Unveiling the Occurrence and Non-Negligible Role of Amino Sugars in Waste Activated Sludge Fermentation by an Enriched Chitin-Degradation Consortium.

Polysaccharides in extracellular polymeric substances (EPS) can form a hybrid matrix network with proteins, impeding waste-activated sludge (WAS) fermentation. Amino sugars, such as N-acetyl-d-glucosamine (GlcNAc) polymers and sialic acid, are the non-negligible components in the EPS of aerobic granules or biofilm. However, the occurrence of amino sugars in WAS and their degradation remains unclear. Thus, amino sugars (∼6.0%) in WAS were revealed, and the genera of Lactococcus and Zoogloea were identified for the first time. Chitin was used as the substrate to enrich a chitin-degrading consortium (CDC). The COD balances for methane production ranged from 83.3 and 95.1%. Chitin was gradually converted to oligosaccharides and GlcNAc after dosing with the extracellular enzyme. After doing enriched CDC in WAS, the final methane production markedly increased to 60.4 ± 0.6 mL, reflecting an increase of ∼62%. Four model substrates of amino sugars (GlcNAc and sialic acid) and polysaccharides (cellulose and dextran) could be used by CDC. Treponema (34.3%) was identified as the core bacterium via excreting chitinases (EC 3.2.1.14) and N-acetyl-glucosaminidases (EC 3.2.1.52), especially the genetic abundance of chitinases in CDC was 2.5 times higher than that of WAS. Thus, this study provides an elegant method for the utilization of amino sugar-enriched organics.

Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

Sestrin2 protects against lethal sepsis by suppressing the pyroptosis of dendritic cells.

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sestrin2 (SESN2), a highly evolutionarily conserved protein, is critically involved in the cellular response to various stresses and has been confirmed to maintain the homeostasis of the internal environment. However, the potential effects of SESN2 in regulating dendritic cells (DCs) pyroptosis in the context of sepsis and the related mechanisms are poorly characterized. In this study, we found that SESN2 was capable of decreasing gasdermin D (GSDMD)-dependent pyroptosis of splenic DCs by inhibiting endoplasmic reticulum (ER) stress (ERS)-related nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-mediated ASC pyroptosome formation and caspase-1 (CASP-1) activation. Furthermore, SESN2 deficiency induced NLRP3/ASC/CASP-1-dependent pyroptosis and the production of proinflammatory cytokines by exacerbating the PERK-ATF4-CHOP signaling pathway, resulting in an increase in the mortality of septic mice, which was reversed by inhibiting ERS. These findings suggest that SESN2 appears to be essential for inhibiting NLRP3 inflammasome hyperactivation, reducing CASP-1-dependent pyroptosis, and improving sepsis outcomes through stabilization of the ER. The present study might have important implications for exploration of novel potential therapeutic targets for the treatment of sepsis complications.

Autocrine Regulation of Interleukin-3 in the Activity of Regulatory T Cells and its Effectiveness in the Pathophysiology of Sepsis.

Regulatory T cells (Tregs) play a crucial role in modulating the inflammatory response and participated in sepsis-related immune dysfunctions. However, little is known about the regulatory mechanisms by which Tregs are kept in check during immune responses. Here, we verified the simultaneous expression of interleukin-3 (IL-3) and its receptor (IL-3R) in Tregs. Then, by modulation of IL-3 expression via lentiviral transduction-mediated small interfering RNA, we demonstrated that IL-3 negatively regulated Tregs activity via an autocrine mechanism. Furthermore, we found that anti-IL-3 antibody treatment significantly diminished inflammatory cytokines and organ injury, and improved survival in septic mice, which was associated with enhanced Treg percentage and function. Collectively, these results suggest that IL-3 negatively regulates the activity of Tregs in a previously unrecognized autocrine manner, and plays an important role in the excessive inflammatory response in sepsis, which might be utilized as a therapeutic strategy for the treatment of complications in sepsis.

Inflammatory myofibroblastic tumor arising from soft tissues of extremities harboring a novel CLIP2-ALK fusion.

