 73 patients with TBI in neurological intensive care unit. Factors that discriminate non-survivors from survivors were determined by two-way ANOVA. Biomarkers associated with mortality were determined by binary logistic regression and Cox proportional hazard regression. RESULTS: The non-survivors had higher infectious SOFA scores (p < 0.001), lower first 3 days' body temperature (p = 0.017), greater chance of cerebral hernia (p = 0.048), and decompressive craniectomy (p = 0.001) than the survivors. Higher 14-day plasma GLP-1 (p < 0.0001), glucose (p = 0.002), and IL-6 (p = 0.005) levels, in contrast with lower insulin level at days 4-7 (p = 0.020) were found in non-survivors than in survivors. Except the survivors who had an increased 14-day platelet number (p < 0.001), the two groups did not differ in hematological profile and intestinal barrier function. Although GLP-1 correlated closely with IL-6 in both the groups, it correlated with neither insulin nor glucose in each group. GLP-1 on days 8-10 and IL-6 on days 1-3 were positively, while insulin on days 4-7 was negatively associated with mortality. CONCLUSION: Persistent higher GLP-1 level in non-survivors over the survivors may present more severe central resistance to endogenous GLP-1 in non-survivors, which may be associated with progressive hyperglycemia with increased mortality in TBI.

Prognostic Significance of Plasma Insulin Level for Deep Venous Thrombosis in Patients with Severe Traumatic Brain Injury in Critical Care.

BACKGROUND: Whether insulin resistance underlies deep venous thrombosis (DVT) development in patients with severe traumatic brain injury (TBI) is unclear. In this study, the association between plasma insulin levels and DVT was analyzed in patients with severe TBI. METHODS: A prospective observational study of 73 patients measured insulin, glucose, glucagon-like peptide 1 (GLP-1), inflammatory factors, and hematological profiles within four preset times during the first 14 days after TBI. Ultrasonic surveillance of DVT was tracked. Two-way analysis of variance was used to determine the factors that discriminated between patients with and without DVT or with and without insulin therapy. Partial correlations of insulin level with all the variables were conducted separately in patients with DVT or patients without DVT. Factors associated with DVT were analyzed by multivariable logistic regression. Neurological outcomes 6 months after TBI were assessed. RESULTS: Among patients with a mean (± standard deviation) age of 53 (± 16 years), DVT developed in 20 patients (27%) on median 10.4 days (range 4-22), with higher Acute Physiology and Chronic Health Evaluation II scores but similar Sequential Organ Failure Assessment scores and TBI severity. Patients with DVT were more likely to receive insulin therapy than patients without DVT (60% vs. 28%; P = 0.012); hence, they had higher 14-day insulin levels. However, insulin levels were comparable between patients with DVT and patients without DVT in the subgroups of patients with insulin therapy (n = 27) and patients without insulin therapy (n = 46). The platelet profile significantly discriminated between patients with and without DVT. Surprisingly, none of the coagulation profiles, blood cell counts, or inflammatory mediators differed between the two groups. Patients with insulin therapy had significantly higher insulin (P = 0.006), glucose (P < 0.001), and GLP-1 (P = 0.01) levels and were more likely to develop DVT (60% vs. 15%; P < 0.001) along with concomitant platelet depletion. Insulin levels correlated with glucose, GLP-1 levels, and platelet count exclusively in patients without DVT. Conversely, in patients with DVT, insulin correlated negatively with GLP-1 levels (P = 0.016). Age (P = 0.01) and elevated insulin levels at days 4-7 (P = 0.04) were independently associated with DVT. Patients with insulin therapy also showed worse Glasgow Outcome Scale scores (P = 0.001). CONCLUSIONS: Elevated insulin levels in the first 14 days after TBI may indicate insulin resistance, which is associated with platelet hyperactivity, and thus increasing the risk of DVT.

Exendin-4 Exacerbates Burn-Induced Mortality in Mice by Switching to Th2 Response.

