Serum High Mobility Group Box 1 Concentrations Research Articles

Prognostic value of serum high-mobility group box 1 in neonates with neonatal encephalopathy.

This study aimed to investigate the diagnostic potential of serum high-mobility group box 1 (HMGB1) in neonatal encephalopathy (NE). A retrospective study was conducted, analyzing 216 neonates diagnosed with NE. The neonates were divided into two groups based on their outcomes at 28 days. Serum HMGB1 levels were compared between the two groups. ROC analysis was used to determine the predictive value of HMGB1. At 28 days, 174 infants had a good prognosis, while 42 had a poor prognosis. Infants with a poor prognosis had higher serum HMGB1 concentrations within 24 h of birth. Multifactorial analysis revealed that extremely preterm birth, extremely low birth weight, an Apgar score of 0-3 at 5 min, premature rupture of membranes by the mother, moderate to severe NE, and serum HMGB1 > 6.14 ng/mL are independent risk factors for poor prognosis. HMGB1 has predictive value for short-term prognosis with an area under the curve of 0.79. Elevated HMGB1 levels in the acute phase of NE are associated with poor short-term neonatal outcomes. The decrease in HMGB1 concentrations over time correlates with a good prognosis; whereas an increase suggests a poor prognosis. Early measurement of serum HMGB1 could aid in the prognostic assessment of neonates with NE. Although serum HMGB1 has emerged as a potential predictor of neonatal outcomes in neonatal encephalopathy, the relationship of HMGB1 levels to neonatal encephalopathy severity remains unclear. The current results demonstrate that infants with a poor prognosis had higher serum HMGB1 concentrations within 24 h of birth. Importantly, elevated serum HMGB1 levels in the acute phase of neonatal encephalopathy are associated with poor short-term neonatal outcomes. Our findings reveal the clinical values of HMGB1 in the prediction of neonatal outcomes in NE patients.

Insight into the Interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in IgA Vasculitis (IgAV).

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) and protocadherin 1 (PCDH1) in the pathogenesis of IgAV. Our prospective study enrolled 86 patients with IgAV and 70 controls. HMGB1, RAGE, Gd-IgA1 and PCDH1 in serum and urine were determined by the enzyme-linked immunosorbent assay (ELISA) method at the onset of the disease and after a six-month interval in patients and once in the control group. Serum concentrations of HMGB1, RAGE and PCDH1 and urinary concentrations of HMGB1, RAGE, Gd-IgA1 and PCDH1 were significantly higher in patients with IgAV than in the control group (p < 0.001). Concentrations of HMGB1 (5573 pg/mL vs. 3477 pg/mL vs. 1088 pg/mL, p < 0.001) and RAGE (309 pg/mL vs. 302.4 pg/mL vs. 201.3 pg/mL, p = 0.012) in the serum of patients remained significantly elevated when the disease onset was compared with the six-month follow-up interval, and thus could be a potential marker of disease activity. Urinary concentration of HMGB1 measured in the follow-up period was higher in patients with nephritis compared to IgAV without nephritis (270.9 (146.7-542.7) ng/mmol vs. 133.2 (85.9-318.6) ng/mmol, p = 0.049) and significantly positively correlated with the urine albumine to creatinine ratio (τ = 0.184, p < 0.05), the number of erythrocytes in urine samples (τ = 0.193, p < 0.05) and with the outcome of nephritis (τ = 0.287, p < 0.05); therefore, HMGB1 could be a potential tool for monitoring patients with IgAV who develop nephritis. Taken together, our results imply a possible interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in the development of IgAV. The identification of sensitive biomarkers in IgAV may provide disease prevention and future therapeutics.

Serum levels of high mobility group box-1 protein (HMGB1) and soluble receptors of advanced glycation end-products (RAGE) in depressed patients treated with electroconvulsive therapy.

