Serum High Mobility Group Box 1 Levels In Patients Research Articles

Structural changes in the retina and serum HMGB1 levels are associated with decreased cognitive function in patients with Parkinson's disease

BackgroundCognitive impairment is a serious nonmotor symptom in patients with Parkinson's disease (PD). Currently, there are few studies investigating the relationship of serum markers and retinal structural changes with cognitive function in PD. ObjectiveTo investigate the relationship between retinal structural changes, serum high mobility group box-1 (HMGB1) levels and cognitive function and motor symptoms in PD patients. MethodsEighty-nine participants, including 47 PD patients and 42 healthy subjects, were enrolled. PD patients were divided into Parkinson's disease with normal cognitive (PD-NC), Parkinson's disease with mild cognitive impairment (PD-MCI), and Parkinson's disease with dementia (PDD) groups. The motor and nonmotor symptoms of PD patients were evaluated with clinical scale. Serum HMGB1 levels were detected by enzyme-linked immunosorbent assay (ELISA), and ganglion cell-inner plexiform layer complex (GCIPL) thickness changes in the macula were quantitatively analyzed by swept source optical coherence tomography (SS-OCT) in all patients. ResultsCompared with the control group, the macular GCIPL (t = −2.308, P = 0.023) was thinner and serum HMGB1 (z = −2.285, P = 0.022) was increased in PD patients. Macular GCIPL thickness in patients with PD-MCI and PDD were significantly lower than that in PD-NC patients, but there were no significant difference between the PD-MCI and PDD groups. Serum HMGB1 levels in patients with PD-MCI and PDD were significantly higher than those in PD-NC patients, and serum HMGB1 levels in PDD patients were higher than those in PD-MCI patients. Correlation analysis showed that serum HMGB1 levels in PD patients were positively correlated with disease duration, HY stage, UPDRS-I score, UPDRS-III score, and UPDRS total score and negatively correlated with MOCA score. Macular GCIPL thickness was negatively correlated with HY stage and positively correlated with MOCA score, and macular GCIPL thickness was negatively correlated with serum HMGB1 level. Logistic regression analysis showed that elevated serum HMGB1 level, thinner macular GCIPL thickness, and higher HY stage were independent risk factors for Parkinson's disease with cognitive impairment (PD-CI). The areas under the receiver operating characteristic curve (AUC) for the serum HMGB1 level and macular GCIPL thickness-based diagnosis of PD-MCI, PDD and PD-CI based on in patients with PD were 0.786 and 0.825, 0.915 and 0.856, 0.852 and 0.841, respectively. The AUC for the diagnosis of PD-MCI, PDD and PD-CI with serum HMGB1 level and GCIPL thickness combined were 0.869, 0.967 and 0.916, respectively. ConclusionThe macular GCIPL thickness and serum HMGB1 level are potential markers of cognitive impairment in PD patients, and their combination can significantly improve the accuracy of the diagnosis of cognitive impairment in PD.

The Role of HMGB1 in Invasive Candida albicans Infection.

High mobility group box 1 (HMGB1) is an important "late" inflammatory mediator in bacterial sepsis. Ethyl pyruvate (EP), an inhibitor of HMGB1, can prevent bacterial sepsis by decreasing HMGB1 levels. However, the role of HMGB1 in fungal sepsis is still unclear. Therefore, we investigated the role of HMGB1 and EP in invasive C. albicans infection. We measured serum HMGB1 levels in patients with sepsis with C. albicans infection and without fungal infection, and control subjects. We collected clinical indices to estimate correlations between HMGB1 levels and disease severity. Furthermore, we experimentally stimulated mice with C. albicans and C. albicans + EP. Then, we examined HMGB1 levels from serum and tissue, investigated serum levels of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), determined pathological changes in tissues, and assessed mortality. Serum HMGB1 levels in patients with severe sepsis with C. albicans infection were elevated. Increased HMGB1 levels were correlated with procalcitonin (PCT), C-reactive protein (CRP), 1,3-β-D-Glucan (BDG) and C. albicans sepsis severity. HMGB1 levels in serum and tissues were significantly increased within 7days after mice were infected with C. albicans. The administration of EP inhibited HMGB1 levels, decreased tissue damage, increased survival rates and inhibited the release of TNF-α and IL-6. HMGB1 levels were significantly increased in invasive C. albicans infections. EP prevented C. albicans lethality by decreasing HMGB1 expression and release. HMGB1 may provide an effective diagnostic and therapeutic target for invasive C. albicans infections.