INTRODUCTION: To determine if Exendin-4 could be a therapeutic agent for burn-induced hyperglycemia. MATERIALS AND METHODS: Male Balb/c mice received a bolus of Exendin-4 intraperitoneally immediately after 15% total body surface area scald injury. Tail glucose levels were recorded and T-cell functions were analyzed at 4 h and 24 h postburn (pb). Pancreatic pathology was observed consecutively. The secretions of cytokines were detected in serum, spleen, and lung. Apoptosis of splenic CD3+ T-cells was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling and flow cytometry. RESULTS: Although Exendin-4 could attenuate burn-induced hyperglycemia in mice at 4 h pb, it accelerated their survival dose dependently with progressive depletion of splenocyte number. T-cell function underwent two-phasic changes following Exendin-4 treatment. Compared to placebo mice, T-cell from Exendin-4-treated mice was manifested with increased proliferation, while decreased IL-2 secretion and lower ratio of IL-4/IFN-γ at 4 h pb. However, at 24 h pb, it showed decreased proliferation, while increased IL-2 secretion and higher ratio of IL-4/IFN-γ. Exendin-4 could elicit higher circulating IL-6 and IL-10 levels at 4 h pb, which were pronounced in the lung at 24 h pb. In the meanwhile, severe inflammation could be found in the pancreas. At 24 h pb, the numbers of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling or caspase-3 positive cells and the apoptosis of CD3+ T-cells were significantly increased in the spleens of Exendin-4 mice relative to placebo mice. CONCLUSIONS: These data support a pathogenic role of Exendin-4 signaling during thermal injury, warning against its clinical application in acute insults.

The management of vascular access in hemodialysis patients during the coronavirus disease 2019 epidemic: A multicenter cross-sectional study.

BACKGROUND: Coronavirus disease 2019 is an epidemic disease throughout the world. The management of vascular access during the epidemic is currently unknown. METHODS: In this multicenter cross-sectional study, we collected vascular access data from hemodialysis patients treated at 44 hospitals in Hubei from 22 January to 10 March 2020. We estimated the management of vascular access during the coronavirus disease 2019 outbreak. RESULTS: Of the 9231 hemodialysis patients included, 5387 patients (58.4%) were men and 2959 patients (32.1%) were older than 65 years. Arteriovenous fistula was the predominant type of vascular access, accounting for 76.5%; 496 patients (5.4%) developed vascular access complications; catheter flow reduction was the most common vascular access complication, and stenosis was the predominant complication among those with arteriovenous access. Overall, 280 vascular access sites were placed in patients newly diagnosed with uremia, of whom 260 (92.8%) underwent catheter insertion; 149 rescue procedures were carried out to treat the vascular access complications, which consisted of 132 catheters, 7 percutaneous transluminal angioplasties, 6 arteriovenous fistula repairs, and 4 arteriovenous fistulas. Occlusion of the arteriovenous access had the highest rescue rate (92.7%), while many other vascular access complications remained untreated; 69 and 142 patients were diagnosed with confirmed and suspected coronavirus disease 2019, respectively. A total of 146 patients died, of whom 29 patients (19.9%) died due to vascular access complications. CONCLUSION: Catheter flow reduction and stenosis of arteriovenous access were the major vascular access complications. Most of the vascular access sites established were catheters, and many of the vascular access complications remained untreated.

Plasma glucagon-like peptide 1 was associated with hospital-acquired infections and long-term mortality in burn patients.

