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Background: Schizophrenia is a chronic mental disorder, characterized byacute exacerbation and remission phases. Immune system has a role in the pathophysiology of schizophrenia. High mobility group box-1 (HMGB-1) is a macrophage secreted protein activating immune cells to produce cytokines. The aim of this study was to evaluate HMGB-1 levels among patients with schizophrenia both in acute exacerbation and remission phases. Methods: Consecutive schizophrenia patients in acute exacerbation and remission phases were enrolled and compared with each other and with age-sex matched healthy subjects. Patients were assessed with the Scale for the Assessment of Positive Symptoms (SAPS), Scale for the Assessment of Negative Symptoms (SANS), Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression Scale (CGI). Results: Mean HMGB-1 levels were not significantly different in acute exacerbation phase versus remission phase schizophrenia patients (2.139±0.564 g/L vs. 2.326± 0.471 g/L, p=0.335) and both were individually higher than the control group (1.791±0.444 g/L, p=0.05 for acute exacerbation vs control, p=0.002 for remission vs control). In remission phase schizophrenic patients, HMGB-1 levels were positively correlated with Scale For The Assessment of Positive Symptoms (r=0.447, p=0.015) and BPRS (r=0.397, p=0.033) scores and HMGB-1 levels were independently associated with BPRS. Conclusions: Serum HMGB-1 levels were shown to be increased in patients with schizophrenia patients irrespective of phase, there were no differences between patients in acute exacerbation and remission phase in terms of biomarker and HMGB-1 levels were related to symptom severity according to psychiatric scales among patients in remission phase of schizophrenia.

Made available in DSpace on 2020-12-12T01:38:15Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-01. Added 1 bitstream(s) on 2021-07-15T14:37:56Z : No. of bitstreams: 1 S0102-09352020000401329.pdf: 189178 bytes, checksum: 335871ee1c1b6f459790e0709840f12f (MD5) The aim of this work was to measure HMGB1, TNF-alpha, and IL-8 in bronchoalveolar lavage (BAL), serum and TLR2 and TLR4mRNA expression in lung tissue of rabbits with two grades of acute lung injury (ALI). The animals were randomly assigned to groups with severe (S) and mild/moderate (MM) ALI, induced with warm saline, and a control group. HMGB1, TNF-alpha, IL-8, TLR2mRNA and TLR4mRNA were measured after ALI induction. The results showed increased levels of IL-8, TNF-alpha, HMGB1 and TLR4mRNA in the ALI groups. HMGB1, IL-8 and TNF-alpha concentrations in BAL were higher in S compared MM. Increased TLR4mRNA was observed in S and MM versus control. The results suggest an early participation of HMGB1 in ALI together with IL-8 and TNF-alpha and association with severity. TLR4 has early expression and role in ALI pathophysiology but is not associated with severity. Unesp Faculdade de Medicina Unesp Instituto de Biociências Unesp Faculdade de Medicina Unesp Instituto de Biociências

Urothelial carcinoma of bladder (UBC), a highly prevalent urological malignancy associated with high mortality and recurrence rate. Standard diagnostic method currently being used is cystoscopy but its invasive nature and low sensitivity stresses for identifying predictive diagnostic marker. Autophagy, a cellular homeostasis maintaining process, is usually dysregulated in cancer and its role is still enigmatic in UBC. In this study, 30 UBC patients and healthy controls were enrolled. Histopathologically confirmed tumor and adjacent normal tissue were acquired from patients. Molecular expression and tissue localization of autophagy-associated molecules (HMGB-1, RAGE, beclin, LC-3, and p62) were investigated. Serum HMGB-1 concentration was measured in UBC patients and healthy controls. ROC curves were plotted to evaluate diagnostic potential. Transcript, protein, and IHC expression of HMGB-1, RAGE, beclin, and LC-3 displayed upregulated expression, while p62 was downregulated in bladder tumor tissue. Serum HMGB-1 levels were elevated in UBC patients. Transcript and circulatory levels of HMGB-1 showed positive correlation and displayed a positive trend with disease severity. Upon comparison with clinicopathological parameters, HMGB-1 emerged as molecule of statistical significance to exhibit association. HMGB-1 exhibited optimum sensitivity and specificity in serum. The positive correlation between tissue and serum levels of HMGB-1 showcases serum as a representation of in situ scenario, suggesting its clinical applicability for non-invasive testing. Moreover, optimum sensitivity and specificity displayed by HMGB-1 along with significant association with clinicopathological parameters makes it a potential candidate to be used as diagnostic marker for early detection of UBC but requires further validation in larger cohort. Supplementary Information The online version contains supplementary material available at 10.1007/s11010-021-04299-8.

Alport syndrome (ALP) is a rare genetic condition characterized by progressive involvement of the basal membranes and renal dysfunction. The purpose of the study was to evaluate urinary (u) and serum (s) levels of tumor growth factor (TGF)-beta(β) and high mobility group box (HMGB)-1 in ALP patients with normal renal function, albuminuria and proteinuria. A prospective, single-center study was performed with a follow-up period of 12 months, enrolling 11 pediatric ALP patients and 10 healthy subjects (HS). Normal values of serum creatinine, albuminuria and proteinuria, as well as unaltered estimated glomerular filtration rate (eGFR) were required at enrollment. ALP patients had significantly higher levels of serum and urinary HMGB1 compared to HS. The same trend was observed for TGF-β1, with higher values in ALP patients than in HS. HMGB1 and TGF-β1 correlated with each other and with markers of renal function and damage. Urinary biomarkers did not correlate with eGFR, whereas sHMGB1 and sTGF-β1 were negatively related to filtration rate (r: − 0.66; p = 0.02, r: − 0.96; p