High mobility group box-1 (HMGB1) is one of the damage-associated molecular patterns produced by stress and induces inflammatory responses mediated by receptors of advanced glycation end-products (RAGE) on the cell surface. Meanwhile, soluble RAGE (sRAGE) exhibits an anti-inflammatory effect by capturing HMGB1. Animal models have shown upregulation of HMGB1 and RAGE in the brain or blood, suggesting the involvement of these proteins in depression pathophysiology. However, there have been no reports using blood from depressed patients, nor ones focusing on HMGB1 and sRAGE changes associated with treatment and their relationship to depressive symptoms. Serum HMGB1 and sRAGE concentrations were measured by enzyme-linked immunosorbent assay in a group of patients with severe major depressive disorder (MDD) (11 males and 14 females) who required treatment with electroconvulsive therapy (ECT), and also in a group of 25 age- and gender-matched healthy subjects. HMGB1 and sRAGE concentrations were also measured before and after a course of ECT. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression (HAMD). There was no significant difference in HMGB1 and sRAGE concentrations in the MDD group compared to healthy subjects. Although ECT significantly improved depressive symptoms, there was no significant change in HMGB1 and sRAGE concentrations before and after treatment. There was also no significant correlation between HMGB1 and sRAGE concentrations and the HAMD total score or subitem scores. There were no changes in HMGB1 and sRAGE in the peripheral blood of severely depressed patients, and concentrations had no relationship with symptoms or ECT.

Implication of High-mobility group box-1 and skin post mortem changes in estimation of time passed since death: Animal and human study.

Determination of postmortem interval (PMI) is one of the goals of the forensic autopsy. The study aimed to correlate the postmortem skin changes and High-mobility group box-1 (HMGB1) alterations in serum and skin immunohistochemical staining with time since death. We used animal and human specimens; forty adult male albino rats were dissected to obtain samples at PMI (0, 3, 6, 12, 24h); forty human medicolegal autopsy cases with a known time of death (within the first 24h PMI). Cases were classified into 5 groups according to the PMI: I (0h); II (≤3h); III (4 to 6); IV (7 to 12); V (13 to 24) hour intervals after death; blood and full-thickness skin samples were collected from both models. Results showed a significant time-dependent elevation in serum HMGB1 levels along with its overexpression in immunohistochemically stained skin tissue. Also, the degree of histopathological changes in epidermis, dermis, and hypodermis progressively increased with PMI in both models. The timetable of postmortem skin histological changes, serum HMGB1 concentration, and immunoexpression for HMGB1 proteins in skin tissues has a profile that could serve as actual and simply convenient parameters for accurate determination of postmortem intervals in both models. HMGB1 displayed a pivotal role in the estimation of PMI at the examined periods.

CSF high-mobility group box 1 is associated with drug-resistance and symptomatic etiology in adult patients with epilepsy

PurposeExtracellular high-mobility group box 1 (HMGB1) is considered a proinflammatory mediator and is involved in various neurological disorders. This study aims to determine the expression profiles of HMGB1 in cerebrospinal fluid (CSF) and paired serum, and to explore whether there is a relationship between CSF HMGB1 concentrations with seizure parameters in adult patients with epilepsy. MethodsCSF and paired serum HMGB1 concentrations were measured in patients with drug-refractory epilepsy (DRE, n = 27), newly diagnosed epilepsy (NDE, n = 56), and other non-inflammatory neurological disorders (ONNDs, n = 22). The correlations in HMGB1 levels between CSF and blood were performed. The associations between HMGB1 levels and seizure parameters were analyzed. ResultsMean (± SD) CSF HMGB1 concentrations were 5.08 ± 3.06, 3.03 ± 2.25, 0.83 ± 0.77 ng/mL in patients with DRE, NDE, and ONNDs, respectively. Corresponding mean (± SD) serum concentrations were 4.53 ± 2.81, 2.32 ± 1.54, 1.56 ± 0.84 ng/mL. The CSF HMGB1 concentrations were significantly higher in the DRE and NDE groups compared with the ONNDs group (p < 0.001). There were no correlations in HMGB1 levels between CSF and serum in the DRE, NDE, and ONNDs groups. Furthermore, patients with symptomatic etiology showed significantly high levels of CSF HMGB1. Patients without remission expressed elevated levels of CSF HMGB1 at one-year follow-up. Additionally, the CSF HMGB1 levels were positively associated with seizure frequency. ConclusionOur study shows that HMGB1 may be a critical player in seizure mechanisms and CSF HMGB1 might be predictive in determining epilepsy etiology and prognosis.

Clinical signs, duodenal histopathological grades, and serum high-mobility group box 1 concentrations in dogs with inflammatory bowel disease.

