Serum Levels Of High-mobility Group Box Protein 1 Research Articles

Dynamic changes and clinic significance of serum high mobility group box 1 in patients with total hip arthroplasty.

Deeper understanding on the risk factors and seeking potential predicted biomarkers for prognosis of total hip arthroplasty (THA) patients are of great significance. Limited researches focused the correlation between high mobility group box protein-1 (HMGB1) and the prognosis of THA patients. The objective of this study was to investigate the role of HMGB1 and inflammatory factors in patients underwent total hip arthroplasty (THA). The present prospective study enrolled 208 THA patients who went to our hospital during January 2020 to January 2022. Serum levels of HMGB1, C-reactive protein (CRP), interleukin-1b (IL-1β), and IL-6 were detected at the admission, 1 day, 3 days, 7 days, 30 days, and 90 days after surgery. The levels of Harris score, Fugl-Meyer, 36-item short-form health survey (SF-36), and Pittsburgh sleep quality index (PSQI) were detected on 90 days after surgery in two groups. Receiver operating characteristic curve (ROC) was performed for analyzing the diagnostic value of HMGB1 and logistic regression model was used for identifying the risk factor for poor prognosis of THA patients. Serum levels of HMGB1 and inflammatory factors increased after surgery compared with the baselines. A positive correlation was found between HMGB1 and CRP on 1 day after surgery, and positive correlations were found among HMGB1, IL-1β, and IL-6 on 3 day after surgery. Besides, low HMGB1 reduced the incidence of post-operative complications and improved prognosis of THA patients. Serum HMGB1 was correlated with inflammatory factors and the prognosis of THA patients.

High mobility group box protein 1 (HMGB1) serum and urinary levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus: A possible relation to lupus nephritis.

The aim of this study was to evaluate the effects of the high mobility group box protein 1 (HMGB1) serum and urinary levels and gene polymorphisms on systemic lupus erythematosus (SLE) development and investigate their link to lupus nephritis (LN). We enrolled 120 Egyptian SLE patients and 120 healthy controls. Thorough medical and clinical evaluation were carried out, and SLE disease activity index (SLEDAI) was assessed. Lupus patients were divided into two groups according to the presence of LN. Measurement of HMGB1 serum and urinary levels was done using ELISA and genotyping for HMGB1 (rs1045411) was performed. There were statistically significantly higher HMGB1 serum and urinary levels in SLE patients (p < 0.001). There was a marginally significant association between lupus and alleles (p = 0.059, φ = -0.086). 'C' allele was marginally significant risk allele for SLE. After classifying SLE patients based on the presence or absence of LN, there was no significant difference as regard sex (p = 0.387), age (p = 0.208) and disease duration (p = 0.094).However, there was a significant difference between the 2 groups in regard to the frequency of musculoskeletal manifestations (p = 0.035), SLEDAI score (p < 0.001), both serum (p < 0.001) and urinary HMGB1 levels (p < 0.001) in addition to the frequency of HMGB1 genotypes (p = 0.003). Lupus patients with C/T-T/T HMGB1 genotypes had 3.5-times higher odds to exhibit LN. Serum and urine HMGB1 measurements are helpful in the diagnosis of SLE and the prediction of LN. There is a link between HMGB1 gene variations and the risk of SLE, with evidence that the C/T-T/T HMGB1 genotype is linked to a significantly greater risk of LN in the Egyptian population.

Ac2‑26 alleviates hepatic ischemia‑reperfusion injury based on inhibiting the positive feedback loop of HMGB1/TLR4/NF‑κB/neutrophils.