Serum high‐mobility group box 1 is associated with the onset and severity of acute exacerbation of idiopathic pulmonary fibrosis

High-mobility group box 1 (HMGB1) is a known mediator of acute lung injury through the acceleration of pro-inflammatory -signalling. Previous studies showed that HMGB1 is increased in the lung and circulation of patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). This study investigated the predictive value of circulatory HMGB1 for disease progression and prognosis of IPF in the stable phase and AE phase. In total, 76 patients with stable IPF, 17 patients with AE-IPF, 37 patients with chronic obstructive pulmonary disease (COPD) and 74 healthy controls were included. Serum HMGB1 levels were compared among the four groups and the associations of HMGB1 levels with the onset of AE and prognosis were evaluated in patients with stable IPF. The prognostic value of HMGB1 was determined in AE-IPF. Serum HMGB1 levels in patients with stable IPF were significantly higher than those in healthy controls, and in patients with AE-IPF they were even higher than the levels in either of these groups (6.26 ± 5.27, 3.42 ± 2.69 and 19.20 ± 16.76 ng/mL, respectively). There was no significant difference in serum HMGB1 levels between stable IPF patients and COPD patients. Higher levels of HMGB1 were associated with earlier onset of AE in stable IPF patients and with shorter survival in AE-IPF patients (P = 0.030 and 0.001, respectively). Higher levels of serum HMGB1 predict earlier onset of AE in stable IPF patients and shorter survival in AE-IPF patients, indicating that HMGB1 is associated with acute deterioration of the disease.

A8855 Serum high mobility group box 1 are increaseed in patients of systemic vasculitis with hypertension

Objectives: High mobility group box 1 (HMGB1) is a kind of proinflammatory mediator that acts as an alarmin when released by dying, injured or activated cells. However, whether HMGB-1 as a kind of proinflammatory mediator is associated with VAs is still controversial, and studies are scarce especially in polyarteritis nodosa (PAN). This study aims to evaluate whether serum HMGB1 levels were associated with systemic vasculitis (VAs). Methods: The study population consisted of 43 patients with VAs and 43 healthy controls (HC). 30 patients with VAs had inactive stage, the other 13 patients were selected for having disease activity. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay (ELISA). Associations between serum HMGB1 levels with clinical and laboratory variables were analyzed. Results: Serum HMGB1 levels in patients with VAs were significantly higher than HC (P < 0.001). Serum HMGB1 levels were similar between active and inactive patients (P = 0.622) and no difference regarding serum HMGB1 levels could be found among VAs subsets (P = 0.366). Patients with renal involvement had higher serum HMGB1 levels than patients without renal involvement, but these differences did not reach statistical significance (P = 0.087). Correlation analysis showed that serum HMGB1 levels are not correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and serum creatinine (Scr). Receiver operating characteristic (ROC) analysis shown that the sensitivity of 72.1% and specificity of 83.7% for the diagnosis of VAs. Conclusion: Patients with VAs of serum HMGB1 levels are increased compared with HC, but might not reflect the disease activity and renal involvement of VAs

Elevated Serum High-Mobility Group Box-1 Protein Level Is Associated with Poor Functional Outcome in Ischemic Stroke

In experimental models, inhibition of high-mobility group box-1 (HMGB1) signaling has been reported to protect against the sequelae of ischemic stroke. Here, we determined the clinical significance of serum HMGB1 levels in patients with acute ischemic stroke. We enrolled 183 patients (114 men, 69 women; mean age: 72.7 years) over 6 consecutive months. On admission and day 7, we recorded the National Institutes of Health Stroke Scale scores and measured serum high-sensitivity C-reactive protein (hs-CRP) and HMGB1 levels. Stroke volumes were estimated using diffusion-weighted magnetic resonance imaging performed on admission. One year later, clinical outcome was assessed using the modified Rankin Scale (mRS). Serum hs-CRP and HMGB1 levels in patients with ischemic stroke were increased relative to healthy controls (both P < .01). On day 7, hs-CRP, but not HMBG1, levels had increased significantly relative to levels at admission (P < .01 and .54, respectively). Higher HMGB1, but not hs-CRP, levels at day 7 correlated with larger stroke volumes (P < .01 and .28, respectively). HMGB1 levels did not significantly differ between stroke subtypes. Multiple logistic regression analysis indicated that a serum HMGB1 level higher than 7.5 ng/mL was an independent risk factor for poor prognosis, defined as a 1-year mRS score of 3-6 (odds ratio, 2.34; 95% confidence interval, 1.02-5.38). Acute ischemic stroke is associated with elevated serum HMGB1 levels, and HMGB1 levels at admission independently predict poor outcome at 1 year. These results suggest that HMGB1 quantification provides more accurate prognostic information after ischemic stroke.