A 34-year-old Chinese woman found a lump in her left leg for more than 3 weeks without any discomfort. Grossly, the tumor was relatively well delineated with focal infiltration. Histopathologic evaluation showed a compact fascicular spindle cell proliferation with variable myxoid and collagenous stroma and scattered inflammatory infiltrate. Immunohistochemically, the tumor cells showed positive expression of ALKD5F3 and SMA and negative expression of CD34, desmin, and cytokeretin. Fluorescence in situ hybridization analysis of the ALK locus showed break-apart signals in 20% of tumor cells, and DNA sequencing discovered a novel CLIP2-ALK fusion gene. The lesion was diagnosed as an inflammatory myofibroblastic tumor (IMT). To the best of our knowledge, this is the first case with CLIP2-ALK gene fusion in the somatic soft tissue IMTs.

Impact of diabetic hyperglycaemia and insulin therapy on autophagy and impairment in rat epididymis.

Blood glucose dysregulation and hyperglycaemia caused by diabetes mellitus are intimately associated with male infertility. Two-month-old Sprague-Dawley rats were given a single dose of streptozotocin (55 mg/kg) by intraperitoneal injection to induce type I diabetes mellitus (DM group). The treatment group was given 1 unit/day of insulin for 16 weeks (INS group). The normal control group (NC group) was given food ad libitum. In the DM group, the histological analysis of caput and cauda epididymal ducts showed broken stereocilia and more lipid vacuolisations in the principal cells. The interstitial hyperplasia and inflammatory cell infiltration were observed in epididymal tissues. Transmission electron microscopy observation showed that the principal cells in the DM group contained more vacuoles, partly lost stereocilia, and swollen mitochondria. The autophagosomes were observed as well. Western blotting results of LC3II/I and P62 protein expression indicated that autophagy was downregulated in the DM group. The total antioxidant activity and GPx5 expression of epididymal tissues were also decreased. In the INS group, significant improvements were observed in epididymal tissues. Our study suggests that diabetic hyperglycaemia causes autophagy dysregulation in epididymal tissues, which may play a role in diabetes-induced rat epididymal injury. Insulin treatment is beneficial for diabetic-associated epididymal dysfunction.

Community-acquired bacterial co-infection predicts severity and mortality in influenza-associated pneumonia admitted patients.

BACKGROUND: Influenza is frequently complicated by bacterial co-infection, causing additional hospitalization and mortality. We determined the incidence, risk factors and outcomes of patients with influenza-associated community-acquired bacterial co-infection. METHOD: This was a retrospective, observational study. Influenza was diagnosed using the polymerase chain reaction. Co-infection had to be confirmed using standard bacteriological tests. The primary endpoint was presence of community-acquired co-infection, and the secondary endpoint was in-hospital mortality. RESULTS: During the 8 influenza seasons from 2010 to 2018, of the 209 influenza-associated pneumonia admitted patients, 41 (19.6%) were identified with community-acquired bacterial co-infections and Staphylococcus aureus was the predominant strain. Compared with patients without co-infection, patients with co-infection had similar demographic characteristics and co-morbidities, obtained a higher APACHE II score and a higher SOFA score, and had higher ratio of sepsis shock, invasive mechanical ventilation, and ICU requirement. In-hospital mortality independently associated with bacterial co-infection (adjusted hazard ratio (aHR) 2.619; 95%CI 1.252-5.480; p = 0.011); in subgroup S. aureus (aHR 6.267; 95%CI 2.679-14.662; p < 0.001) and other pathogens (aHR 2.964; 95%CI 1.160-7.577; p = 0.023); and in subgroup positive findings in bloodstream (aHR 7.420; 95%CI 2.712-20.302; p < 0.001) and positive findings in other site (aHR 3.427; 95%CI 1.514-7.757; p = 0.003). CONCLUSION: Community-acquired bacterial co-infection was frequent in influenza-associated pneumonia, without risk factor identified yet. Bacterial co-infection was likely to predict severity, and was an independent risk factor for in-hospital mortality. Co-infection of Staphylococcus aureus with influenza was identified as a lethal synergism, and should be targeted when developing clinical antibiotic strategies.

Successful Treatment of Eczema-Like Mucormycosis in a Child by Combination of Intravenous Drip and Percutaneous Injection Amphotericin B.

We report a case of eczema-like cutaneous mucormycosis caused by Rhizopus arrhizus. A 4-year-old child was presented to our hospital with a history of gradually enlarging papule and plaque in the periumbilical area for nearly 4 years since 2 weeks after his birth, and it has been misdiagnosed as eczema for nearly 3 years. Based on histopathology examination, the fungus culture test and DNA sequencing, it was revealed that R. arrhizus should be the responsible fungus for skin infection. The patient was successfully cured by combination of intravenous drip and percutaneous injection amphotericin B for nearly 3 months, and no recrudescence was seen during a follow-up of 6-month observation.