Inflammation is one of the most crucial mechanism underlying hepatic ischemia-reperfusion injury (HIRI). Several studies have shown that Ac2-26, the active N-terminal peptide of Annexin A1, could modulate anti-inflammatory processes and protect the organs from ischemia-reperfusion injury (IRI). However the effects of Ac2-26 on an HIRI model have not been reported to date. The purpose of the present study was to determine whether Ac2-26 pretreatment could protect hepatocytes against acute HIRI by inhibiting neutrophil infiltration through regulation of the high mobility group box protein 1 (HMGB1)/Toll-like receptor 4 (TLR4)/NF-κB signaling pathway. To this end, a total of 72 adult C57BL/6 mice were randomly divided into sham operation (sham), ischemia-reperfusion (I/R), I/R + Ac2-26 and Ac2-26 groups. The HIRI model was established by occluding the branch of the hepatic pedicle to the left and median liver lobes with an atraumatic vascular clamp for 45 min, followed by reperfusion for 24 h. The expression of HMGB1, TLR4, NF-κB, IκBα and lymphocyte antigen 6 complex locus G6D (Ly6G) was detected using reverse transcription-quantitative PCR, western blotting and immunohistochemical staining; serum levels of HMGB1 were evaluated using an enzyme-linked immunosorbent assay. Flow cytometry was used to detect the proportion of neutrophil. The results indicated that Ac2-26 preconditioning rescued hepatocyte dysfunctions induced by HIRI. In addition, HIRI was associated with a significant increase in HMGB1 expression and release, accompanied by increased expression of TLR4, which was significantly inhibited by Ac2-26. Furthermore, the expression of phosphorylated (p)-NF-κB and the ratio of p-NF-κB to NF-κB were markedly increased, while the expression of IκBα was decreased in the I/R group compared with those in the sham group; however, these effects were reversed by Ac2-26 administration. Additionally, Ac2-26 administration significantly inhibited neutrophil infiltration and resulted in low levels of neutrophils and Ly6G as well as reduced myeloperoxidase activity. Taken together, these results indicated that Ac2-26 pretreatment serves a protective role against HIRI by regulating the HMGB1/TLR4/NF-κB signaling pathway and inhibiting neutrophil infiltration.

HMGB1/CXCL12-Mediated Immunity and Th17 Cells Might Underlie Highly Suspected Autoimmune Epilepsy in Elderly Individuals.

PurposeLate-onset epilepsy due to autoimmune dysfunction has been reported. However, definitive diagnosis requires positive antibody results. As a result, patients with negative antibody results, but presenting with classical manifestation of autoimmune epilepsy, may be managed as suspected cases. In this study, we aim to isolate and profile the concentration of cytokines/chemokines in the cerebrospinal fluid (CSF) and the serum to ascertain if they could act as alternative diagnostic biomarkers.Patients and MethodsTwenty patients aged ≥50 years were considered in this study. Ten patients were diagnosed with suspected autoimmune epilepsy (sAE) based on clinic manifestation, electroencephalogram, magnetic resonance imaging, and with negative antibody results of the serum and the CSF. The equivalent control group exhibited neurological disorders due to non-inflammatory pathologies. Serum and CSF were analyzed for cytokines/chemokines concentration, including interleukin (IL)-6, IL-10, IL-17, chemokine (C-X-C motif) ligand (CXCL)12 and CXCL13, as well as high-mobility group box protein 1 (HMGB1) and B cell activation factor (BAFF)).ResultsThe CSF levels of IL-6, IL-17, HMGB1, and CXCL12 were significantly higher in the sAE group than in the control group. There was no difference in the CSF levels of IL-10, CXCL13 and BAFF. The serum levels of HMGB1 and CXCL12 were elevated in the sAE group compared with the control group, and there was no statistical difference in the serum levels of IL-6, IL-10, IL-17, CXCL13, and BAFF between the two groups.ConclusionOur study shows that cytokines/chemokines may act as alternative biomarkers for diagnosis of sAE. The activation of both HMGB1/CXCL12-mediated immunity and T helper cells 17 (Th17) cells may be playing a central role in the pathogenesis of sAE. We suggest that cytokines/chemokines be treated as adjuvant biomarkers, instead of solely relying on antibody screening test. However, a larger cohort in a prospective approach is required to validate our findings.

Aberrant Expression of High Mobility Group Box Protein 1 in the Idiopathic Inflammatory Myopathies.

IntroductionHigh Mobility Group Box Protein 1 (HMGB1) is a DNA-binding protein that exerts inflammatory or pro-repair effects upon translocation from the nucleus. We postulate aberrant HMGB1 expression in immune-mediated necrotising myopathy (IMNM).MethodsHerein, we compare HMGB1 expression (serological and sarcoplasmic) in patients with IMNM with that of other myositis subtypes using immunohistochemistry and ELISA.ResultsIMNM (n = 62) and inclusion body myositis (IBM, n = 14) patients had increased sarcoplasmic HMGB1 compared with other myositis patients (n = 46). Sarcoplasmic HMGB1 expression correlated with muscle weakness and histological myonecrosis, inflammation, regeneration and autophagy. Serum HMGB1 levels were elevated in patients with IMNM, dermatomyositis and polymositis, and those myositis patients with extramuscular inflammatory features.DiscussionAberrant HMGB1 expression occurs in myositis patients and correlates with weakness. A unique expression profile of elevated sarcoplasmic and serum HMGB1 was detected in IMNM.