BACKGROUND: Although glucagon-like peptide 1 levels have been closely associated with inflammation and mortality in septic patients, the clinical importance of glucagon-like peptide 1 on hospital-acquired infections and long-term mortality after burn injury remains unexplored. METHODS: Plasma samples from 144 burn patients were collected on admission to determine total glucagon-like peptide 1, interleukin 6, and monocyte chemotactic protein-1 levels. Hospital-acquired infections were determined by positive microbial culture. One-year mortality was assessed by telephone interview. Factors associated with glucagon-like peptide 1 were determined by multivariable linear logistic regression. Predicting the clinical importance of glucagon-like peptide 1 on the development of hospital-acquired infections and mortality were determined by Cox proportional hazards models and further by receiver operating characteristic curve analysis. Kaplan-Meier analyses were performed to examine whether the mean glucagon-like peptide 1 level of the cohort could discriminate the hospital-acquired infections-free survival. RESULTS: Median burn size was 41% (19%-70%) of total body surface area. Hospital-acquired infections developed in 36 (25%) patients after a mean of 10 ± 1 days after injury. Interleukin 6, monocyte chemotactic protein-1, and blood urea nitrogen levels and thrombin time were independently associated with increased glucagon-like peptide 1 levels. Levels of glucagon-like peptide 1 (median, interquartile range) were greater in patients who developed hospital-acquired infections than in those who did not (237 pmol/L, 76-524 vs 80 pmol/L, 51-158; P < .001) and in patients who died (536 pmol/L, interquartile range: 336-891 pmol vs 98 pmol/L, 47-189; P < .001). Although the glucagon-like peptide 1 level could not predict hospital-acquired infections-free survival in individual patients, it could predict 1-year mortality independently (P = .021). Moreover, a glucagon-like peptide 1 level of 200 pmol/L could discriminate hospital-acquired infections-free survival (P < .001). CONCLUSION: Admission glucagon-like peptide 1 level can discriminate hospital-acquired infections-free survival and predict long-term mortality in a group of patients with burn injury. Our data suggests that glucagon-like peptide 1 may be a predictive biomarker for hospital-acquired infections and mortality in burn patients.

Long-lasting neurobehavioral alterations in burn-injured mice resembling post-traumatic stress disorder in humans.

OBJECTIVE: To establish an animal model for posttraumatic stress disorder in burn-injured patients. METHODS: Thermal-injured mice with 15% total body surface area were subjected to a series of neurobehavioral tests at 1 and 3 months postburn. Brains were collected for analysis of key molecules expression, spleens for T cell function analysis, and blood for biochemistry and hormones detection. RESULTS: Comparison with sham mice, burn mice showed extremely high locomotion in homecage, open field, and forced swimming tests, indicating a hyper-arousal state. Burn mice exhibited improved spatial memory in Morris Water Maze test and heightened context fear memory in context fear conditioning, suggesting re-experiencing behavior. Although burn mice showed pronounced passive avoidance in the step-through test, their active avoidance capability in response to the conditional stimulus in the shuttle box test was relatively deteriorated. Likewise, the retention of cue-feared memory was impaired in fear conditioning test. The above negative alterations in mood were recapitulated in open-field test, in which the burn mice displayed an anxiety-like behavior with less time spent in the center. However, no sign of depression was found in the forced swimming and sucrose preference tests. The negative mood of burn mice was reinforced by a deficit in sociality and preference for social novelty in social interaction test. These neurobehavioral alterations were associated with an increased expression of brain-derived neurotrophic factor along with a remarkable microgliosis and a moderate astrocytosis in the brain of burn vs. sham mice. Moreover, a prominent Th2 switch and consequent increased nuclear NF-κB translocation were seen in the splenic T cells from burn relative to sham mice. CONCLUSIONS: We conclude that even mild burn injury could lead to long-lasting cognitive and effective alterations in mice. These findings shed light on the interactions among neuropsychology, neurobiology, and immunology throughout the recovery period of burn injury.

Band gap, sorption properties and fluorescence sensing behaviour of a novel 1D→2D cathenane-like cobalt(II)-organic framework.