BackgroundInflammatory bowel disease (IBD) commonly occurs in dogs, but there is lack of information about potential biomarkers of clinical and histopathologic severity.ObjectiveTo examine the role of serum C‐reactive protein (CRP) and high‐mobility group box 1 (HMGB1) concentrations in dogs with IBD.AnimalsSeventeen dogs with IBD and 25 healthy dogs.MethodsIn this prospective study, duodenal histopathologic severity was graded, and the clinical severity of IBD was assessed by the canine IBD assessment index (CIBDAI) score in dogs with IBD. Serum CRP and HMGB1 concentrations were compared between IBD and healthy dogs and analyzed according to histopathologic grade in dogs with IBD. The correlations between serum CRP and HMGB1 concentrations and the CIBDAI score were evaluated.ResultsDogs with IBD had higher serum CRP (median [range] = 20.39 [1.53‐67.69] μg/mL vs 2.31 [0.17‐11.49] μg/mL; P < .001) and HMGB1 concentrations (0.44 [0.07‐1.58] ng/mL vs 0.05 [0.01‐0.25] ng/mL; P < .001) than healthy dogs. The serum HMGB1 concentration was higher in IBD dogs with a moderate to severe histopathologic grade (0.51 [0.30‐1.58] ng/mL, P = .03) than in those with a mild histopathologic grade (0.17 [0.07‐0.75] ng/mL). Serum CRP concentrations and CIBDAI score were positively correlated in dogs with IBD (r s = .49, P = .05).Conclusions and Clinical ImportanceSerum HMGB1 could be a potential biomarker for diagnosing IBD and might be indicative of histopathologic severity in dogs, whereas serum CRP might be an indicator of clinical severity.

HMGB1 signaling-regulated endoplasmic reticulum stress mediates intestinal ischemia/reperfusion-induced acute renal damage

BackgroundIschemia/reperfusion of the intestine often leads to distant organ injury, but the mechanism of intestinal ischemia/reperfusion-induced renal dysfunction is still not clear. The present study aimed to investigate the mechanisms of acute renal damage after intestinal ischemia/reperfusion challenge and explore the role of released high-mobility group box-1 in this process. MethodsIntestinal ischemia/reperfusion was induced in male Sprague-Dawley rats by clamping the superior mesenteric artery for 1.5 hours. At different reperfusion time points, anti−high-mobility group box-1 neutralizing antibodies or ethyl pyruvate were administered to neutralize or inhibit circulating high-mobility group box-1, respectively. ResultsSignificant kidney injury was observed after 6 hours of intestinal reperfusion, as indicated by increased serum levels of urea nitrogen and creatinine, increased expression of neutrophil gelatinase-associated lipocalin, interleukin-6, and MIP-2, and enhanced cell apoptosis, as indicated by cleaved caspase 3 levels in renal tissues. The levels of phosphorylated eIF2ɑ, activating transcription factor 4, and C/EBP-homologous protein (CHOP) were markedly elevated, indicating the activation of endoplasmic reticulum stress in the impaired kidney. High-mobility group box-1 translocated to cytoplasm in the intestine and serum concentrations of high-mobility group box-1 increased notably during the reperfusion phase. Both anti−high-mobility group box-1 antibodies and ethyl pyruvate treatment significantly reduced serum high-mobility group box-1 concentrations, attenuated endoplasmic reticulum stress in renal tissue and inhibited the development of renal damage. Moreover, the elevated expression of receptor for advanced glycation end products in the kidneys after intestinal ischemia/reperfusion was abrogated after high-mobility group box-1 inhibition. ConclusionThese results suggested that high-mobility group box-1 signaling regulated endoplasmic reticulum stress and promoted intestinal ischemia/reperfusion-induced acute kidney injury. High-mobility group box-1 neutralization/inhibition might serve as a pharmacological intervention strategy for these pathophysiological processes.

Evaluation of serum high-mobility group box 1 concentration in dogs with epilepsy: A case-control study.

BackgroundHigh‐mobility group box 1 (HMGB1) is a key mediator of neuroinflammation and there are increased HMGB1 levels in laboratory animal models of epilepsy and human patients with epilepsy.ObjectivesTo determine serum HMGB1 levels in dogs with epilepsy.AnimalsTwenty‐eight epileptic dogs, 12 dogs with nonepileptic brain diseases, and 26 healthy dogs.MethodsIn this case‐control study, serum HMGB1 concentrations were estimated using the canine‐specific enzyme‐linked immunosorbent assay kit. Diagnosis of dogs with epilepsy was based on medical history, physical and neurological examination findings, laboratory test results, magnetic resonance image, and cerebrospinal fluid analysis.ResultsSerum HMGB1 levels were significantly higher in epileptic dogs (median = 0.41 ng/mL; range, 0.03‐5.28) than in healthy dogs (median = 0.12 ng/mL; range, 0.02‐1.45; P = .002). In contrast, serum HMGB1 levels of dogs with non‐epileptic brain diseases (median = 0.19 ng/mL; range, 0.03‐1.04) were not significantly increased compared to those of healthy dogs (P = .12). Regarding idiopathic epilepsy, dogs with an epilepsy course of >3 months showed a higher serum HMGB1 concentration (median = 0.87 ng/mL; range, 0.42‐2.88) than those with that of ≤3 months (median = 0.26 ng/mL; range, 0.03‐0.88; P = .02).Conclusions and Clinical ImportanceSerum HMGB1 could be a biomarker of epilepsy.