Expression of HMGB1 and TLR4 in neuropsychiatric systemic lupus erythematosus patients with seizure disorders.

Previous studies show that the high-mobility group box protein 1 (HMGB1) and the toll-like receptor 4 (TLR4) participate in systemic lupus erythematosus (SLE). The two molecules contribute to the occurrence and persistence of seizures in various disease conditions, such as epilepsy. Since seizures are one of the most severe complications associated with neuropsychiatric SLE (NPSLE), the current study aimed at investigating whether HMGB1 and TLR4 play any role in NPSLE related seizures. Data from 291 SLE patients and 100 healthy controls (HC) were prospectively collected from 2013 to 2018. The ELISA test was used to determine serum levels of HMGB1 for all patients and HC and cerebrospinal fluid (CSF) levels of NPSLE patients. The expression levels of TLR4 by the peripheral blood monocytes (PBMCs) were determined by real-time PCR of TLR4 mRNA. Binary logistic regression and ROC curve analysis were used to predict NPSLE. Among the 291 SLE patients, 188 had active disease and were grouped into two, NPSLE (N=86) and Non-NPSLE (N=102) groups. Among the NPSLE patients, 21 had seizure disorders. Serum HMGB1 levels were increased in NPSLE (8.73±0.29 ng/mL) and were associated with disease activity (r=0.6527, P=0.000). Both serum and CSF HMGB1 levels in NPSLE patients with seizure disorders (9.59±0.63 and 2.90±2.29 ng/mL, respectively) were higher than in patients with other neuropsychiatric symptoms (8.45±0.33 and 2.56±1.70 ng/mL, respectively), though without significance. The gene expression of mRNA TLR4 in PBMCs was similar to serum HMGB1 in the investigated groups. Independent predictors of NPSLE were SLEDAI-2k (OR 1.25; 95% CI: 1.155-1.353), serum HMGB1 (OR 1.659; 95% CI: 1.266-2.175), and anti-Rib-P Ab (OR 3.296; 95% CI: 1.013-10.725). ROC curves for the above predictors had a large AUC (95% CI) of 0.936 (0.900-0.971), indicating a good prediction of NPSLE occurrence. The expression of HMGB1 and TLR4 was increased in NPSLE, but HMGB1 and TLR4 had minimal effect on NPSLE related seizures. The serum levels of HMGB1 were positively correlated with disease activity, and could, therefore, be a potential biomarker of NPSLE for use in future clinical practice.

Serum high mobility group box protein 1 (HMGB1) levels reflect clinical features of childhood hemophagocytic lymphohistiocytosis.

PurposeHemophagocytic lymphohistiocytosis (HLH) is a potentially lethal hyperinflammatory disorder. For further understanding of the pathogenesis of HLH, we examined serum levels of high mobility group box protein 1 (HMGB1) in children with HLH.Patients and methodsSerum HMGB1 levels were measured in 28 patients with HLH and 6 normal controls using a quantitative enzyme-linked immunosorbent assay. The patients were 21 boys and 7 girls, aged from 10 days to 21 years, with a median age of 8.5 years. The underlying conditions of HLH were infection-associated HLH in 18 patients, malignancy-associated HLH in 7 patients, and genetic HLH in 3 patients. The relations between serum HMGB1 levels and clinical symptoms and laboratory parameters were analyzed.ResultsSerum HMGB1 levels were significantly higher in patients with HLH than in normal controls (median, 6.5 ng/mL, interquartile range, 4.25–13.1). The serial serum HMGB1 levels in one patient fell to reflect the disease activity. Serum HMGB1 levels were significantly higher in patients with disseminated intravascular coagulation (DIC) than in patients without DIC (p<0.001) and were also significantly higher in patients with central nervous system (CNS) complications than in patients without CNS complications (p<0.01). Serum HMGB1 levels were positively correlated with aspartate aminotransferase (rs =0.48, p<0.01, Spearman’s rank correlation coefficient) and negatively correlated with fibrinogen (rs = −0.475, p=0.011) and hemoglobin (rs = −0.465, p=0.013).ConclusionSerum HMGB1 levels reflect clinical features of childhood HLH. HMGB1 is a potential mediator involved in the pathogenesis and determining the clinical findings of HLH.