A novel hydrolytic stable CoII-organic framework, namely poly[[bis(2-amino-4-sulfonatobenzoato-κO1)tetraaquatris{µ-1,4-bis[(imidazol-1-yl)methyl]benzene-κ2N3:N3'}dicobalt(II)] tetrahydrate], {[Co(C7H5NO5S)(C14H14N4)1.5(H2O)2]·2H2O}n, (1), based on multifunctional 2-amino-5-sulfobenzoic acid (H2asba) and the auxiliary flexible ligand 1,4-bis[(imidazol-1-yl)methyl]benzene (bix), was prepared using the solution evaporation method. The purity of (1) was confirmed by elemental analysis and powder X-ray diffraction (PXRD) analysis. Complex (1) shows a novel 1D→2D interpenetrating network, which is further extended into a 3D supramolecular framework with channels occupied by the lattice water molecules. The 2-amino-4-sulfonatobenzoate (asba2-) ligand adopts a monodentate coordination mode. The bix ligands exhibit gauche-gauche (GG) and trans-trans (TT) conformations. A detailed analysis of the solid-state diffuse-reflectance UV-Vis spectrum reveals that an indirect band gap exists in the complex. The band structure, the total density of states (TDOS) and the partial density of states (PDOS) were calculated using the CASTEP program. The calculated band gap (Eg) matches well with the experimental one. The complex exhibits a reversible dehydration-rehydration behaviour. Interestingly, gas sorption experiments demonstrate that the new fully anhydrous compound obtained by activating complex (1) at 400 K shows selective adsorption of CO2 over N2. Complex (1) retains excellent framework stability in a variety of solvents and manifests distinct solvent-dependent fluorescence properties. Moreover, the complex shows multiresponsive fluorescence sensing for some nitroaromatics in aqueous medium.

Impact of the 21-gene recurrence score assay on chemotherapy decision making and outcomes for breast cancer patients with four or more positive lymph nodes.

BACKGROUND: To assess the impact of the 21-gene recurrence score (RS) on chemotherapy decision making and survival outcomes for breast cancer patients with >4 positive lymph nodes. METHODS: Patients with non-metastatic estrogen receptor-positive breast cancer with >4 positive lymph nodes diagnosed between 2004 and 2013 were identified using the Surveillance, Epidemiology, and End Results database. The relationships between the 21-gene RS value and survival outcomes, chemotherapy decision-making, and chemotherapy benefit were analyzed. RESULTS: A total of 410 patients were identified, including 191 (46.6%), 164 (40.0%), and 55 (13.4%) in the low-, intermediate-, and high-risk RS groups, respectively. The 21-gene RS assay results were independently related to chemotherapy receipt. A total of 59.0%, 68.0%, and 78.0% of patients received chemotherapy in the low-, intermediate-, and high-risk RS groups, respectively. The 21-gene RS was an independent indicator of breast cancer specific survival (BCSS) and overall survival (OS). Intermediate-risk [BCSS: hazards ratio (HR), 2.832, 95% confidence interval (CI): 1.160-6.910, P=0.022; OS: HR, 3.704, 95% CI: 1.750-7.836, P=0.001] and high-risk RS (BCSS: HR, 6.440, 95% CI: 2.597-15.974, P<0.001; OS: HR, 5.053, 95% CI: 2.199-11.608, P<0.001) cohorts had significantly lower survival outcomes compared to low-risk RS cohort. The 5-year BCSS were 92.7%, 88.3%, and 70.7% in patients in the low-, intermediate-, and high-risk RS cohorts, respectively (P<0.001), and the 5-year OS were 92.1%, 80.6%, and 66.6%, respectively (P<0.001). CONCLUSIONS: The 21-gene RS is an independent predictor of chemotherapy receipt and survival outcomes for breast cancer patients with > 4 positive lymph nodes.

Exendin-4 Exacerbates Burn-Induced Morbidity in Mice by Activation of the Sympathetic Nervous System.

