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Group Box (group + box)
Kinds of Group Box Terms modified by Group Box Selected AbstractsAutoantibodies to the islet cell antigen SOX-13 are associated with duration but not type of diabetesDIABETIC MEDICINE, Issue 3 2003T. M. E. Davis Abstract Aims The autoantigen SOX-13 of the SRY-related high mobility group box is a low-frequency reactant in sera from patients with Type 1 diabetes. We further investigated the potential diagnostic role of anti-SOX-13, and in particular its ability to distinguish Type 1 from Type 2 diabetes, in two large, well-characterized cohorts. Methods SOX-13 autoantibody status was ascertained using a radioimmunoprecipitation assay in (i) a random sample of 546 participants in an Australian community-based study (the Fremantle Diabetes Study; FDS) of whom 119 had Type 1 and 427 Type 2 diabetes, and (ii) a sample of 333 subjects with Type 2 diabetes from the United Kingdom Prospective Diabetes Study (UKPDS) stratified by age, anti-glutamic acid decarboxylase (GAD) and islet cell antibody (ICA) status, and requirement for insulin therapy within 6 years of diagnosis. Results The frequencies of anti-SOX-13 in the FDS subjects were 16.0% and 14.8% for Type 1 and Type 2 patients, respectively, and levels were similar. In the UKPDS subjects, the frequency was 4.5%. In a logistic regression model involving demographic, anthropometric and metabolic variables, only diabetes duration was significantly associated with anti-SOX-13 positivity, especially for duration > 5 years (P < 0.002). When the coexistence of autoantibodies was assessed in the two study samples, there were no significant associations between anti-SOX-13 and ICA, anti-GAD or ICA512/IA-2. Conclusions Whilst the frequency of anti-SOX-13 may be increased in some populations of diabetic patients, this reactivity does not usefully distinguish Type 1 from Type 2 diabetes. However, the association with diabetes duration suggests that anti-SOX-13 may be a non-specific marker of tissue damage associated with chronic hyperglycaemia. Diabet. Med. 20, 198,204 (2003) [source] High mobility group box-1 recognition: The beginning of a RAGEless era?EMBO MOLECULAR MEDICINE, Issue 6 2010Filipe Branco-Madeira Abstract High mobility group box 1 (HMGB1) is a molecular alarm signal that triggers an immune response when released. It was assumed that the receptor for advanced glycation end-products (RAGE) would mediate the signal to the immune system. Recently pattern recognition receptors that are triggered by molecules of bacterial origin (the Toll-like receptor (TLR) family) were shown to also respond to HMGB1. Now two papers establish the TLR4,HMGB1 axis as proinflammatory, eventually leading to disparate conditions like seizures or skin cancer. These reports add a new twist to our understanding of the mode of action of the alarm signal HMGB1. [source] Intracellular HMGB1 transactivates the human IL1B gene promoter through association with an Ets transcription factor PU.1EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2008Fumihiko Mouri Abstract High mobility group box 1 protein (HMGB1), originally described as a non-histone, DNA binding protein, was recently identified as a late mediator of inflammation via its extracellular release from activated macrophages/monocytes. In the present study, we report that intracellular HMGB1 synergizes with a macrophage/monocyte-specific E26 transformation-specific sequence (Ets) transcription factor PU.1 to transactivate the promoter of the IL1B gene coding a 31-kDa proIL-1, protein. The ,131 to +12 IL1B promoter, which possesses a PU.1 binding motif essential for its transactivation, was induced when HMGB1 expression vector was transfected into murine RAW264.7 macrophage cells. Our glutathione S -transferase-pulldown and coimmunoprecipitation assays demonstrated direct physical interaction of HMGB1 with PU.1. Deletion of the PU.1 winged helix-turn-helix DNA-binding domain inhibited the association of the two proteins. In electrophoretic mobility shift assay using recombinant PU.1 protein, a ternary complex of PU.1, HMGB1 and PU.1-binding element within the IL1B promoter was generated. The importance of PU.1 was further supported by our observation that induction of the IL1B promoter was obtained only after PU.1 expression in PU.1-deficient murine EL4 thymoma cells. Thus, our data raise the possibility of a novel mechanism which sustains and amplifies inflammatory reactions through physical interaction of PU.1 with intracellular HMGB1 in macrophages/monocytes. [source] Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2005Ingrid Abstract Dendritic cells (DC) are key components of innate and adaptive immune responses. Plasmacytoid DC (PDC) are a specialized DC subset that produce high amounts of type I interferons in response to microbes. High mobility group box 1 protein (HMGB1) is an abundant nuclear protein, which acts as a potent pro-inflammatory factor when released extracellularly. We show that HMGB1 leaves the nucleus of maturing PDC following TLR9 activation, and that PDC express on the plasma membrane the best-characterized receptor for HMGB1, RAGE. Maturation and type I IFN secretion of PDC is hindered when the HMGB1/RAGE pathway is disrupted. These results reveal HMGB1 and RAGE as the first known autocrine loop