Elevated high-mobility group B1 levels in active adult-onset Still's disease associated with systemic score and skin rash.

High-mobility group box-1 (HMGB1) is a nuclear protein, and such prototypical damage-associated molecular patterns mediate the immune response in the noninfectious inflammatory response. Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder involved in the dysregulation of innate immunity. We investigated the serum HMGB1 level in patients with AOSD and evaluated its clinical significance. Blood samples were collected from 40 patients with active AOSD and 40 healthy controls (HC). Of the patients with AOSD, follow-up samples were collected from 16 patients after a resolution of AOSD disease activity. Serum HMGB1 levels in patients with AOSD were higher than those of the HC (10.0 ± 5.85 vs. 5.15 ± 1.79ng/mL, p < 0.001). Serum HMGB1 levels were found to be correlated with C-reactive protein (CRP) and the systemic score. The AOSD patient who had a sore throat showed a higher serum HMGB1 level than those patients who did not, and the patient with a skin rash had higher levels than the patients without. In addition, the serum HMGB1 levels were decreased after the resolution of disease activity in the AOSD patients who were followed up. The serum HMGB1 levels were elevated in AOSD patients compared to the HC and were correlated with both CRP and the systemic score. The HMGB1 levels were associated with skin rash and a sore throat in AOSD patients. After the resolution of disease activity, serum HMGB1 levels were found to have decreased.

The association of HMGB1 expression with clinicopathological significance and prognosis in hepatocellular carcinoma: a meta-analysis and literature review.

BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer, and it is the second most common cancer-related mortality globally. The prognostic value of high mobility group box 1 (HMGB1) remains controversial. The purpose of this study is to conduct a meta-analysis and literature review to evaluate the association of HMGB1 expression with the prognosis of patients with HCC.MethodsA detailed literature search was made in Medline, Google Scholar and others for related research publications. The data were extracted and assessed by two reviewers independently. Analysis of pooled data were performed, Hazard Ratio (HR) and mean difference with corresponding confidence intervals (CIs) were calculated and summarized respectively.Results10 relevant articles were included for this meta-analysis study. HMGB1 mRNA levels in HCC were significantly higher than those in normal (p<0.00001) and para-tumor tissues (p = 0.002) respectively. The protein levels of HMGB1 in HCC were significantly higher than those in para-tumor tissues (p = 0.005). Two studies reported the serum HMGB1 levels in patients with HCC of TNM stages, and indicating significantly different between stage I and II, stage II and III, as well as stage III and IV (two studies showed p<0.01 and p<0.001 respectively). The overall survival (OS) was significantly shorter in HCC patients with high HMGB1 expression compared those with low HMGB1 expression and the pooled HR was 1.31 with 95% CI 1.20–1.44, Z = 5.82, p<0.0001. Two additional studies showed that there were higher serum HMGB1 levels in patients with chronic hepatitis than those in healthy people (p<0.05).ConclusionsThe results of this meta-analysis suggest that HMGB1 mRNA and protein tissue levels in the patients with HCC are significantly higher than those in para-tumor and normal liver tissues respectively. Tissue HMGB1 overexpression is a potential biomarker for HCC diagnosis, and it is significantly associated with the prognosis of patients with HCC.

Increased serum HMGB1 levels in patients with Henoch-Schönlein purpura.