[Study on the Emission Spectrum of Hydrogen Production with Microwave Discharge Plasma in Ethanol Solution].

Hydrogen is regarded as a kind of clean energy with high caloricity and non-pollution, which has been studied by many experts and scholars home and abroad. Microwave discharge plasma shows light future in the area of hydrogen production from ethanol solution, providing a new way to produce hydrogen. In order to further improve the technology and analyze the mechanism of hydrogen production with microwave discharge in liquid, emission spectrum of hydrogen production by microwave discharge plasma in ethanol solution was being studied. In this paper, plasma was generated on the top of electrode by 2.45 GHz microwave, and the spectral characteristics of hydrogen production from ethanol by microwave discharge in liquid were being studied using emission spectrometer. The results showed that a large number of H, O, OH, CH, C2 and other active particles could be produced in the process of hydrogen production from ethanol by microwave discharge in liquid. The emission spectrum intensity of OH, H, O radicals generated from ethanol is far more than that generated from pure water. Bond of O-H split by more high-energy particles from water molecule was more difficult than that from ethanol molecule, so in the process of hydrogen production by microwave discharge plasma in ethanol solution; the main source of hydrogen was the dehydrogenation and restructuring of ethanol molecules instead of water decomposition. Under the definite external pressure and temperature, the emission spectrum intensity of OH, H, O radicals increased with the increase of microwave power markedly, but the emission spectrum intensity of CH, C2 active particles had the tendency to decrease with the increase of microwave power. It indicated that the number of high energy electrons and active particles high energy electron energy increased as the increase of microwave power, so more CH, C2 active particles were split more thoroughly.

Prognostic value of continuous electroencephalography monitoring in children with severe brain damage.

PURPOSE: The purpose of this study is to determine whether there is a relationship between continuous electroencephalography (EEG) monitoring patterns and prognosis for children with severe brain damage. Patients and METHODS: The different patterns of EEG were analyzed for 103 children (Glasgow Coma Scale [GCS] score < 8) who were monitored with continuous video-EEG (CVEEG) within 72 hours after the onset of coma. The clinical outcomes were scored and evaluated at hospital discharge by the modified Pediatric Cerebral and Overall Performance Category Scale (PCOPCS). EEG parameters of the different prognosis groups were compared and risk factors for prognosis were identified. RESULTS: Of the 103 children, 36 were in the good prognosis group (PCOPCS scores 1 and 2) and 67 were in the poor prognosis group (PCOPCS scores 3-6). The poor prognosis group had the lower proportion of events in reactive EEG patterns and sleep architecture, and a higher proportion of low-voltage events. Multivariate analyses showed that the lower GCS score and no sleep architecture were significantly associated with poor prognosis. CONCLUSIONS: Comatose children with higher GCS score and sleep architecture have better clinical outcomes in terms of morbidity and mortality.

Role of mitofusin-2 in high mobility group box-1 protein-mediated apoptosis of T cells in vitro.

BACKGROUND: High mobility group box-1 protein (HMGB1), a ubiquitous nuclear protein, which is recognized as a danger-associated molecular pattern (DAMP) triggering activation of the innate immune system. Previous studies have shown that HMGB1 also plays a role in T cell-mediated immunity, but the effect of HMGB1 on apoptosis of T cells and its precise mechanism remain to be determined. METHODS: Two kinds of apoptosis assay techniques were used, i.e., Annexin V-FITC conjunction with PI to identify early apoptotic cells, Hoechst 33342 staining for double-stranded DNA to observe nuclear fragmentation or apoptotic body. The activation status of caspase-3, caspase-8, as well as caspase-9 was examined by colorimetric assay. The dynamic changes in intracellular calcium concentration ([Ca(2+)]i) was monitored by flow cytometry. Overexpression of Mfn2 was preformed by lentiviral vector transfection. The mRNA and protein levels of Mfn2 were determined by RT-PCR and Western-blotting. RESULTS: Treatment of Jurkat T cells with recombinant human HMGB1 (rhHMGB1) causes a significant dose-dependent increase in percentage of apoptotic cells. When T cells are incubated with HMGB1 they express decreased mitochondria fusion-related protein mitofusin-2 (Mfn2) and activate mitochondrial apoptotic pathway via elevation of [Ca(2+)]i, Bax insertion, and activation of caspase. Furthermore, overexpression of Mfn2 ameliorates the apoptosis of T cells induced by HMGB1. This occurs at least partly through Mfn2 keeps Ca(2+) homeostasis in T cells evidenced by monitoring [Ca(2+)]i dynamics. CONCLUSION: HMGB1 can trigger apoptosis of T lymphocytes through mitochondrial death pathway associated with [Ca(2+)]i elevation. Mfn2 plays a pivotal role in this process, and it might be a novel therapeutic target in T cell apoptosis related disorders.