Corrigendum: Clinical Improvement Following Stroke Promptly Reverses Post-stroke Cellular Immune Alterations

This study aimed to determine the expression of some cytokines, such as cyclooxygenase-2 (COX-2), High Mobility Group Box-1 (HMGB-1) and CD68, in the lung tissue of sheep with fibrinous bronchopneumonia by immunohistochemical methods. Forty sheep which had suffered from respiratory problems were brought for necropsy to the Faculty of Veterinary Medicine, Department of Pathology, Aksaray University, between November 2014 and December 2017. After necropsy, lung tissues grossly diagnosed with fibrinous bronchopneumonia were processed histologically, and stained histopathologically and immunohistochemically. Bacteriological culture was also applied to the lung tissues to isolate the agents. In histopathological examinations, congestion, red consolidation and grey consolidation stages were detected in the lung tissues. In such cases, we observed fibrin masses accumulated in some alveolar lumens, as well as inflammatory cell infiltrations of various extent in alveolar and bronchiolar lumens. In the interalveolar septum, a thickening was observed due to a fibrin mass and thrombotic vessels. Immunohistochemically, it was determined that COX-2 and HMGB-1 cytokines showed positive reactions, especially in bronchial, bronchiolar and alveolar epithelia, as well as goblet cells and macrophages. CD68 was found to be expressed in alveolar macrophages. COX-2 and HMGB-1, which have been implicated in the inflammatory response, were also shown to be expressed in fibrinous bronchopneumonia in sheep for the first time. Thus, these cytokines are thought to play a role in the pathogenesis of the disease. Moreover, their increased expression suggests that it may be helpful in the diagnosis of the disease.

High mobility group box-1 (HMGB-1), a typical damage-associated molecular pattern protein released from various cells, was first identified in 1973. It is usually stored in the nuclei of cells. Several modifications of HMGB-1 promote its translocation to the cytosol, and it is actively or passively released from cells. When outside of the cells, HMGB-1is crucial in inflammation. It exerts its biological functions via interaction with its receptors, including receptor for advanced glycation end products (RAGE) and Toll-like receptor 4(TLR4). A large number of studies showed a close link between inflammation and thrombosis. This review demonstrated the increased expression of HMGB-1 in thrombosis-related diseases, including coronary artery disease, stroke, peripheral arterial disease, disseminated intravascular coagulation, and venous thrombosis. Besides, it summarized the current understanding of the emerging link between HMGB-1 and thrombosis from three aspects: platelet, NETs, and coagulation and fibrinolysis factors. Finally, it explored the possible therapeutic strategies targeting HMGB-1 for treating thrombosis-related diseases.

High-mobility group box-1 (HMGB-1) is expressed in almost all cells, and its dysregulated expression correlates with inflammatory diseases, ischemia, and cancer. Some of these conditions accompany HMGB-1-mediated abnormal angiogenesis. Thus far, the mechanism of HMGB-1-induced angiogenesis remains largely unknown. In this study, we performed time-dependent DNA microarray analysis of endothelial cells (ECs) after HMGB-1 or VEGF treatment. The pathway analysis of each gene set upregulated by HMGB-1 or VEGF showed that most HMGB-1-induced angiogenic pathways were also activated by VEGF, although the activation time and gene sets belonging to the pathways differed. In addition, HMGB-1 upregulated some VEGFR signaling-related angiogenic factors including EGR1 and, importantly, novel angiogenic factors, such as ABL2, CEACAM1, KIT, and VIPR1, which are reported to independently promote angiogenesis under physiological and pathological conditions. Our findings suggest that HMGB-1 independently induces angiogenesis by activating HMGB-1-specific angiogenic factors and also functions as an accelerator for VEGF-mediated conventional angiogenesis. [BMB Reports 2017; 50(11): 590-595].

Background Recently, some studies demonstrated that HMGB1, as proinflammatory mediator belonging to the alarmin family, has a key role in different acute and chronic immune disorders. Asthma is a complex disease characterised by recurrent and reversible airflow obstruction associated to airway hyper-responsiveness and airway inflammation. Objective This literature review aims to analyse advances on HMGB1 role, employment and potential diagnostic application in asthma. Methods We reviewed experimental studies that investigated the pathogenetic role of HMGB in bronchial airway hyper-responsiveness, inflammation and the correlation between HMGB1 level and asthma. Results A total of 19 studies assessing the association between HMGB1 and asthma were identified. Conclusions What emerged from this literature review was the confirmation of HMGB-1 involvement in diseases characterised by chronic inflammation, especially in pulmonary pathologies. Findings reported suggest a potential role of the alarmin in being a stadiation method and a marker of therapeutic efficacy; finally, inhibiting HMGB1 in humans in order to contrast inflammation should be the aim for future further studies.

Background Cyclosporine-A has been regarded as an immunoregulatory and anti-inflammatory drug for the treatment of various immune inflammatory diseases. However, the effect of Cyclosporine-A on the retina of type 2 diabetic rats and the underlying mechanism remains to be elucidated. The objective of the present study was to investigate the effect and mechanism of Cyclosporine-A on diabetic retinopathy. Methods Male Sprague-Dawley rats were established to type 2 diabetic model. After 6 weeks, diabetic rats and normal controls were intravitreally injected with. Cs-A (42 ng/2 μL) to the left eye, and 2 μL DMSO to the right eye for the control.. Another group of normal wild-type rats was subjected to intravitreal injections into. The left eyes with 5 μL PBS or HMGB-1 (5 ng/5 μL) or HMGB-1(5 ng/5 μL) plus. Cs-A (42 ng/2 μL), respectively. Retinal morphological changes were observed with. Hematoxylin–eosin staining. Expressions of HMGB-1, IL-1β and TNF-α were. Detected by immunohistochemistry, ELISA or Western blot or RT-PCR. Results Retinal expression levels of IL-1β and TNF-α were upregulated in type 2. diabetic rats and in normal rats with intravitreal injection of HMGB-1, which were. Attenuated by intravitreal Cs-A. Moreover, Cs-A decreased HMGB-1 expression in. diabetic retina and relieved the retinopathy in type 2 diabetic rats. Conclusions Intravitreal administration of Cs-A showed a protective effect on retina. of diabetic rats, possibly by downregulating retinal expressions of IL-1β and TNF-α. via the suppression of HMGB-1.