Prognostic role of serum high mobility group box 1 concentration in cardiac surgery

Outcomes of cardiac surgery are influenced by systemic inflammation. High mobility group box 1 (HMGB1), a pivotal inflammatory mediator, plays a potential role as a prognostic biomarker in cardiovascular disease. The aim of this prospective, observational study was to investigate the relationship between serum HMGB1 concentrations and composite of morbidity endpoints in cardiac surgery. Arterial blood samples for HMGB1 measurement were collected from 250 patients after anaesthetic induction (baseline) and 1 h after weaning from cardiopulmonary bypass (post-CPB). The incidence of composite of morbidity endpoints (death, myocardial infarction, stroke, renal failure and prolonged ventilator care) was compared in relation to the tertile distribution of serum HMGB1 concentrations. The incidence of composite of morbidity endpoints was significantly different with respect to the tertile distribution of post-CPB HMGB1 concentrations (p = 0.005) only, and not to the baseline. Multivariable analysis revealed post-CPB HMGB1 concentration (OR, 1.072; p = 0.044), pre-operative creatinine and duration of CPB as independent risk factors of adverse outcome. Accounting for its prominent role in mediating sterile inflammation and its relation to detrimental outcome, HMGB1 measured 1 h after weaning from CPB would serve as a useful biomarker for accurate risk stratification in cardiac surgical patients and may guide tailored anti-inflammatory therapy.

Changes in serum human cartilage glycoprotein-39 and high-mobility group box 1 in preterm infants with bronchopulmonary dysplasia

To study the association of the dynamic changes of peripheral blood human cartilage glycoprotein-39 (YKL-40) and high-mobility group box 1 (HMGB1) with bronchopulmonary dysplasia (BPD) in preterm infants. Preterm infants, with a gestational age of 28-32 weeks and a birth weight of <1 500 g, who were admitted to the neonatal intensive care unit from July 2017 to August 2019 were prospectively selected and divided into a BPD group with 35 infants and a non-BPD group with 51 infants. ELISA was used to measure the serum concentrations of YKL-40 and HMGB1 in preterm infants on days 3, 7, and 14 after birth. The BPD group had a significantly lower serum YKL-40 concentration and a significantly higher serum HMGB1 concentration than the non-BPD group on days 3, 7, and 14 (P<0.001). The serum concentrations of YKL-40 and HMGB1 on days 7 and 14 were significantly higher than those on day 3 in both groups (P<0.017). In the BPD group, HMGB1 concentration on day 14 was significantly higher than that on day 7 (P<0.017), while there was no significant change in YKL-40 concentration from day 7 to day 14 (P>0.017). In the non-BPD group, YKL-40 concentration on day 14 was significantly higher than that on day 7 (P<0.017), while there was no significant change in HMGB1 concentration from day 7 to day 14 (P>0.017). There are significant differences in the levels of YKL-40 and HMGB1 in peripheral blood between the preterm infants with BPD and those without BPD on days 3, 7, and 14 after birth, suggesting that YKL-40 and HMGB1 might be associated with the development of BPD.