Glycyrrhizin, a High-Mobility Group Box 1 Inhibitor, Improves Lipid Metabolism and Suppresses Vascular Inflammation in Apolipoprotein E Knockout Mice

Background: High-mobility group box protein 1 (HMGB1) is known to have proinflammatory properties; however, the mechanisms by which HMGB1 influences immune responses during atherosclerosis (AS) development are not well understood. Thus, this study investigated the relationship between HMGB1 and vascular inflammation in Apoe^–/– mice and whether glycyrrhizin (GLY), a small inhibitor of HMGB1, could have atheroprotective effects in AS. Methods: Apoe^–/– mice on a high-fat diet were treated with GLY (50 mg/kg) or vehicle by gavage once daily for 12 weeks, respectively. Results: The GLY group exhibited significantly decreased serum lipid levels, atherosclerotic plaque deposition, and serum HMGB1 levels, as well as an increased Treg/Th17 ratio. The GLY group displayed increased interleukin-10 (IL-10) and IL-2 expression and decreased IL-17A and IL-6 expression. Furthermore, the GA treatment significantly reduced STAT3 phosphorylation in Th17 cells and increased STAT5 phosphorylation in Treg cells. Conclusions: Our findings indicate that the attenuation of atherosclerotic lesions in Apoe^–/– mice by GLY might be associated with the amelioration of lipid metabolism abnormalities, inhibition of HMGB1 expression, and alterations in the Treg/Th17 ratio.

High expression of the HMGB1-TLR4 axis and its downstream signaling factors in patients with Parkinson's disease and the relationship of pathological staging.

ObjectiveTo detect the expression of high‐mobility group box protein 1 (HMGB1) and toll‐like receptor 4 (TLR4) and their downstream signaling factors—myeloid differentiation factor 88 (MyD88), nuclear factor kappa B (NF‐κB), and tumor necrosis factor alpha (TNF‐α)—in the sera of patients with Parkinson's disease (PD) in order to evaluate the relationship of the HMGB1–TLR4 axis with PD development and progression.MethodsThe serum HMGB1 and TLR4 protein levels of 120 patients with PD and 100 healthy volunteers were measured using double‐antibody sandwich ELISA, and their correlations with PD staging, disease duration, drug treatment effectiveness, and clinical classification were analyzed. In addition, their correlations with the key downstream factors of the HMGB1–TLR4 axis (MyD88, NF‐κB, and TNF‐α) were analyzed.ResultsHMGB1 and TLR4 expressions were higher in the peripheral blood of patients with PD than in healthy volunteers. PD patients with poor drug treatment outcomes had significantly higher HMGB1 and TLR4 expressions than PD patients with stable drug treatment outcomes. Higher HMGB1 and TLR4 expressions were found in patients at higher PD stages, and patients with >4‐year disease duration had significantly higher HMGB1 and TLR4 expressions than patients with <4‐year disease duration. No significant difference in HMGB1 and TLR4 expressions was found among patients with tremor‐dominant, akinetic‐rigid, and mixed subtypes of PD. NF‐κB and TNF‐α expressions were positively correlated with high expression of the HMGB1–TLR4 axis.ConclusionHigh expression of the HMGB1–TLR4 axis is closely associated with PD development, progression, drug treatment effectiveness, staging, and disease duration and has great significance for PD diagnosis and treatment.

Blood purification treatment initiated at the time of sepsis diagnosis effectively attenuates serum HMGB1 upregulation and improves patient prognosis.