OBJECTIVES: To investigate the relationship between the serum levels of NLRP3 and HMGB-1 and the prognosis of patients with severe blunt abdominal trauma. METHODS: In total, 299 patients were included in the current study from July 2014 to December 2015. All patients were divided into the mild/moderate blunt abdominal trauma group and the severe blunt abdominal trauma group according to their injury severity scores. Serum levels of NLRP3 and HMGB-1 were measured upon admission (0 h) and at 12 h, 24 h, 48 h, 72 h and 7 days after admission. RESULTS: Compared with the healthy controls, both the mild/moderate and severe blunt abdominal trauma groups had higher serum levels of NLRP3 and HMGB-1 at admission. At all points, the serum levels of NLRP3 and HMGB-1 were significantly higher in the severe group than in the mild/moderate group. The serum levels of both NLRP3 and HMGB-1 were significantly higher in the deceased patients than in the living patients. The Kaplan-Meier curve showed that compared with patients with higher levels of NLRP3 or HMGB-1, those with lower levels had longer survival times. The serum levels of both NLRP3 and HMGB-1 were independent risk factors for 6-month mortality in severe blunt abdominal trauma patients. CONCLUSION: The serum levels of NLRP3 and HMGB-1 were significantly elevated in severe blunt abdominal trauma patients, and the serum levels of both NLRP3 and HMGB-1 were correlated with 6-month mortality in severe blunt abdominal trauma patients.

Background and Purpose: Stroke induces immediate profound alterations of the peripheral immune system rendering patients more susceptible to post-stroke infections. The precise mechanisms maintaining stroke-induced immune alterations (SIIA) remain unknown. High-Mobility-Group-Protein B1 (HMGB-1) is elevated for at least 7 days post-stroke and has been suggested to mediate SIIA. Patients with rapid clinical recovery of neurological deficits rarely develop severe infections. We therefore investigated whether rapid neurological recovery (either spontaneous or secondary to neurovascular recanalization therapy) alters the course of SIIA. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement. Methods: Fluorescence-activated cell sorting was used to define leukocyte subpopulations. C-reactive protein (CRP), procalcitonin (PCT), HMGB-1, GM-CSF; IFN-β, IFN-γ, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-17F, IL-18, TNF-α, MIF, IL-8, MCP-1, MCP-4, MIP-3α, MIP-3β, Eotaxin, soluble IL-6 receptor, E-selectin, and P-selectin were analyzed by ELISA or Multiplex Assays. Serum miRNA expression changes were analyzed by qPCR. Results: Cellular parameters were similar in the improved and non-improved cohort on admission. In patients with rapid clinical recovery absolute and relative leukocyte, neutrophil, and lymphocyte numbers normalized promptly overnight. In contrast, HMGB-1 serum levels did not differ between the two groups. Nine miRNA were found to be differentially expressed between improved and non-improved patients. Conclusions: SIIA are detectable on admission of acute stroke patients. While it was assumed that post-stroke immunosuppression is rapidly reversed with improvement this is the first data set that shows that improvement actually is associated with a rapid reversal of SIIA demonstrating that SIIA require a constant signal to persist. The observation that HMGB-1 serum concentrations were similar in improved and non-improved cohorts argues against a role for this pro-inflammatory mediator in the maintenance of SIIA. Serum miRNA observed to be regulated in stroke in other publications was counter regulated with improvement in our cohort.

Purpose We determined vitreous and serum levels of high mobility group box‐1 (HMGB‐1) in patients with proliferative diabetic retinopathy (PDR) and elucidate their relationship with receptor for advanced glycation end products (RAGE), vascular endothelial growth factor (VEGF) and interleukin‐1β (IL‐1β). Methods In this cross‐sectional study, patients with PDR who underwent vitrectomy were enrolled, and the control group included non‐diabetic eyes. Vitreous and serum samples were analysed for HMGB‐1, RAGE, VEGF and IL‐1β by ELISA. We investigated the correlation between serum and vitreous levels of each cytokine, and we analysed the influence of intravitreal anti‐VEGF treatment prior to vitrectomy on the cytokine levels in PDR. Results Of 78 eyes of 78 patients enrolled consecutively, there were 32 PDR eyes and 46 control eyes. The serum levels were higher in diabetic than in non‐diabetic subjects for HMGB‐1, RAGE, VEGF and IL‐1β (all p

BACKGROUND Thromboangiitis obliterans (TAO), or Buerger's disease, is an inflammatory occlusive disorder that affects the limb arteries of young smokers. In the aetiology of TAO the immune system appears to play a critical role; however, information on the aspects involved in the evolution of vascular tissue inflammation and of this disease are still limited. OBJECTIVE This study was carried out to investigate HMGB-1 (high mobility group box-1), MMP (matrix metalloproteinase)- 2, MMP-9, MMP-11 and ICAM (intercellular adhesion molecule)-1 circulating levels in subjects with Buerger's disease. METHODS Between January 2010 and December 2012, eight patients underwent surgical revascularization of the lower limbs and a specimen of the affected arterial wall was obtained for histological confirmation of Buerger's disease. A blood sample was collected on the same day for measuring HMGB-1, MMP-3, MMP-9 and ICAM-1 by western blot analysis. Controls (n=7) were healthy non-smokers. RESULTS TAO subjects had a significant increase in HMGB-1, MMP-9 and ICAM-1 compared with controls (P