modulating the maturation of PDC, and suggest that antagonists of HMGB1/RAGE might have therapeutic potential for the treatment of systemic human diseases. [source] High mobility group box 1 protein as a marker of hepatocellular injury in human liver transplantationLIVER TRANSPLANTATION, Issue 10 2008Minna Ilmakunnas High mobility group box 1 protein (HMGB1), a cytokine actively secreted by phagocytes and passively released from necrotic cells, is an inflammatory mediator in experimental hepatic ischemia/reperfusion injury. We characterized its expression in human liver transplantation. In 20 patients, in addition to systemic samples, blood was drawn from portal and hepatic veins during and after reperfusion to assess changes within the graft. Plasma HMGB1, tumor necrosis factor , (TNF-,), and interleukin-6 (IL-6) levels were measured, and HMGB1 immunohistochemistry was performed on biopsies taken before and after reperfusion. Plasma HMGB1 was undetectable before reperfusion, and levels in systemic circulation peaked after graft reperfusion. At portal declamping, HMGB1 levels were substantially higher in the caval effluent [188 (80-371) ng/mL] than in portal venous blood [0 (0-3) ng/mL, P < 0.001]. HMGB1 release from the graft continued thereafter. HMGB1 levels were not related to TNF-, or IL-6 levels. HMGB1 expression was up-regulated in biopsies taken after reperfusion (P = 0.020), with intense hepatocyte and weak neutrophil staining. HMGB1 levels in hepatic venous blood correlated with graft steatosis (r = 0.497, P = 0.03) and peak postoperative alanine aminotransferase levels (r = 0.588, P = 0.008). Our results indicate that HMGB1 originates from the graft and is a marker of hepatocellular injury in human liver transplantation. Liver Transpl 14:1517,1525, 2008. © 2008 AASLD. [source] Apoptosis and Necrosis in the Ischemic Zone Adjacent to Third Degree BurnsACADEMIC EMERGENCY MEDICINE, Issue 6 2008Adam J. Singer MD Abstract Objectives:, Burns are characterized by a central zone of necrosis surrounded by a zone of potentially reversible ischemia. The authors explored the contribution of necrosis and apoptosis to cell death in the zone of ischemia. Methods:, A previously established rat contact thermal injury model that utilizes a brass comb to produce four distinctive burns sites separated by three "interspaces" of unburned skin was used. The interspaces represent the zone of stasis or ischemia while the burn sites represent the zone of coagulation. With this model, most unburned interspaces progress to necrosis over 2 to 3 days. Full-thickness 3-mm biopsies were obtained from the interspaces, burns, and normal skin controls at 30 minutes, 24 hours, and 48 hours after injury. Slides were stained with hematoxylin and eosin as well as activated cleaved caspase-3 (CC3a) for evidence of apoptosis and high-mobility group box 1 (HMGB1) for evidence of necrosis. Results:, Necrosis was not seen at 30 minutes, but was found in a large number of cells within the epidermis, sebaceous glands, and follicles at 24 and 48 hours. Faint nuclear CC3a staining indicative of apoptosis was present in a minority of cells within the epidermis, dermal fibroblasts, dermal follicles, and dermal sebaceous glands at 30 minutes and to a lesser degree at 24 and 48 hours. Conclusions:, Both early apoptosis and delayed necrosis are present in the zone of ischemia, contributing to injury progression. Necrosis appears to play a larger role than apoptosis in injury progression in the comb burn model. [source] Co-treatment with deoxycholic acid and azoxymethane accelerates secretion of HMGB1 in IEC6 intestinal epithelial cellsCELL PROLIFERATION, Issue 5 2009K. Fujii Objectives:, High-mobility group box 1 (HMGB1) is a nuclear protein that acts as a ligand of the receptor for advanced glycation end products (RAGE) and its expression enhances progression of cancer. However, the mechanism underlying HMGB1 secretion is still unclear. In this study, we examined the effect of deoxycholic acid (DCA), a promoter of colon carcinogenesis, on HMGB1 secretion. Materials and Methods:, We used an in vitro transformation model comprised of IEC6 intestinal epithelial cells treated with azoxymethane (AOM) and/or DCA. HMGB1 expression and secretion were examined by Western and Northern blot analyses, and ELISA. Intracellular translocation of HMGB1 was examined by protein fractionation. Results:, AOM + DCA-treated IEC6 cells showed upregulation of HMGB1 mRNA expression and increased level of HMGB1 protein in culture medium, but decreased level of HMGB1 protein in the nucleus. AOM + DCA treatment increased level of histone H4 acetylation, which induced translocation of HMGB1 from the nucleus to the cytoplasm and increased HMGB1 secretion. Leptomycin B inhibited extranuclear translocation and secretion of the HMGB1 protein. Conclusion:, These findings suggest that DCA affects intracellular localization and secretion of HMGB1. [source] THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2009Masamune Kuno SUMMARY 1TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate. 2Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS). 3In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1,3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment. 4In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis. [source] | |||||||||||||