Anti-RAGE antibody ameliorates severe thermal injury in rats through regulating cellular immune function.

AIM: The receptor of advanced glycation end products (RAGE) participates in a variety of pathophysiological processes and inflammatory responses. The aim of this study was to investigate the therapeutic potential of an anti-RAGE neutralizing antibody for severe thermal injury in rats, and to determine whether the treatment worked via modulating cellular immune function. METHODS: Full-thickness scald injury was induced in Wistar rats, which were treated with the anti-RAGE antibody (1 mg/kg, iv) at 6 h and 24 h after the injury. The rats were sacrificed on d 1, 3, 5, and 7. Blood and spleen samples were harvested to monitor organ function and to analyze dendritic cell (DC) and T cell cytokine profiles. The survival rate was analyzed up to d 7 after the injury. RESULTS: Administration of the antibody significantly increased the 7 d survival rate in thermally injured rats (6.67% in the model group; 33.33% in anti-RAGE group). Treatment with the antibody also attenuated the multiple organ dysfunction syndrome (MODS) following the thermal injury, as shown by significant decreases in the organ dysfunction markers, including serum ALT, AST, blood urea nitrogen, creatinine and CK-MB. Moreover, treatment with the antibody significantly promoted DC maturation and T cell activation in the spleens of thermally injured rats. CONCLUSION: Blockade of the RAGE axis by the antibody effectively ameliorated MODS and improved the survival rate in thermally injured rats, which may be due to modulation of cellular immune function.

[Study on the emission spectrum of microwave plasma in liquid].

After the technology of microwave discharge in liquid is realized for the first time in China, the basic physical phenomena and characteristic of microwave discharge in liquid is studied in order to lay a theoretical foundation of research on microwave discharge in liquid. In the present paper, the active particles generated by microwave discharge in liquid were detected using the emission spectrometer, and the statistical method of spectrum data of microwave discharge in liquid was also studied. The emission spectrometer and numerically controlled camera were used to detect synchronously the process of the initial discharge and stable discharge of microwave discharge in liquid. The results show that: the emission intensity of microwave plasma in liquid has a large fluctuation, and the spectrum intensity can be calculated using the average of 10 spectrum data points. The intensity of discharge is reflected by the plasma area in a certain extent, however, the variation gradient of the intensity of discharge is different from that of the plasma area. This is mainly because that, in the process of discharging, the discharge intensity is not only reflected by the plasma area, but also reflected by the brightness of the plasma.

Interleukin-33/serum stimulation-2 pathway: Regulatory mechanisms and emerging implications in immune and inflammatory diseases.

Interleukin (IL)- 33, a nuclear factor and pleiotropic cytokine of the IL-1 family, is gaining attention owing to its important role in chronic inflammatory and autoimmune diseases. This review extends our knowledge of the effects exerted by IL-33 on target cells by binding to its specific receptor serum stimulation-2 (ST2). Depending on the tissue context, IL-33 performs multiple functions encompassing host defence, immune response, initiation and amplification of inflammation, tissue repair, and homeostasis. The levels and activity of IL-33 in the body are controlled by complex IL-33-targeting regulatory pathways. The unique temporal and spatial expression patterns of IL-33 are associated with host homeostasis and the development of immune and inflammatory disorders. Therefore, understanding the origin, function, and processes of IL-33 under various conditions is crucial. This review summarises the regulatory mechanisms underlying the IL-33/ST2 signalling axis and its potential role and clinical significance in immune and inflammatory diseases, and discusses the current complex and conflicting findings related to IL-33 in host responses.

The incremental value of CCTA-derived myocardial radiomics signature for ischemia diagnosis with reference to CT myocardial perfusion imaging.