The aim of the present study was to investigate the increase in serum and urine levels of high mobility group box protein 1 (HMGB1) during sepsis and the effect of blood purification treatments on HMGB1 levels and patient prognosis. A total of 40 intensive care patients with sepsis were randomly assigned to different groups (n=10 per group): A control group (sepsis group), a continuous renal replacement treatment (CRRT) group, a hemoperfusion (HP) group and an HP+CRRT group. The blood purification treatments using HP and/or CRRT were performed immediately after the diagnosis of sepsis. HMGB1 levels were measured using ELISA, and Acute Physiology and Chronic Health Evaluation (APACHE) II scores and 30-day survival rates were evaluated. Relative to a healthy control group (n=10), HMGB1 levels were observed to be significantly upregulated during sepsis (P<0.05). Following the initiation of sepsis, serum HMGB1 continued to increase in the sepsis group and was significantly elevated at 24 h (P<0.05), whereas urine HMGB1 levels decreased significantly at 12 and 24 h (P<0.05). Serum HMGB1 levels were significantly positively correlated with APACHE II scores (r=0.7284, P<0.01) and significantly negatively correlated with urine HMGB1 levels (r=−0.5103, P=0.026). Serum HMGB1 levels were significantly reduced in the HP and HP+CRRT groups by 12 and 24 h following the initiation of treatment (both P<0.05). Changes in the urine HMGB1 level differed in each group. Relative to the sepsis group, the APACHE II scores of all blood purification groups were significantly reduced (P<0.05) and the 30-day survival rate of the HP+CRRT group was significantly increased (P=0.0107). The results of the present study indicate that blood purification initiated at the point of diagnosis in patients with sepsis may attenuate serum HMGB1 upregulation, promote urinary excretion of HMGB1 and improve the prognosis of sepsis.

OA22.03 HMGB1, a Target for Mesothelioma Therapy and a Biomarker to Detect Asbestos Exposure and to Identify Mesothelioma Patients

Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. We compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. Previously proposed MM biomarkers fibulin-3, osteopontin, and mesothelin were also blindly measured in blood collected from participants to the study. HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. Moreover, we found that HMGB1 drives MM development and sustains MM progression, and we demonstrated that targeting HMGB1 inhibits MM cell growth and motility in vitro, reduced tumor growth in vivo and prolonged survival. Despite the relatively small size of our cohorts, our results are of exceptional significance and clinical relevance as they provide the first biomarker of asbestos exposure and indicate that hyper-acetylated HMGB1 is a very sensitive and specific biomarker to differentiate MM patients from individuals occupationally exposed to asbestos and unexposed controls. Moreover, our results on HMGB1 inhibitors indicate that HMGB1 targeting hampers the malignant phenotype of MM, offering a novel potential therapeutic approach to patients afflicted with this dismal disease.

High mobility group box protein 1-A prognostic marker for structural joint damage in 10-year follow-up of patients with juvenile idiopathic arthritis.

High mobility group box protein 1 (HMGB1) is an important pro-inflammatory mediator in adult rheumatoid arthritis. The diagnostic utility of HMGB1 in Juvenile Idiopathic Arthritis (JIA) is still unclear. The aim was to examine whether serum HMGB1 levels are associated with inflammation, radiological disease progression, and long-term prognosis in JIA. We included 131 children with JIA from a population-based prevalence study; 38 of them were prospectively followed up for 10 years. Clinical and laboratory disease characteristics at study entry and after 10 years as well as radiological progression over 10 years were recorded. HMGB1 levels were analyzed by an ELISA. The HMGB1 levels were similar in children with different JIA subgroups and in children with established (53%) or newly diagnosed (47%) disease. HMGB1 levels did not differ between groups at entry into the study or at 10 years, by sex, or by the presence or absence of RF or ANA antibodies. HMGB1 levels at the study entry correlated with HMGB1 levels at 10 years and with blood neutrophil count. Most importantly, children with destructive arthritis at 10 years had a tendency toward higher HMGB1 levels at study entry (median 1.2 vs 0.6ng/ml, ns) and displayed 4-fold higher circulating HMGB1 levels (median 3.4 vs 0.8ng/ml, p = 0.0014) than children without radiological destructions. Our results suggest that HMGB1 is a marker of inflammatory activity in children with JIA. Higher serum HMGB1 levels are related to more destructive JIA and could be used as a negative prognostic marker at the disease start. Clinicaltrials.gov NCT01905319. Registered July 16, 2013.

HMGB1 and thrombin mediate the blood-brain barrier dysfunction acting as biomarkers of neuroinflammation and progression to neurodegeneration in Alzheimer's disease.