High-mobility group box-1 (HMGB1) has been implicated as a pro-inflammatory cytokine in the pathogenesis of various inflammatory and autoimmune diseases. However, information about HMGB1 in Henoch-Schönlein purpura (HSP) is still unclear. Herein, we investigated the role of HMGB1 in patients with HSP and the pro-inflammatory effects of HMGB1 on human dermal microvascular endothelial cell line (HMEC-1). Serum HMGB1 levels in patients with HSP together with patients with allergic vasculitis (AV) and urticarial vasculitis (UV) were detected by enzyme-linked immunosorbent assay (ELISA). HMEC-1 cells were treated with HMGB1 at concentrations ranging from 4 ng/ml to 100 ng/ml. Serum HMGB1 levels were significantly increased in patients with HSP, AV and UV, when compared with those in control group. Moreover, abundant cytoplasmic expression of HMGB1 was observed in endothelial cells in lesional skin of HSP patients. Using membrane cytokine antibody array, we indicate that HMGB1 markedly induced TNF-α and IL-6 release in cultured supernatant. Furthermore, by real-time quantitative PCR and ELISA, the effects of HMGB1 on these cytokines production in HMEC-1 cells were established. Finally, Western blot data revealed that HMGB1 can induce phosphorylation of inhibitor of κB-α (IκBα) and the nuclear translocation of nuclear factor-κB (NF-κB) p65 in HMEC-1 cells. In conclusion, this study provides first observations on the association of HMGB1 with HSP. We suggest that HMGB1 may be an important mediator of endothelial inflammation through the induction of TNF-α and IL-6 production and may play a crucial role in the pathogenesis of HSP.

Correlation between serum high-mobility group box-1 levels and high-sensitivity C-reactive protein and troponin I in patients with coronary artery disease

The aim of this study was to evaluate the correlation between levels of serum high-mobility group box-1 (HMGB1) and high-sensitivity C-reactive protein (hs-CRP) and cardiac troponin I in patients with coronary artery disease. The levels of serum HMGB1, hs-CRP and cardiac troponin I were measured in 98 patients with coronary artery disease and in 30 healthy subjects. The correlation between serum HMGB1 levels and hs-CRP and cardiac troponin I levels was analyzed. Serum HMGB1 levels in patients with coronary artery disease were higher compared with those in healthy volunteers (63.5±15.29 vs. 21.98±4.33 μg/l; P<0.01). Serum HMGB1 levels in patients with acute myocardial infarction were higher compared with those in patients with unstable and stable angina pectoris (77.53±6.86 vs. 63.67±8.6 and 44.39±9.01 μg/l, respectively; both P<0.01). The levels of HMGB1 were positively correlated with hs-CRP and cardiac troponin I levels (r=0.657 and 0.554, respectively; both P<0.01) in patients with coronary artery disease. In conclusion, serum HMGB1 levels were elevated in patients with coronary artery disease, particularly in those with acute myocardial infarction. The levels of HMGB1 were correlated with the levels of hs-CRP and cardiac troponin I.

Targeting HMGB1 inhibits ovarian cancer growth and metastasis by lentivirus‐mediated RNA interference

High-mobility group box 1 (HMGB1), a nuclear and extracellular protein, is implicated in the development and progression of some types of cancers. However, no information is available to date regarding the function of HMGB1 in ovarian cancer. In this study, we performed cDNA microarray analysis and identified HMGB1 as a gene dramatically elevated in the highly invasive subclone S1 compared with the low invasive subclone S21 derived from the same cell line SKOV3. Then lentivirus vector with HMGB1 shRNA was constructed and infected the highly invasive cell line S1, A1, and HO8910PM. Real-time RT-PCR, Western blot, and IHC results confirmed the down-regulation of HMGB1 expression by its shRNA was about 80-90% at both the mRNA and protein levels. Knockdown of HMGB1 significantly suppressed ovarian cancer cell proliferation and induced cell cycle arrest at the G1/G0 phase, which was accompanied by decreased expressions of cyclin D1 and PCNA. Furthermore, knockdown of HMGB1 induced ovarian cancer cell apoptosis, which was mediated by increased expression of Bax and decreased expression of Bcl-2. Finally, knockdown of HMGB1 significantly inhibited ovarian cancer cell invasion and metastasis, which was regulated by decreased expressions of MMP2 and MMP9. Serum HMGB1 levels in patients with epithelial ovarian cancer were significantly higher than that in patients with benign ovarian tumor and healthy controls. These results indicate that HMGB1 is a newly identified gene associated with ovarian cancer growth and metastasis. HMGB1 may serve as a new therapeutic target for the treatment of ovarian cancer in the future.