Cytokines, key contributors to tumorigenesis, are mediators between inflammatory immune or nonimmune and cancer cells. Here, IL-6 production by tumor cells was assessed in a cohort of patients with lung adenocarcinoma treated with conventional therapy. IL-6 levels and neutrophil&ndash, lymphocyte ratio (NLR) or systemic immune-inflammation index (SII) markers were evaluated. Changes in pro- and anti-inflammatory cytokines, HMGB1 concentration, and CD4+ and CD8+ T-lymphocyte populations and their subpopulations were investigated. IL-6 expression was detected immunohistochemically in lung adenocarcinoma biopsies. Cytokines were quantified using the cytometric bead array, and TGF-&beta, and HMGB-1 through ELISA. Clinical parameters were collected to assess NLR and SII. CD4+ and CD8+ T-lymphocytes and na&iuml, ve, memory, and effector subpopulations were quantified by flow cytometry. The data obtained were associated with patients&rsquo, median overall survival (OS). IL-6 showed the highest increase, probably because the lung adenocarcinoma cells produced IL-6. Patients with higher OS had lower NLR and SII from the third cycle of chemotherapy. Patients with lower OS had significantly lower percentages of CD8+ T-lymphocyte and its effector subpopulations, with a concomitant increase in the na&iuml, ve subpopulation. This study suggests that in addition to the known inflammatory markers, IL-6, CD8+ T-lymphocytes and their effector and na&iuml, ve subpopulations could be useful as predictive markers in lung adenocarcinoma.

Background Biomarkers of inflammation predictive of cystic fibrosis (CF) disease outcomes would increase the power of clinical trials and contribute to better personalization of clinical assessments. A representative patient cohort would improve searching for believable, generalizable, reproducible and accurate biomarkers. Methods We recruited patients from Mountain West CF Consortium (MWCFC) care centers for prospective observational study of sputum biomarkers of inflammation. After informed consent, centers enrolled randomly selected patients with CF who were clinically stable sputum producers, 12 years of age and older, without previous organ transplantation. Results From December 8, 2014 through January 16, 2016, we enrolled 114 patients (53 male) with CF with continuing data collection. Baseline characteristics included mean age 27 years (SD = 12), 80% predicted forced expiratory volume in 1 s (SD = 23%), 1.0 prior year pulmonary exacerbations (SD = 1.2), home elevation 328 m (SD = 112) above sea level. Compared with other patients in the US CF Foundation Patient Registry (CFFPR) in 2014, MWCFC patients had similar distribution of sex, age, lung function, weight and rates of exacerbations, diabetes, pancreatic insufficiency, CF-related arthropathy and airway infections including methicillin-sensitive or -resistant Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, fungal and non-tuberculous Mycobacteria infections. They received CF-specific treatments at similar frequencies. Conclusions Randomly-selected, sputum-producing patients within the MWCFC represent sputum-producing patients in the CFFPR. They have similar characteristics, lung function and frequencies of pulmonary exacerbations, microbial infections and use of CF-specific treatments. These findings will plausibly make future interpretations of quantitative measurements of inflammatory biomarkers generalizable to sputum-producing patients in the CFFPR.

Trauma is common in dogs and causes significant morbidity and mortality, but it remains challenging to predict the prognosis of dogs with traumatic injuries. This study aimed to quantify plasma high-mobility group box-1 (HMGB-1) and cytokine concentrations in dogs with moderate-to-severe trauma, and to evaluate the association between these biomarkers and the injury severity and survival to discharge. Using a prospective, observational case-control study design, 49 dogs with an animal trauma triage (ATT) score ≥3 were consecutively enrolled from 07/2015 to 10/2017 and followed to hospital discharge. Dogs

Background Acute gastrointestinal disease occurs commonly in horses. Novel biomarkers might improve the understanding of SIRS and aid diagnosis and determination of prognosis. Hypotheses Increased plasma concentrations of the biomarkers HMGB-1 and nucleosomes are associated with severity of gastrointestinal lesions in horses; concentrations of these biomarkers will be greater in horses with lesions more likely to cause SIRS; and will provide additional information compared with standard biomarkers fibrinogen and SAA. Animals Thirty horses with gastrointestinal disease, 22 healthy horses. Methods Prospective study. Plasma samples taken on admission were used for measurement of HMGB-1, nucleosomes, fibrinogen, and SAA. Values were compared between healthy horses and those with gastrointestinal disease, and between horses with gastrointestinal disease grouped by lesion type (inflammatory, strangulating, and nonstrangulating). Correlations between biomarkers were assessed. Results Plasma concentrations of all biomarkers were significantly higher in horses with gastrointestinal disease compared to healthy horses (P ≤ .001). HMGB-1 and nucleosomes were significantly higher in inflammatory and strangulating groups compared to healthy horses (3.5-fold and 5.4-fold increases, respectively, for HMGB-1 (P < .05) and 4.8-fold and 5.6-fold increases for nucleosomes (P < .05)), but concentrations in the group with nonstrangulating disease did not differ from healthy horses. There was significant correlation between HMGB-1 and nucleosomes (Spearman's r = 0.623; P < .001), and fibrinogen and SAA (Spearman's r = 0.801; P < .001) but not between other biomarkers. Conclusions and Clinical Importance High mobility group box-1 and nucleosomes might have use as biomarkers for horses with gastrointestinal disease. Further studies are required to determine kinetics and prognostic value of serial measurements of these biomarkers in horses.