BackgroundThe blood-brain barrier (BBB) dysfunction represents an early feature of Alzheimer’s disease (AD) that precedes the hallmarks of amyloid beta (amyloid β) plaque deposition and neuronal neurofibrillary tangle (NFT) formation. A damaged BBB correlates directly with neuroinflammation involving microglial activation and reactive astrogliosis, which is associated with increased expression and/or release of high-mobility group box protein 1 (HMGB1) and thrombin. However, the link between the presence of these molecules, BBB damage, and progression to neurodegeneration in AD is still elusive. Therefore, we aimed to profile and validate non-invasive clinical biomarkers of BBB dysfunction and neuroinflammation to assess the progression to neurodegeneration in mild cognitive impairment (MCI) and AD patients.MethodsWe determined the serum levels of various proinflammatory damage-associated molecules in aged control subjects and patients with MCI or AD using validated ELISA kits. We then assessed the specific and direct effects of such molecules on BBB integrity in vitro using human primary brain microvascular endothelial cells or a cell line.ResultsWe observed a significant increase in serum HMGB1 and soluble receptor for advanced glycation end products (sRAGE) that correlated well with amyloid beta levels in AD patients (vs. control subjects). Interestingly, serum HMGB1 levels were significantly elevated in MCI patients compared to controls or AD patients. In addition, as a marker of BBB damage, soluble thrombomodulin (sTM) antigen, and activity were significantly (and distinctly) increased in MCI and AD patients. Direct in vitro BBB integrity assessment further revealed a significant and concentration-dependent increase in paracellular permeability to dextrans by HMGB1 or α-thrombin, possibly through disruption of zona occludins-1 bands. Pre-treatment with anti-HMGB1 monoclonal antibody blocked HMGB1 effects and leaving BBB integrity intact.ConclusionsOur current studies indicate that thrombin and HMGB1 are causal proximate proinflammatory mediators of BBB dysfunction, while sTM levels may indicate BBB endothelial damage; HMGB1 and sRAGE might serve as clinical biomarkers for progression and/or therapeutic efficacy along the AD spectrum.

Abstract 3112: HMGB1 and its isoform are sensitive and specific biomarkers to detect asbestos exposure and to identify mesothelioma patients

Abstract Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. We propose total and hyper-acetylated HMGB1 as valuable biomarkers to differentiate MM patients from individuals professionally exposed to asbestos and from unexposed people. Citation Format: Andrea Napolitano, Daniel J. Antoine, Laura Pellegrini, Francine Baumann, Ian Pagano, Sandra Pastorino, Chandra M. Goparaju, Kirill Prokrym, Claudia Canino, Harvey I. Pass, Michele Carbone, Haining Yang. HMGB1 and its isoform are sensitive and specific biomarkers to detect asbestos exposure and to identify mesothelioma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3112.

Analysis of the expression of HMGB-1, CXCL16, miRNA-30a, and TGF-β1 in primary nephritic syndrome patients and its significance.

We investigated the expression levels of high-mobility group box protein 1 (HMGB-1), CXC chemokine ligand 16 (CXCL16), microRNA (miRNA)-30a and transforming growth factor ß1 (TGF-ß1) in primary nephritic syndrome (PNS) patients and the clinical significance of this expression. A total of 56 patients with PNS were included in the PNS group, while 50 healthy subjects formed the normal control group. Serum levels of HMGB-1, CXCL16, miRNA-30a, and urinary TGF-ß1 concentrations were quantified along with other biochemical indices, including serum albumin, triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and urinary proteins. The correlation between levels of HMGB-1, CXCL16, miRNA-30a, and TGF-ß1 and biochemical indexes was further analyzed. PNS group patients had significantly higher levels of HMGB-1, CXCL16, miRNA- 30a, and TGF-ß1 compared to the control group (P < 0.05). PNS patients also had higher 24-h urinary protein, TG, TC, and LDL levels but lower serum albumin compared to subjects in the control group (P < 0.05). Serum HMGB-1, CXCL16, miRNA-30a, and urinary TGF-ß1 levels were all negatively correlated with serum albumin levels, but were positively correlated with TG, TC, LDL, and 24-h urinary protein (P < 0.05 in all cases). Additionally, a positive correlation existed among serum HMGB-1, CXCL16, miRNA-30a, and urinary TGF-ß1 levels (P < 0.01). HMGB-1, CXCL16, miRNA-30a, and urinary TGF-ß1 were highly expressed in PNS patients and may play important roles in the pathogenesis and development of PNS.