BACKGROUND: Although glucagon-like peptide 1- (GLP-1-) based therapy of hyperglycemia in burn injury has shown great potential in clinical trials, its safety is seldom evaluated. We hypothesize that exendin-4, a GLP-1 analogue, might affect the immune response via the activation of the sympathetic nervous system in burn injury. METHODS: Male Balb/c mice were subjected to sham or thermal injury of 15% total body surface area. Exendin-4 on T cell function in vitro was examined in cultured splenocytes in the presence of ß-adrenoceptor antagonist propranolol (1 nmol/L) or GLP-1R antagonist exendin (9-39) (1 µmol/L), whereas its in vivo effect was determined by i.p. injection of exendin-4 (2.4 nmol/kg) in mice. To further elucidate the sympathetic mechanism, propranolol (30 mg/kg) or vehicle was applied 30 min prior to injury. RESULTS: Although the exacerbated burn-induced mortality by exendin-4 was worsened by propranolol pretreatment, the inhibition of T cell proliferation by exendin-4 in vitro could be restored by propranolol instead of exendin (9-39). However, a Th2 switch by exendin-4 in vitro could only be reversed by exendin (9-39). Likewise, the inhibition of splenic T cell function and NFAT activity by exendin-4 in vivo was restored by propranolol. By contrast, the increased splenic NF-κB translocation by exendin-4 in vivo was potentiated by propranolol in sham mice but suppressed in burn mice. Accordingly, propranolol abrogated the heightened inflammatory response in the lung and the accelerated organ injuries by exendin-4 in burn mice. On the contrary, a Th2 switch and higher serum levels of inflammatory mediators by exendin-4 were potentiated by propranolol in burn mice. Lastly, exendin-4 raised serum stress hormones which could be remarkably augmented by propranolol. CONCLUSIONS: Exendin-4 suppresses T cell function and promotes organ inflammation through the activation of the sympathetic nervous system, while elicits Th2 switch via GLP-1R in burn injury.

The Effect of Marital Status on Nasopharyngeal Carcinoma Survival: A Surveillance, Epidemiology and End Results Study.

Purpose: This study examined the role of marital status on survival outcome of nasopharyngeal carcinoma (NPC) patients using a population-based cancer registry. Methods: Patients with primary NPC diagnosed between 2004 and 2013 were included using the Surveillance, Epidemiology and End Results program. Patient demographic, clinicopathologic features, management, and survival outcomes were compared according to marital status. Cause-specific survival (CSS, NPC-related death) for marital status was analyzed. Results: The data of 3018 patients were included, with 61.4%, 11.1%, 21.8, and 5.6% of patients married, divorced (or separated), single, and widowed, respectively. Widowed patients had the highest proportion of elderly age (p < 0.001), were more likely to be female (p < 0.001), and had more well-to-moderately differentiated (p < 0.001) and node-negative disease (p = 0.038). Widowed patients were also less likely to have received radiotherapy and chemotherapy compared with patients of other marital status (p < 0.001). The 5-year CSS was 76.1%, 70.8%, 73.4%, and 59.8% in the married, divorced, single, and widowed groups, respectively (p = 0.001). Marital status was the independent prognostic factor for CSS. Widowed patients had a significantly increased risk of NPC-related death compared with married (hazard ratio [HR] 2.014, 95% confidence interval [CI] 1.477-2.747, p < 0.001), divorced (HR 1.580, 95% CI 1.087-2.295, p = 0.017), and single (HR 2.000, 95% CI 1.402-2.854, p < 0.001) patients. The divorced (p = 0.067) and single (p = 0.949) groups had similar CSS to the married group. Conclusions: Being widowed was associated with an increased the risk of cancer mortality in NPC compared with being married, divorced, or single.

Designable ultra-smooth ultra-thin solid-electrolyte interphases of three alkali metal anodes.

Dendrite growth of alkali metal anodes limited their lifetime for charge/discharge cycling. Here, we report near-perfect anodes of lithium, sodium, and potassium metals achieved by electrochemical polishing, which removes microscopic defects and creates ultra-smooth ultra-thin solid-electrolyte interphase layers at metal surfaces for providing a homogeneous environment. Precise characterizations by AFM force probing with corroborative in-depth XPS profile analysis reveal that the ultra-smooth ultra-thin solid-electrolyte interphase can be designed to have alternating inorganic-rich and organic-rich/mixed multi-layered structure, which offers mechanical property of coupled rigidity and elasticity. The polished metal anodes exhibit significantly enhanced cycling stability, specifically the lithium anodes can cycle for over 200 times at a real current density of 2 mA cm-2 with 100% depth of discharge. Our work illustrates that an ultra-smooth ultra-thin solid-electrolyte interphase may be robust enough to suppress dendrite growth and thus serve as an initial layer for further improved protection of alkali metal anodes.

The effect of lymphadenectomy in advanced ovarian cancer according to residual tumor status: A population-based study.