Studies have shown that LPS-preconditioned tolerant state could protect against brain injury to subsequent challenges. We hypothesized astrocytes were directly involved in the readjustment to confer neuroprotective effects with LPS pretreatment. High-mobility group box 1(HMGB-1) from LPS-preconditioned astrocytes, presumably serving as a positive regulator, might contribute to the favorable preconditioned effects. Furthermore, a potential cellular pathway (PI3K/AKT pathway), has been proposed for the active regulation of LPS-primed reactive astrocytes to secrete HMGB-1. In the present study, we used a low concentration of LPS to directly prime the astrocytes in vitro, and the subsequent astrocytic reactions, including cytokine secretion, the expression of transcription factors, and the release of HMGB-1 were examined after the blockade of the PI3K pathway. The data showed that LPS preconditioning could reduce some capacity of astrocytes to subsequent challenge in vitro. PI3K/AKT pathway was partially involved in the modulation of the release HMGB-1 from reactive astrocytes. These findings offer direct evidence supporting the flexible roles of astrocytes in mediating LPS-primed neuroprotection, and highlight additional targets for future attempts to modify the protective effects of astrocytes through LPS preconditioning.

Background High mobility group box-1 (HMGB-1) is a nuclear protein also acting as inflammatory mediator, whilst osteoprotegerin (OPG), member of tumor necrosis factor receptor superfamily, is indicated as marker of vascular calcification. Peripheral artery disease (PAD) and type 2 diabetes (T2D) are clinical conditions characterized by elevated serum inflammatory markers and vascular calcification enhancement. The aim of this study was to investigate the potential role of HMGB-1, OPG and several inflammatory mediators such as C-reactive protein (HsCRP), tumor necrosis factor-alpha and interleukin-6 (IL-6) on the presence and severity of peripheral artery disease in patients with T2D. Methods In this retrospective observational study, we have analyzed HMGB-1, OPG and inflammatory cytokines serum levels in 1393 type 2 diabetic patients with PAD and without PAD (WPAD). Results HMGB-1 (7.89 ± 15.23 ng/mL), OPG (6.54 ± 7.76 pmol/L), HsCRP (15.6 ± 14.4 mg/L) and IL-6 (56.1 ± 28.6 pg/mL) serum levels were significantly higher in patients with PAD than in those WPAD (3.02 ± 8.12 ng/mL, P ˂ 0.001; 2.98 ± 2.01 pmol/L, P

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an acute respiratory worsening of unidentifiable cause that sometimes develops during the clinical course of IPF. Although the incidence of AE-IPF is not high, prognosis is poor. The pathogenesis of AE-IPF is not well understood; however, evidence suggests that coagulation abnormalities and inflammation are involved. Thrombomodulin is a transmembranous glycoprotein found on the cell surface of vascular endothelial cells. Thrombomodulin combines with thrombin, regulates coagulation/fibrinolysis balance, and has a pivotal role in suppressing excess inflammation through its inhibition of high-mobility group box 1 protein and the complement system. Thus, thrombomodulin might be effective in the treatment of AE-IPF, and we and other groups found that recombinant human soluble thrombomodulin improved survival in patients with AE-IPF. This review summarizes the existing evidence and considers the therapeutic role of thrombomodulin in AE-IPF.

Injured blood vessel repair and blood circulation re-establishment are crucial events for tissue repair. We investigated in primary cultures of human umbilical vein endothelial cells (HUVEC), the effects of platelet lysate (PL), a cocktail of factors released by activated platelets following blood vessel disruption and involved in the wound-healing process triggering. PL exerted a protective effect on HUVEC in an inflammatory milieu by inhibiting IL-1&alpha, activated NF-&kappa, B pathway and by inducing the secretion of PGE2, a pro-resolving molecule in the wound microenvironment. Moreover, PL enhanced HUVEC proliferation, without affecting their capability of forming tube-like structures on matrigel, and activated resting quiescent cells to re-enter cell cycle. In agreement with these findings, proliferation-related pathways Akt and ERK1/2 were activated. The expression of the cell-cycle activator Cyclin D1 was also enhanced, as well as the expression of the High Mobility Group Box-1 (HMGB1), a protein of the alarmin group involved in tissue homeostasis, repair, and remodeling. These in vitro data suggest a possible in vivo contribution of PL to new vessel formation after a wound by activation of cells resident in vessel walls. Our biochemical study provides a rationale for the clinical use of PL in the treatment of wound healing-related pathologies.

AIM Adenosine receptors modulate inflammation in periodontal tissues. No data are available regarding the effects of adenosine A(2A) receptor stimulation in experimental periodontitis (EPD). The aim of this study was to investigate the effects of polynucleotides (also known as polydeoxyribonucleotide, PDRN), a ligand of A(2A) receptor, in EPD in rats. MATERIALS AND METHODS EPD was induced ligating the cervix of the lower left first molar. Sham-EPD had no ligature. After 7 days, EPD animals were randomized to a daily treatment with vehicle gel or 0.75% PDRN gel or PDRN gel with a specific A(2A) antagonist (DMPX). Treatments lasted 7 days. Animals were then euthanized and the periodontium and surrounding gingival tissue were excised for histological evaluation and bio-molecular analysis of inflammatory (p-JNK, p-ERK, TNF-α, IL-6, HMGB-1) and apoptotic proteins (BAX and Bcl-2). RESULTS Vehicle-treated EPD rats showed severe inflammatory infiltrate in both gingival and periodontal ligament, as well as an enhanced expression of p-JNK, p-ERK, TNF-α, IL-6, HMGB-1 and BAX and a reduction in Bcl-2. PDRN gel restored the histological features, blunted inflammatory and apoptotic proteins expression and preserved Bcl-2 expression. DMPX abrogated PDRN positive effects. CONCLUSION Our data suggest that adenosine receptor stimulation by PDRN might represent a new therapeutic strategy for periodontitis.