THU0042 Autoantibodies against High Mobility Group Box Protein-1 in Systemic Lupus Erythematosus: Association with Disease Activity and Other Antinuclear Antibodies

BackgroundSystemic lupus erythematosus (SLE) is a systemic autoimmune condition characterized by reduced ability to degrade and eliminate apoptotic cells. This probably contributes to the excessive production of antinuclear autoantibodies (ANA),...

Effects of postconditioning with electric vagal stimulation at different times on myocardial ischemia-reperfusion injury in rats

Objective To evaluate the optimum time of postconditioning with electric vagal stimulation on myocardial ischemia-reperfusion (I/R) injury in rats.Methods One hundred and twenty male Sprague-Dawley rats,aged 8 weeks,weighing 290-320 g,were randomly allocated into 6 groups (n =20 each):sham operation group (S group); I/R group; electric vagal stimulation postconditioning at 15 min of ischemia,the onset of reperfusion,and 30 and 60 min of reperfusion groups (P1-4 groups).The myocardial I/R model was established by occlusion of left anterior descending branch of coronary artery for 30 min followed by a 120 min of reperfusion.In P1-4 groups,the right vagus nerve was stimulated for 30 min with continuous electric rectangular pulses (2 ms,10 Hz,1-2 V) starting from 15 min of myocardial ischemia and the other procedures were similar to those previously described in group I/R.During the I/R period,the heart rate (HR) and systolic pressure (SP) were recorded and the rate pressure product (RPP) was calculated.Venous blood samples were collected from the jugular vein at 120 min of reperfusion for determination of serum concentrations of cardiac troponin Ⅰ (cTnI),creatine kinase MB (CK-MB),tumor necrosis factor α (TNF-α),high-mobility group box protein 1 (HMGB-1),intercellular adhension molecule 1 (ICAM-1),i nterleukin (IL)-1,IL-6 and IL-10 using ELISA.The animals were then sacrificed and myocardial infarct size was measured by Evans blue and TTC staining.The myocardial contents of TNF-α,HMGB1,ICAM-1,IL-1,IL-6 and IL-10 in ischemic regions were measured using ELISA.The development of ventricular arrhythmias at the initial 30 min of reperfusion was recorded.The severity of arrhythmias was quantified by a scoring system.Results Compared with S group,the myocardial infarct size and serum concentrations of cTnI and CK-MB in I/R and P1-4 groups,serum concentrations of TNF-α,HMGB-1,ICAM-1,IL-1 and IL-6 in I/R group,serum concentrations of HMGB-1,ICAM-1,IL-1 and IL-6 in P2-4 groups,and the serum concentration of IL-10 in P1 group were all significantly increased,the serum concentrations of TNF-α were significantly decreased in P1-4groups (P ＜ 0.05),while no significant changes were found in serum concentrations of HMGB-1,ICAM-1,IL-1 and IL-6 in P1 group (P ＞ 0.05).The myocardial infarct size was significantly smaller and serum concentrations of cTnI and CK-MB,both serum and myocardial levels of TNF-α,HMGB-1,ICAM-1,IL-1 and IL-6 in P1-4 groups,RPP,incidence and scores of ventricular arrhythmias in P1 group were all significantly lower than those in I/R group,while the myocardial content of IL-10 was significantly higher in P1 group than in I/R group (P ＜ 0.05).As compared with P1 group,RPP,incidence and scores of ventricular arrhythmias,serum concentrations of HMGB-1 and ICAM-1,myocardial content of ICAM-1 in P2-4 groups,myocardial contents of TNF-α and IL-1 in P3 group,myocardial infarct size,serum concentrations of cTnI and CK-MB,serum and myocardial levels of TNF-α,HMGB-1,ICAM-1,IL-1 and IL-6 in P4 group were all significantly increased,while the myocardial content of IL-10 was decreased in P4 group (P ＜ 0.05).Conclusion Postconditioning with electric vagal stimulation at 15 min of ischemia is optimal for reduction of myocardial I/R injury in rats. Key words: Vagus nerve; Electric stimulation therapy; Myocardial reperfusion injury