BACKGROUND: We investigated the effect of lymphadenectomy on the survival outcomes of patients with advanced epithelial ovarian cancer in the Surveillance, Epidemiology, and End Results database according to residual disease status. METHODS: We evaluated 3048 patients with International Federation of Gynecology and Obstetrics stage-IIIC-IV epithelial ovarian cancer. We assessed the effect of lymphadenectomy stratified by residual disease size on cause-specific survival (CSS). RESULTS: A total of 1904 (62.5%) patients received lymphadenectomy, and 1355 (71.2%) patients had nodal metastases. Lymph-node status had no significant association with residual tumor size in the lymphadenectomy group. In multivariate analysis, lymphadenectomy was associated with a significantly better CSS and was an independent prognostic factor for CSS. Patients with >10 lymph nodes removed had better CSS compared with non-lymphadenectomy and 1-10 lymph nodes removed groups. Lymphadenectomy was associated with a significantly better CSS in patients with no gross residual tumor, but not in patients with residual tumor ≤1 cm or >1 cm. CONCLUSIONS: Lymphadenectomy is significantly associated with a better survival outcome in patients advanced ovarian cancer, but its positive effect diminishes as residual tumor size increases.

Proinflammatory switch from Gαs to Gαi signaling by Glucagon-like peptide-1 receptor in murine splenic monocyte following burn injury.

OBJECTIVE: Glucagon-like peptide-1 (GLP-1)-based therapy via G protein-coupled receptor (GPCR) GLP-1R, to attenuate hyperglycemia in critical care has attracted great attention. However, the exaggerated inflammation by GLP-1R agonist, Exendin-4, in a mouse model of burn injury was quite unexpected. Recent studies found that GPCR might elicit proinflammatory effects by switching from Gαs to Gαi signaling in the immune system. Thus, we aimed to investigate the possible Gαs to Gαi switch in GLP-1R signaling in monocyte following burn injury. MATERIALS AND METHODS: Splenic monocytes from sham and burn mice 24 h following burn injury were treated with consecutive doses of Exendin-4 alone or in combination with an inhibitor of Gαi signaling (pertussis toxin, PTX), or a blocker of protein kinase A (H89). Cell viability was assessed by CCK-8, and the supernatant was collected for cytokine measurement by ELISA. Intracellular cAMP level, phosphorylated PKA activity, and nuclear NF-κB p65 were determined by ELISA, ERK1/2 activation was analyzed by Western blot. The expression of GLP-1R downstream molecules, Gαs, Gαi and G-protein coupled receptor kinase 2 (GRK2) were examined by immunofluorescence staining and Western blot. RESULTS: Exendin-4 could inhibit the viability of monocyte from sham rather than burn mice. Unexpectedly, it could also reduce TNF-α secretion from sham monocyte while increase it from burn monocyte. The increased secretion of TNF-α by Exendin-4 from burn monocyte could be reversed by pretreatment of PTX or H89. Accordingly, Exendin-4 could stimulates cAMP production dose dependently from sham instead of burn monocyte. However, the blunt cAMP production from burn monocyte was further suppressed by pretreatment of PTX or H89 after 6-h incubation. Nevertheless, phosphorylated PKA activity was significantly increased by low dose of Exendin-4 in sham monocyte, by contrast, it was enhanced by high dose of Exendin-4 in burn monocyte after 1-h incubation. Following Exendin-4 treatment for 2 h ex vivo, total nuclear NF-κB and phosphorylated NF-κB activity, as well as cytoplasmic pERK1/2 expressions were reduced in sham monocyte, however, only pERK1/2 was increased by Exendin-4 in burn monocytes. Moreover, reduced expressions of GLP-1R, GRK-2 and Gαs in contrast with increased expression of Gαi were identified in burn monocyte relative to sham monocyte. CONCLUSIONS: This study presents an unexpected proinflammatory switch from Gαs to Gαi signaling in burn monocyte, which promotes ERK1/2 and NF-κB activation and the downstream TNF-α secretion. This phenomenon is most probably responsible for proinflammatory response evoked by Gαs agonist Exendin-4 following burn injury.