Autism spectrum disorders (ASDs) represent a disabling condition in early childhood. A number of risk factors were proposed in order to explain their pathogenesis. A multifactorial model was proposed, and data supported the implication of genetic and environmental factors. One of the most accepted speculations is the existence of an imbalance of the immune system. Altered levels of cytokines, chemokines and immunoglobulins were demonstrated in patients with ASDs; in particular, proinflammatory mediators were significantly increased. Alarmins are a multifunctional heterogeneous group of proteins, structurally belonging to specific cells or incorporated by them. They are released in the surrounding tissues as a consequence of cell damage or inflammation. Their functions are multiple as they could activate innate immunity or recruit and activate antigen-presenting cells stimulating an adaptive response. Alarmins are interesting both for understanding the inflammatory process and for diagnostic purposes as biomarkers. Moreover, recent studies, separately, showed that alarmins like interleukin (IL)-33, high-mobility group box 1 (HMGB1), heat-shock protein (HSP) and S100 protein (S100) could play a relevant role in the pathogenesis of ASDs. According to the literature, some of these alarmins could be suitable as biomarkers of inflammation in ASD. Other alarmins, by interfering with the immune system blocking pro-inflammatory mediators, could be the key for ameliorating symptoms and behaviours in autistic disorders.

Objective To obtain pilot data to evaluate the discriminatory power of biomarkers microRNA-122 (miR-122), high-mobility group box 1 (HMGB1), full-length keratin-18 (flk-18) and caspase-cleaved keratin-18 (cck-18) in plasma to identify potential biliary complications that may require acute intervention. Design An observational biomarker cohort pilot study. Setting In a Scottish University teaching hospital for 12 months beginning on 3 September 2014. Participants Blood samples were collected from adults (≥16 years old) referred with acute biliary-type symptoms who have presented to hospital within 24 hours prior were recruited. Patients unable or refused to give informed consent or were transferred from a hospital outside the National Health Service regional trust were excluded. Primary outcome measures To evaluate whether circulating miR-122, HMGB1, flk-18 and cck-18 can discriminate between people with and without gallstone disease and uncomplicated from complicated gallstone disease during the first 24 hours of hospital admission. Results 300 patients were screened of which 285 patients were included. Plasma miR-122, cck-18 and flk-18 concentrations were increased in patients with gallstones compared with those without (miR-122: median: 2.89×104 copies/mL vs 0.90×104 copies/mL (p

INTRODUCTION: The high mobility group box 1 protein (HMGB-1)/advanced glycation end products (RAGE) system is recently shown to play an important part in immune/inflammatory disorders. However, the association of this system in systemic sclerosis (SSc) remains unknown. MATERIALS AND METHODS: To determine clinical association of serum levels of HMGB-1 and soluble RAGE (sRAGE) in patients with SSc, sera from 70 patients with SSc and 25 healthy controls were examined by enzyme-linked immunosorbent assay. Sera from tight-skin mice and bleomycin-induced scleroderma mice, animal models for SSc, were also examined. Skin HMGB-1 and RAGE expression was assessed by immunohistochemistry. RESULTS AND DISCUSSION: Serum HMGB-1 and sRAGE levels in SSc were higher than those in controls. Similarly, HMGB-1 and sRAGE levels in animal SSc models were higher than those in control mice. SSc patients with elevated HMGB-1 and sRAGE levels had more frequent involvement of several organs and immunological abnormalities compared to those with normal levels. Furthermore, HMGB-1 and sRAGE levels correlated positively with modified Rodnan total skin thickness score and negatively with pulmonary function test. CONCLUSIONS: HMGB-1 and sRAGE expression in the sclerotic skin was more intense than normal skin. These results suggest that elevated serum HMGB-1 and sRAGE levels are associated with the disease severity and immunological abnormalities in SSc., Journal of clinical immunology, 29(2), pp.180-189; 2009

Plasma levels of high mobility group box chromosomal protein-1 (HMGB-1), as well as of other inflammatory molecules such as interleukin-6 (IL-6), regulated on activation normal T-cell expressed and secreted (RANTES), and soluble intercellular adhesion molecule-1 (sICAM-1), were determined in patients with bacterial pneumonia coinfected with influenza virus. HMGB-1 levels were significantly elevated in these patients compared to patients undergoing mild bacterial pneumonia alone (p < 0.01). Among cases of coinfection, we found a significant correlation between the concentration of HMGB-1 and white blood cell counts (p < 0.05, r = 0.612). Levels of IL-6 were also higher in these patients than in patients with bacterial pneumonia alone (p < 0.05), despite similar levels of RANTES and sICAM-1 in the 2 groups. These data suggest that HMGB-1 is involved in the pathogenesis of severe bacterial pneumonia coinfected with influenza virus., Scandinavian journal of infectious diseases, 40(4), pp.338-342; 2008

The receptor for advanced glycation endproducts (RAGE) can engage a diverse class of ligands and contribute to the immune and inflammatory response to infection and injury. It is known to be a pathogenic receptor in many inflammatory diseases, including ischemia/reperfusion (IR) injuries in several tissues; however, its role has not been investigated in IR injuries of the intestine to date. Mesenteric (or intestinal) IR leads to recruitment of inflammatory cells into intestinal interstitial spaces, which markedly disrupts intestinal mucosa. IR-induced mucosal injury is accompanied by the development of a local and systemic inflammatory response and remote organ injury, and results in high mortality in the clinic. We hypothesized that elimination of RAGE signaling using RAGE(-/-) mice would result in decreased local and remote organ injury and reduced inflammation in a mesenteric IR model, and thus be a target for therapeutic intervention. We found that RAGE ligands including HMGB-1 and C3a were elevated after mesenteric IR indicating the potential for enhanced RAGE activation in this model. However despite this, wild-type and RAGE(-/-) mice both displayed similar degrees of mesenteric injury, neutrophil infiltration, intestinal edema, cytokine generation, neutrophil mobilization, and remote organ injury after mesenteric IR. We, therefore, conclude that despite its role in other organ IR injuries, and the robust production of RAGE ligands after intestinal ischemia, RAGE itself does not directly influence tissue injury and the inflammatory response in mesenteric IR.