Differential evaluation of hepatocyte apoptosis and necrosis in acute liver injury

The significance of cytokelatin-18 fragment cleaved by caspase-3 (CK-18-fr) and high mobility group box-1 (HMGB-1) were evaluated experimentally and clinically for the differential evaluation of hepatocyte apoptosis and necrosis in patients with acute hepatic injury (AHI). In this study, typical apoptosis and necrosis were induced in HepG2 cells by staurosporin (STS) and hydrogen peroxide, respectively. Intracellular generation of CK-18-fr and extracellular leakage of CK-18-fr and HMGB-1 were determined. In the clinical study, serum CK-18-fr and HMGB-1 levels in 84 patients with AHI of varied severity and etiology were measured and compared with conventional liver tests. In the experimental study, CK-18-fr was rapidly increased after STS stimulation, and peaked after 6 h inside the cells but increased in the medium 12 h after stimulation, while hydrogen peroxide stimulation caused no increase either in- or outside the cells. Extracellular HMGB-1 levels markedly increased after hydrogen peroxide stimulation, but did not change after STS stimulation. In the clinical study, serum CK-18-fr increased in correlation with serum aminotransferase, but not other liver tests or markers of disease severity of AHI,. Serum HMGB-1 levels mildly increased without any correlation to liver test or disease severity. Serum HMGB-1 levels in patients with circulation disturbance was significantly higher than that in patients with other etiologies. The simultaneous determination of the serum CK-18-fr and HMGB-1 may be useful in the differential diagnosis of hetocellular death in AHI, which is primarily due to apoptosis except in patients with circulation disturbance.

Increased HMGB1 expression and release by mononuclear cells following surgical/anesthesia trauma

IntroductionHigh mobility group box 1 (HMGB1) is a key mediator of inflammation that is actively secreted by macrophages and/or passively released from damaged cells. The proinflammatory role of HMGB1 has been demonstrated in both animal models and humans, since the severity of inflammatory response is strictly related to serum HMGB1 levels in patients suffering from traumatic insult, including operative trauma. This study was undertaken to investigate HMGB1 production kinetics in patients undergoing major elective surgery and to address how circulating mononuclear cells are implicated in this setting. Moreover, we explored the possible relationship between HMGB1 and the proinflammatory cytokine interleukin-6 (IL-6).MethodsForty-seven subjects, American Society of Anesthesiologists physical status I and II, scheduled for major abdominal procedures, were enrolled. After intravenous medication with midazolam (0.025 mg/Kg), all patients received a standard general anesthesia protocol, by thiopentone sodium (5 mg/Kg) and fentanyl (1.4 μg/Kg), plus injected Vecuronium (0.08 mg/Kg). Venous peripheral blood was drawn from patients at three different times, t0: before surgery, t1: immediately after surgical procedure; t2: at 24 hours following intervention. Monocytes were purified by incubation with anti-CD14-coated microbeads, followed by sorting with a magnetic device. Cellular localization of HMGB1 was investigated by flow cytometry assay; HMGB1 release in the serum by Western blot. Serum samples were tested for IL-6 levels by ELISA. A one-way repeated-measures analysis ANOVA was performed to assess differences in HMGB1 concentration over time, in monocytes and serum.ResultsWe show that: a) cellular expression of HMGB1 in monocytes at t1 was significantly higher as compared to t0; b) at t2, a significant increase of HMGB1 levels was found in the sera of patients. Such an increase was concomitant to a significant down-regulation of cellular HMGB1, suggesting that the release of HMGB1 might partially derive from mononuclear cells; c) treatment of monocytes with HMGB1 induced in vitro the release of IL-6; d) at t2, high amounts of circulating IL-6 were detected as compared to t0.ConclusionsThis study demonstrates for the first time that surgical/anesthesia trauma is able to induce an early intracellular upregulation of HMGB1 in monocytes of surgical patients, suggesting that HMGB1 derives, at least partially, from monocytes.

Activation of gene expression in human neutrophils by high mobility group box 1 protein.

High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-kappaB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.