Redox Modulation of HMGB1-Related Signaling

In the cells' nuclei, high-mobility group box protein 1 (HMGB1) is a nonhistone chromatin-binding protein involved in the regulation of transcription. Extracellularly, HMGB1 acts as a danger molecule with properties of a proinflammatory cytokine. It can be actively secreted from myeloid cells or passively leak from any type of injured, necrotic cell. Increased serum levels of active HMGB1 are often found in pathogenic inflammatory conditions and correlate with worse prognoses in cancer, sepsis, and autoimmunity. By damaging cells, superoxide and peroxynitrite promote leakage of HMGB1. The activity of HMGB1 strongly depends on its redox state: Inflammatory-active HMGB1 requires an intramolecular disulfide bond (Cys23 and Cys45) and a reduced Cys106. Oxidation of the latter blocks its stimulatory activity and promotes immune tolerance. Reactive oxygen and nitrogen species create an oxidative environment and can be detoxified by superoxide dismutase (SOD), catalase, and peroxidases. Modifications of the oxidative environment influence HMGB1 activity. In this review, we hypothesize that manipulations of an oxidative environment by SOD mimics or by hydrogen sulfide are prone to decrease tissue damage. Both the concomitant decreased HMGB1 release and its redox chemical modifications ameliorate inflammation and tissue damage.

Elevated serum levels of high mobility group box protein 1 (HMGB1) in patients with ankylosing spondylitis and its association with disease activity and quality of life

This study was carried out to determine the serum levels of high mobility group box protein 1 (HMGB1) in patients with ankylosing spondylitis (AS) and to evaluate its correlation with disease activity and quality of life. According to our knowledge, it is the first trial evaluating HMGB1 levels in AS. Serum samples of 30 patients (18 males and 12 females) with AS and 29 healthy controls (HC) (15 females and 14 males) were collected. HMGB1 levels were measured by enzyme-linked immunosorbent assay, activity of disease was assessed according to the Bath AS Disease Activity Index (BASDAI), and functional status of patients was evaluated with Bath AS Functional Index (BASFI). Modified Schober, chest expansion values and AS Quality of Life Questionnaire (ASQoL) scores were noted. The serum levels of HMGB1 were obtained significantly increased in AS patients compared to HC (p < 0.05). There was no significant correlation between HMGB1 levels and ESR (p > 0.05), and CRP (p > 0.05) values. BASDAI, BASFI and ASQoL scores were also not correlated with serum levels of HMGB1 (p > 0.05). Our results suggest that HMGB1 might play an important role in the pathogenesis of AS; however, it seems not to be a good candidate for reflecting disease activity, functional abilities and the quality of life in patients with AS; on the other hand, the increased levels of HMGB1 in patients may open a new dimension for targeting this cytokine as a new therapy option in AS.

Relationship and mechanism between the serum level of HMGB1 and the mortality rate in patients with sepsis

Objective To investigate the relationship and mechanism between the serum level of high mobility group box protein-1(HMGB1)and the mortality rate in patients with sepsis.Methods The serum levels of HMGB1,superoxide dismutase(SOD)and malondialdehyde(MDA)in 48 patients with sepsis were determined.The clinical outcomes in those patients were recorded and anlyzed.Results After the onset of sepsis,the serum HMGB1 levels of both death group and survival group were increased gradually and peaked at 72h after the onset of the disease.The semm HMGB1 levels of death group were much higher than those of survival group except at 24h(t=6.07,6.20,24.43,all P＜0.05).The activity of serum SOD of death group was markedly lower than that of survival group at 12h,24h,48h and 72h(t=10.24,20.61,11.67,33.33,all P＜0.05),and the level of serum MDA of death group was significantly higher than those of survival group at all time points(t=26.06,22.17,23.86,9.49,5.95,all P＜0.05).There was a significantly positive correlation between the serum HMGB1 and MDA level.Conlusioa The increase in serum HMGB1 level may be the important reasoll for the increased mortality rate in patients with sepsis;Oxidant/antioxidant imbalance may be olle reason for the increase in serum HMGB1 level. Key words: High mobility group protein box 1; Supemxide dismutase; Malondialdehyde; Sepsis