Early antagonism of cerebral high mobility group box-1 protein is benefit for sepsis induced brain injury.

Sepsis induced brain injury acts as an acute complication and accounts for deterioration and high mortality rate of septic condition. HMGB1 is a late inflammatory mediator that plays a critical role in brain dysfunction and diseases. However, the role of HMGB1 in sepsis induced brain dysfunction remains intricate. The current study investigated the effect of HMGB1 on brain injury in septic mice model with intracerebroventricular injection of BoxA (a specific antagonist of HMGB1). The expression of HMGB1, morphological changes of brain tissues, apoptosis of brain cells, and alteration of behavior were determined. The expressions of HMGB1 in cortex, hippocampus, and striatum were significantly enhanced in the sepsis group when compared with the sham group. In septic conditions, brain tissues showed significant abnormalities in tissue structure, and increased apoptosis of brain cells which was caspase-3 dependent. Septic mice showed suppression of locomotor activity and impairment of memory and learning. Neutralizing brain HMGB1 significantly improved brain injury and apoptosis of brain cells, and further ameliorated disturbed locomotor activities and damaged memory and learning. However, no significant improvement of survival rate was seen after inhibiting central HMGB1. These results reveal that HMGB1 is a potential target for ameliorating sepsis induced brain injury with early antagonizing.

The involvement of endoplasmic reticulum stress response in immune dysfunction of dendritic cells after severe thermal injury in mice.

Suppressed adaptive immune function is one of the major concerns responsible for the development of opportunistic infections and subsequent sepsis with high mortality in severe burns. Endoplasmic reticulum stress (ERS) is the endogenous self-protective mechanism, and it plays an important role in almost every process of living by regulating the balance between homeostasis and apoptosis. The current study investigated the involvement of ERS in the pathogenesis of dysfunction of dendritic cells (DCs) in burn mice. Our results show a significant ERS response in splenic DC after burn injury. Treatment with salubrinal (Sal, reported to protect cells against ERS-induced apoptosis.) decrease the apoptotic rate of DC induced by burns, and promote maturation and activation of DC, as well as the ability to promote T cell proliferation and polarization towards Th1 immunity (all P<0.05). Gene silence of XBP-1 (key molecular in ERS response) results in the increased apoptosis and suppressed phenotypical maturation of splenic DC in burn mice. These results show that the excessive ERS is essential for immunosuppression during severe thermal injury. XBP-1 plays a pivotal role in DC functional immunomodulation in burn mice. Inhibition of apoptotic ERS response benefits mice from major burns.

Tuftsin-derived T-peptide prevents cellular immunosuppression and improves survival rate in septic mice.

The primary mechanisms of sepsis induced cellular immunosuppression involve immune dysfunction of T lymphocytes and negative immunoregulation of regulatory T cells (Tregs). It has been found that tuftsin is an immune modulating peptide derived from IgG in spleen. T-peptide is one of tuftsin analogs. Herein, we examined the effect of T-peptide on cell-mediated immunity in the presence of lipopolysaccharide (LPS) and the survival rate in septic mice. T-peptide regulated the proliferative ability of CD4(+)CD25(-) T cells in dual responses. Meanwhile, 10 and 100 µg/ml T-peptides were able to enhance the apoptotic rate of CD4(+)CD25(-) T cells compared with 1 µg/ml T-peptide, but markedly lowered interleukin (IL)-2 levels. When CD4(+)CD25(+) Tregs were treated with T-peptide for 24 hours, and co-cultured with normal CD4(+)CD25(-) T cells, the suppressive ability of CD4(+)CD25(+) Tregs on CD4(+)CD25(-) T cells was significantly lowered, along with decreased expression in forkhead/winged helix transcription factor p-3 (Foxp-3) as well as cytotoxic T lymphocyte-associated antigen (CTLA)-4, and secretion of transforming growth factor (TGF)-ß. Moreover, T-peptide has the ability to improve outcome of septic mice in a dose- and time- dependent manner, and associated with improvement in the microenvironment of cellular immunosuppression in septic mice.