OBJECTIVES: To explore the incremental value of myocardial radiomics signature derived from static coronary computed tomography angiography (CCTA) for identifying myocardial ischemia based on stress dynamic CT myocardial perfusion imaging (CT-MPI). METHODS: Patients who underwent CT-MPI and CCTA were retrospectively enrolled from two independent institutions, one used as training and the other as testing. Based on CT-MPI, coronary artery supplying area with relative myocardial blood flow (rMBF) value <0.8 was considered ischemia. Conventional imaging features of target plaques which caused the most severe narrowing of the vessel included area stenosis, lesion length (LL), total plaque burden, calcification burden, non-calcification burden, high-risk plaque (HRP) score, and CT fractional flow reserve (CT-FFR). Myocardial radiomics features were extracted at three vascular supply areas from CCTA images. The optimized radiomics signature was added to the conventional CCTA features to build the combined model (radiomics + conventional). RESULTS: There were 168 vessels from 56 patients enrolled in the training set, and the testing set consisted of 135 vessels from 45 patients. From either cohort, HRP score, LL, stenosis ≥50% and CT-FFR ≤0.80 were associated with ischemia. The optimal myocardial radiomics signature consisted of nine features. The detection of ischemia using the combined model was significantly improved compared with conventional model in both training and testing set (AUC 0.789 vs 0.608, p < 0.001; 0.726 vs 0.637, p = 0.045). CONCLUSIONS: Myocardial radiomics signature extracted from static CCTA combining with conventional features could provide incremental value to diagnose specific ischemia. ADVANCES IN KNOWLEDGE: Myocardial radiomics signature extracted from CCTA may capture myocardial characteristics and provide incremental value to detect specific ischemia when combined with conventional features.

Up-regulation of mitofusin-2 protects CD4+ T cells from HMGB1-mediated immune dysfunction partly through Ca(2+)-NFAT signaling pathway.

High mobility group box 1 protein (HMGB1) was recently discovered to be a critical late-acting cytokine and innate immune-modulating factor in sepsis, but the potential role and mechanism of HMGB1 in adaptive immunity remains elusive. The present study demonstrated that HMGB1 had a dual influence on immune function of CD4(+) T lymphocytes. Low dose of HMGB1 had no effect on the proliferation activity of CD4(+) T lymphocytes, but the Th1 cytokines production was increased. In contrast, treatment with high amount of HMGB1 suppressed the proliferative response and induced Th2 polarization of CD4(+) T lymphocytes. We found that the expression of mitofusin-2 (Mfn2; also named hyperplasia suppressor gene), a member of the mitofusin family, was decreased in CD4(+) T lymphocytes when stimulated with high dose of HMGB1. Up-regulation of Mfn2 attenuated the suppressive effect of HMGB1 on CD4(+) T lymphocytes, which was associated with profound elevation of intracellular calcium concentration ([Ca(2+)](i)) and nuclear factor of activated T cells (NFAT) activity. These results indicate that HMGB1 have a direct role on adaptive immunity, and the decrease of Mfn2 expression may be a major cause of HMGB1-mediated immune dysfunction and Ca(2+)-NFAT signaling defect of CD4(+) T lymphocytes.

A New Species and Genus Distribution Record from China: Neoscytalidium novaehollandiae.

One isolate from bark beetle galleries was identified and characterized using morphological and molecular methodology, and described and illustrated based on these data. These results identified a new species distribution record in China for Neoscytalidium novaehollandiae. Species morphology and micrographs are provided in this paper. The specimens are stored in Northeast Forestry University.

Occurrence and morphology of ventricular arrhythmias in apparently normal hearts in relation to late gadolinium enhancement on cardiovascular magnetic resonance.

Cardiac magnetic resonance (CMR) is the gold standard for evaluating myocardial fibrosis. Few studies have explored the association between ventricular arrhythmias (VAs) and fibrosis in apparently normal hearts. We aimed to investigate the association between the occurrence and morphology of VAs and left ventricular late gadolinium enhancement (LV-LGE) in patients without known structural heart diseases. This study enrolled 78 patients with apparently normal hearts who underwent 24-h ambulatory Holter electrocardiogram (ECG) and CMR examinations simultaneously. The presence and extent of LGE was determined using CMR imaging and compared based on occurrence and morphology of VAs. The clinical characteristics were also recorded and calculated. LV-LGE was observed in 19 (37.3%) and 4 (14.8%) patients with and without VAs, respectively (P = 0.039). It was more frequently observed in patients with polymorphic VAs (P = 0.024). The polymorphic VAs had a higher tendency of LGE extent than monomorphic VAs, while the difference did not reach statistical significance (P = 0.055). In multivariable analyses, the presence of polymorphic VAs [hazard ratio (HR) 11.19, 95% CI 1.64-76.53, P = 0.014] and hypertension (HR 4.64, 95% CI 1.08-19.99, P = 0.039) were associated with greater prevalence of LV-LGE. In patients without structural heart diseases, besides hypertension, multiple VA morphologies on Holter ambulatory ECG measurements is another important marker of increased incidence of myocardial fibrosis.