Background Vernal keratoconjunctivitis (VKC) is a chronic disease affecting conjunctiva even though the immunopathogenetic mechanisms underlying this inflammation are unclear. The aim of our study is to investigate serum levels of HMGB1 and circulating sRAGE in children affected by VKC before and after treatment with cyclosporine A (CsA) eye drops and in a group of healthy children. Methods Twenty-four children affected by VKC aged between 5 and 12 yrs of life were enrolled at the Department of Pediatrics, Division of Allergy and Immunology, ‘Sapienza’ University of Rome. Twenty-four healthy children without atopy, ocular, and systemic disease, cross-matched for sex and age to patients affected by VKC, represented the controls. All children affected by VKC were treated with CsA 1% eye drops for 4 wks, and blood samples were collected before and 2 wks after the end of treatment while the controls underwent to a single blood sample at the time of enrollment. Results Serum basal levels of HMGB1 and sRAGE were higher in children with VKC when compared with controls while, in patients affected by VKC, no difference was detected between atopic and non-atopic, and between ANA-positive and ANA-negative children. A significant reduction in serum HMGB1 and sRAGE levels was detected after the therapy while CsA serum levels were negative. Conclusions Our study gives a support to the definition of VKC as a systemic inflammation in which HMGB1 and its soluble receptors could play a role.

Background: Allergic rhinitis (AR) is characterized by an inflammatory reaction. High-mobility group box-1 protein (HMGB1) has many characteristics similar to classic proinflammatory cytokines. No study has yet investigated its role in AR. The aim of this study was to measure HMGB1 levels in the fluid recovered from nasal lavage in children with untreated AR and in control subjects. Materials: The study was conducted on 104 AR subjects (48 males and 56 females, median age 10.3 ± 3.4 years) and 97 healthy children (42 males and 55 females) who were age-matched (median age 9.8 ± 4.1 years). Total serum immunoglobulin E, peripheral eosinophils and nasal symptoms assessed by visual analog scale (VAS) were considered. HMGB1 was measured using an ELISA assay. Results: HMGB1 levels in nasal lavage fluid were higher in AR children than in the control group (96.9 ± 19.3 vs. 9.27 ± 4.01 ng/ml; p < 0.001). There was a very strong relationship between HMGB1 levels and VAS values in AR children (r = 0.919). Considering the symptom severity assessed by VAS, there was a relationship between HMGB1 and VAS in all AR subgroups: more evident in the severe subgroup (r = 0.727). Conclusions: Nasal HMGB1 has significantly increased in children with AR and is significantly related to symptom severity.

Background: High mobility group box protein 1 (HMGB-1) is a chromatin binding protein that bends DNA thereby facilitating gene transcription. HMGB-1 has also been observed as an extracellular secreted protein in serum of patients with sepsis and has putative intracellular signalling effects regulating the production of interleukin-1 and tumour necrosis factor in a number of inflammatory conditions. Methods: We established a model of immune-mediated epithelial-mesenchymal transition (EMT) in human proximal tubular epithelial cells (PTECs). PTECs were cultured with conditioned medium containing supernatant from activated peripheral blood mononuclear cells (aPBMC). The model was characterised using phenotypic and transcriptomic approaches and suppression subtractive hybridisation was performed to identify differentially regulated genes. Results. Activation of PBMCs resulted in increased secretion of HMGB-1. In addition, treatment of PTECs with aPBMC-conditioned medium resulted in significant upregulation of HMGB-1 in PTECs. Direct treatment of PTECs with recombinant human HMGB-1 induced alterations in epithelial morphology consistent with EMT including reduced E-cadherin expression, increased α-SMA expression and enhanced cell migration. HMGB-1 effects were mediated at least in part by the receptor for advanced glycation end products (RAGE) and through induction of TGF-β1 secretion from PTECs. Conclusions. These results suggest that HMGB-1 is a key mediator of immune-mediated EMT of PTECs and a potentially important signalling molecule in the development of renal fibrosis. Science Foundation Ireland Higher Education Authority Health Research Board Other funder Enterprise Ireland Irish Nephrological Society Amgen sp, ab, ke, li - TS 15.05.12

Chest trauma is frequently followed by pulmonary contusion and sepsis. High mobility group box-1 (HMGB-1) is a late mediator of severe sepsis that has been associated with mortality under experimental conditions. We studied HMGB-1 mRNA expression in patients with lung injury and its relationship with the severity of trauma and survival. A total of 24 consecutive patients with chest trauma referring to the Intensive Care Unit of Messina University Hospital, were enrolled. Lung trauma was established on the basis of chest X-ray and computed tomography. Injury Severity Score (ISS), Revised Trauma Score (RTS) and Glasgow Coma Scale (GCS) were also assessed. Accordingly to these results 6 patients were considered as controls because of no penetrating trauma and low ISS. Blood and broncho-alveolar lavage fluid (BALF) from chest trauma patients were withdrawn at admission and 24h after the beginning of the standard therapeutic protocol. HMGB-1 mRNA increased significantly in blood (r=0.84) and BALF (r=0.87) from patients with trauma and pulmonary contusion and positively correlated with the severity of trauma (based on ISS and RTS) and the final outcome. HMGB-1 protein levels were also elevated in BALF macrophages from severe trauma patients compared to control subjects, furthermore TNF-alpha and its receptor TNFR-1 mRNA levels were also markedly increased in patients with a poor outcome respect to other subjects. Our study suggests that HMGB-1 may be an early indicator of poor clinical outcome in patients with chest trauma.