Relationship between expression of high-mobility group box-1 and inflammatory cytokines in patients with bone cancer pain

Objective: To investigate the change and relationship between serum high-mobility group box-1(HMGB1) and related inflammatory cytokines level in patients suffer with bone metastatic pain. Methods: Collection of the bone cancer pain patients who received analgesic therapy the department of pain in The First Affiliated Hospital of Jiaxing University from November 2016 to August 2016. Serum concentration of HMGB1, the Receptor of Advanced Glycation Endproducts (RAGE), monocyte chemotactic protein-1(MCP-1), tumor necrosis factor -α (TNF-α), interleukin-1β (IL-1β), interleukin-10 (IL-10), interleukin-13 (IL-13), and transforming growth factor-β (TGF-β) levels were determined in 15 healthy individuals as healthy donor and 15 patients with bone metastatic pain by enzyme-linked immunosorbent (ELISA) . The healthy individuals and patients with bone metastatic pain were collected before treatment and on 7 d after the treatment. Results: The serum concentration of HMGB1 and RAGE were significantly increased in tumorous group compared with healthy group[(8.8±2.3) vs (1.9±1.1) μg/L,(231±16) vs (46±20) ng/L); t=7.10,12.44, both P<0.05], then decreased after analgesic therapy [(4.77±1.36) μg/L, (129.80±29.32) ng/L, t=7.10, 12.44, both P<0.05]. The serum concentration of proinflammatory cytokines such as MCP-1, TNF-α, and IL-1β were significantly increased in tumorous group when compared with healthy group, and decreased after analgesic therapy (all P<0.05). The expression of anti-inflammatory cytokines such as IL-10, IL-13, and TGF-β were significantly increased in tumorous group when compared with healthy group, and decreased after analgesic therapy (all P<0.05).Compared with healthy group, the levels of MCP-1/IL-10, MCP-1/IL-13, MCP-1/TGF-β, TNF-α/IL-10, TNF-α/IL-13, TNF-α/TGF-β, IL-1β/IL-10, IL-1β/IL-13, IL-1β/TGF-β were significantly increased in tumorous group (all P<0.05). Conclusion: HMGB1 may adjust the proinflammatory-anti-inflammatory system homeostasis to participate in the development of bone metastatic pain.

Evaluation of serum C-reactive protein and high mobility group box 1 concentrations in 22 dogs with acute pancreatitis: a pilot study

Background: High mobility group box 1 (HMGB1) is an important mediator of systemic inflammatory response syndrome (SIRS) in humans with severe acute pancreatitis (AP), but there is little information regarding its role in dogs.Aim: To compare the serum concentrations of C-reactive protein (CRP) and HMGB1 in healthy dogs and those with AP with or without SIRS.Methods: The study included 22 dogs with AP and 20 healthy dogs. CRP and HMGB1 were assessed by ELISA. Statistical analyses were conducted by non-parametric tests.Results: Median (interquartile range) serum CRP and HMGB1 concentrations were significantly (P < 0.05) higher in dogs with AP [60.56 (14.50–140.10) µg/mL and 0.35 (0.03–1.12) ng/mL, respectively] than in healthy dogs [2.23 (1.75–5.14) µg/mL and 0.02 (0.01–0.05) ng/mL, respectively]. After the recommended treatments for AP, serum CRP concentration in AP dogs significantly decreased, but that of HMGB1 in AP dogs significantly increased. There was also a significant difference in median serum HMGB1 concentration between AP dogs with and without SIRS. The use of serum HMGB1 concentration of 0.35 ng/mL to distinguish AP dogs with and without SIRS was associated with a sensitivity of 87.5% and a specificity of 71.5%. A positive correlation was identified between HMGB1 and clinical severity of AP. All AP dogs had a positive outcome during hospitalization [6.0 (1.5–6.0) days].Conclusion: Results indicate that HMGB1 might be a useful biomarker for the progression of AP and may play a role in progression of AP into SIRS in dogs.

Increased HMGB1 expression correlates with higher expression of c-IAP2 and pERK in colorectal cancer.

The aim of this study was to investigate the relationship between high-mobility group box 1 (HMGB1) and colorectal cancer (CRC).In this prospective study, patients with CRC undergoing primary surgery and healthy subjects (control group) were enrolled from July 2013 to December 2014. The serum HMGB1 concentration and HMGB1 mRNA expression were determined using enzyme-linked immunosorbent assay reverse transcription-polymerase chain reaction, respectively. Immunohistochemical analysis was performed to determine HMGB1, pERK, and c-inhibitor of apoptosis protein 2 (c-IAP2) protein expression levels in the cancer tissues.A total 144 patients with CRC and 50 healthy subjects underwent serum HMGB1 testing. Resected specimens of 50 patients were used for HMGB1 mRNA and protein expression analyses. Mean serum HMGB1 level in the patients with CRC was higher than that of the control group (8.42 μg/L vs 1.79 μg/L, P < .05). Mean serum HMGB1 level in the patients with CRC with distant metastasis was significantly higher than that of the controls (13.32 μg/L vs 7.37 μg/L, P < .05). The HMGB1 mRNA and protein expression levels in the CRC tissues were significantly higher than those in the adjacent normal mucosa. HMGB1 protein expression positively correlated with the lymph node metastasis. There were positive correlations between HMGB1 and c-IAP2 (r = 0.457, P < .05), HMGB1 and pERK (r = 0.461, P < .05), as well as pERK and c-IAP2 (r = 0.399, P < .05).HMGB1 expression in CRC correlates with distant and lymph node metastasis. It may inhibit apoptosis by inducing activation of pERK and c-IAP2.