Treatment with gelsolin reduces brain inflammation and apoptotic signaling in mice following thermal injury.

BACKGROUND: Burn survivors develop long-term cognitive impairment with increased inflammation and apoptosis in the brain. Gelsolin, an actin-binding protein with capping and severing activities, plays a crucial role in the septic response. We investigated if gelsolin infusion could attenuate neural damage in burned mice. METHODS: Mice with 15% total body surface area burns were injected intravenously with bovine serum albumin as placebo (2 mg/kg), or with low (2 mg/kg) or high doses (20 mg/kg) of gelsolin. Samples were harvested at 8, 24, 48 and 72 hours postburn. The immune function of splenic T cells was analyzed. Cerebral pathology was examined by hematoxylin/eosin staining, while activated glial cells and infiltrating leukocytes were detected by immunohistochemistry. Cerebral cytokine mRNAs were further assessed by quantitative real-time PCR, while apoptosis was evaluated by caspase-3. Neural damage was determined using enzyme-linked immunosorbent assay of neuron-specific enolase (NSE) and soluble protein-100 (S-100). Finally, cerebral phospho-ERK expression was measured by western blot. RESULTS: Gelsolin significantly improved the outcomes of mice following major burns in a dose-dependent manner. The survival rate was improved by high dose gelsolin treatment compared with the placebo group (56.67% vs. 30%). Although there was no significant improvement in outcome in mice receiving low dose gelsolin (30%), survival time was prolonged against the placebo control (43.1 ± 4.5 h vs. 35.5 ± 5.0 h; P < 0.05). Burn-induced T cell suppression was greatly alleviated by high dose gelsolin treatment. Concurrently, cerebral abnormalities were greatly ameliorated as shown by reduced NSE and S-100 content of brain, decreased cytokine mRNA expressions, suppressed microglial activation, and enhanced infiltration of CD11b+ and CD45+ cells into the brain. Furthermore, the elevated caspase-3 activity seen following burn injury was remarkably reduced by high dose gelsolin treatment along with down-regulation of phospho-ERK expression. CONCLUSION: Exogenous gelsolin infusion improves survival of mice following major burn injury by partially attenuating inflammation and apoptosis in brain, and by enhancing peripheral T lymphocyte function as well. These data suggest a novel and effective strategy to combat excessive neuroinflammation and to preserve cognition in the setting of major burns.

High mobility group box-1 protein regulate immunosuppression of regulatory T cells through toll-like receptor 4.

INTRODUCTION: High mobility group box-1 protein (HMGB1), a recently recognized mediator of immune response might contribute to immune suppression when released extracellularly. The present study was performed to clarify effects of HMGB1 on regulatory T cells (Tregs) and the involvement of toll-like receptor (TLR) 4 signaling. METHODS: CD4(+)CD25(+)Tregs, isolated from spleens of normal mice and treated with HMGB1 in vitro, and those isolated from HMGB1-treated C3H/HeN (wild type) or C3H/HeJ (TLR4 mutant type) mice, were analyzed for expressions of cytotoxic T lymphocyte-associated antigen (CTLA)4, forkhead/winged helix transcription factor p3 (Foxp3) and interleukin (IL)-10 secretion. RESULTS: HMGB1-treatment was found to markedly decrease the expressions of CTLA4 and Foxp3, as well as IL-10 secretion. Administration of TLR4 neutralizing antibody abolished the phenotypic and functional changes in Tregs induced by HMGB1. Tregs from HMGB1-treated normal mice showed lower expression of CTLA4, Foxp3, and IL-10 secretion when compared with non-treated mice. Yet opposite results were observed in that of C3H/HeJ mice. Moreover, HMGB1 stimulation could down-regulate the expression of TLR4 on Tregs. CONCLUSION: Our data suggest that HMGB1 has the ability to directly modulate the suppressive capacity of CD4(+)CD25(+)Tregs, and TLR4 might be a potential receptor essential for the negative effect of HMGB1 on CD4(+)CD25(+)Tregs activity.