IntroductionThe innate immune response molecules and their use as a predictor of mortality in cancer patients with severe sepsis and septic shock are poorly investigated.ObjectiveTo analyze the value of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor α (TNF-α), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), and high-mobility group box 1 (HMGB-1) as predictors of mortality in cancer patients with severe sepsis and septic shock compared with septic patients without malignancies.DesignProspective, observational cohort study.SettingTertiary level adult intensive care unit (ICU).SubjectsSeventy-five patients with severe sepsis or septic shock, 40 with cancer and 35 without.Interventions and MeasurementsLaboratory data were collected at ICU admission, 24and 48 hours after. Plasma concentrations of HMGB-1 and sTREM-1 were measured by enzyme-linked immunosorbent assay, whereas cytokines were measured by cytometric bead array.ResultsIntensive care unit mortality in cancer and noncancer patients was 40% and 28.6% (P = .29), and 28-day mortality was 45% and 34.3% (P = .34). Proinflammatory cytokines IL-1ß, IL-6, IL-8, IL-12, and TNF-α showed significantly higher values in the cancer group. Interleukin-10 at 48 hours (P = .01), sTREM-1 in all measurements (P < .01) and HMGB-1 at 24 hours (P < .01) showed significantly lower values in the cancer group. In addition, for the cancer group, sTREM-1 at 24 hours (P = .02) and 48 hours (P = .01) showed higher levels in nonsurvivors patients. The area under the receiver operating characteristic curve for predicting ICU mortality for sTREM-1 was 0.73 (95% confidence interval, 0.57-0.89; P = .01). Multivariate logistic analysis showed that the days spent in mechanical ventilation and levels of sTREM-1 and IL-1ß at 48 hours were independent predictors of ICU mortality; corticosteroids requirement and levels of sTREM-1 and TNF-α at 24 hours were independent predictors of 28-day mortality.ConclusionsPatients with cancer have different immune profile in sepsis when compared with patients without cancer, as demonstrated for levels of cytokines, sTREM-1 and HMGB-1. sTREM-1 and days spent in mechanical ventilation proved to be good predictors of ICU and 28-day mortality in cancer patients.

BACKGROUND: Gastroesophageal varices and associated bleeding are a major cause of morbidity and mortality in cirrhotic patients. OBJECTIVE: To evaluate the potential role of the biomarkers HMGB1 (High Mobility Group Box 1) and IL-6 (Interleukin-6) as predictors of infection, acute kidney injury and mortality in these patients. METHODS: It is a prospective, observational study that included 32 cirrhotic patients with variceal bleeding. RESULTS: The subjects’mean age was 52±5 years and 20 (62.5%) were male. The average MELD was 17.53±5 and the average MELD-Na was 20.63±6.06. Thirty patients (93.3%) patients were Child-Pugh class B or C. Infection was present in 9 subjects (28.1%), acute kidney injury was present in 6 (18.1%) and 4 (12.5%) patients died. The median serum levels of HMGB1 were 1487 pg/mL (0.1 to 8593.1) and the median serum level of IL-6 was 62.1 pg/mL (0.1 to 1102.4). The serum levels of HMGB1 and IL-6 were significantly higher in patients who developed infection, acute kidney injury and death (P

Stress and glucocorticoids (GCs) have universally been considered to be anti-inflammatory, however in recent years, stress and GCs have been found to exert permissive effects (immunological priming) on neuroinflammatory processes. This phenomenon of priming is characterized by prior stress or GC exposure potentiating the neuroinflammatory response to a subsequent immune challenge. A considerable body of evidence is discussed here that supports this permissive effect of stress and GCs. In light of this evidence, a mechanism of neuroinflammatory priming is proposed involving a signal cascade in the brain involving danger-associated molecular patterns (HMGB-1) and inflammasomes (NLRP3), which results in an exaggerated or amplified neuroinflammatory response and subsequently, the amplification of the physiological and behavioral sequelae of this response (i.e. sickness). Finally, we explore the notion that stressor-induced sensitization of the neuroimmune microenvironment may predispose individuals to psychiatric disorders, in which exaggerated innate immune/inflammatory responses in the brain are now thought to play a key role.

Introduction Acute liver failure (ALF), like sepsis, is associated with an overwhelming activation of the immune response in which hepatic and circulating inflammatory cytokines play a pivotal role. Cholinesterase inhibition has been shown to have anti-inflammatory properties in experimental sepsis. We investigated the role of neostigmine in attenuating d-galactosamine (d-GalN)-induced ALF. Methods Thirty-six female wistar rats were randomly allocated to three groups: a control group, a d-GalN group receiving a single i.p. injection of d-galactosamine (400 mg kg−1 BW) and a neostigmine-treated d-GalN group receiving a single i.p. injection of d-galactosamine followed 24 h later by i.p. injection of neostigmine methylsulfate 0.25% (80 μg kg−1 BW) three times daily for 3 successive days. Rats were sacrificed 24 h after the last injection. Plasma levels of liver transaminases, total proteins, albumin, prothrombin, total bilirubin and hepatic levels of superoxide dismutase and malondialdehyde were measured. Liver expression of cytokines (HMGB-1, TNF-α and IL-10) and histopathology were evaluated. Results Neostigmine attenuated liver dysfunction and improved liver synthetic and excretory functions, reduced proinflammatory cytokine HMGB1 (95% CI 0.33–1.09) and TNF-α (95% CI 1.26–2.06) expression compared to d-GalN group (95% CI 2.67–4.73 and 7.33–14.53, respectively, P