Systemic High-Mobility Group Box-1: A Novel Predictive Biomarker for Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

To investigate the release of proinflammatory damage-associated molecular pattern molecule "high-mobility group box-1" in the serum of patients after aneurysmal subarachnoid hemorrhage and its association with cerebral vasospasm. Retrospective observational study. University hospital. Aneurysmal subarachnoid hemorrhage patients admitted within 24 hours of ictus. Standard subarachnoid hemorrhage treatment after clipping or coiling of aneurysm. We enrolled 53 aneurysmal subarachnoid hemorrhage patients from which peripheral venous blood was withdrawn on days 1, 3, 5, 7, 9, 11, and 13 and once from the controls to obtain the serum. Serum high-mobility group box-1 concentration was quantified by enzyme-linked immunosorbent assay. Serum interleukin-6 and peripheral blood leukocytes were also determined over the first 2 weeks after subarachnoid hemorrhage. Patients' data were recorded prospectively. Serum high-mobility group box-1 was significantly elevated in subarachnoid hemorrhage patients from day 1 to day 13 when compared with nonsubarachnoid hemorrhage patients (p < 0.05). Patients with cerebral vasospasm showed significantly higher high-mobility group box-1 starting from day 1 to day 13 when compared with patients without cerebral vasospasm. Cumulative levels of high-mobility group box-1 showed significant correlation with peripheral blood leukocytes and interleukin-6 levels (p < 0.05). Receiver operating characteristic curve analysis showed that serum high-mobility group box-1 level at admission may be a predictive biomarker for cerebral vasospasm with a sensitivity of 59% and a specificity of 82% at a cutoff value of 5.6 ng/mL. Serum high-mobility group box-1 is differentially elevated after subarachnoid hemorrhage. Serum high-mobility group box-1 levels were elevated early after subarachnoid hemorrhage (day 1) and remained significantly high until day 13 in patients who developed cerebral vasospasm. Our data suggest that serum high-mobility group box-1 may be a predictive biomarker for the detection of CVS.

Translationally controlled tumor protein affects colorectal cancer metastasis through the high mobility group box 1-dependent pathway.

Recently, accumulating evidence from clinical and experimental researches have suggested that translationally controlled tumor protein (TCTP) and high mobility group box 1 (HMGB1) are implicated in colorectal cancer (CRC) metastasis. However, whether there is an interconnection between these two tumor-promoting proteins and how they affect CRC metastasis remain to be fully elucidated. In the present study, the expression level of TCTP in CRC tissues was assessed by immunohistochemical staining and immunoblotting, and the serum concentration of HMGB1 in patients with CRC was detected by enzyme-linked immunosorbent assay. In vitro, following the modulation of TCTP expression in colon cancer LoVo cells, the translocation behavior of HMGB1 was observed by immunofluorescence assay. Furthermore, the activity of nuclear factor-κB (NF-κB) in LoVo cells was evaluated by immunoblotting and luciferase assay, and the invasion ability of LoVo cells after different treatments was determined using cell invasion assay. In vivo, xenograft tumor model was established and the correlation of TCTP and HMGB1 expression in xenografted tumors was studied by immunohistochemical examination. The results revealed that the expression level of TCTP in CRC tissue and the serum concentration of HMGB1 in patients with CRC were significantly increased, and there was a strong positive correlation between them. In vitro experiments showed that the overexpression of TCTP on LoVo cells resulted in the release of HMGB1 from the nucleus to the cytoplasm and into the extracellular space. In addition, the overexpression of TCTP led to the activation of NF-κB in LoVo cells, and this effect was reversed by treatment with antibodies targeting HMGB1 or to its receptors Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products advanced glycation end products (RAGE). Furthermore, inhibition of the HMGB1-TLR4/RAGE-NF-κB pathway significantly inhibited the TCTP-stimulated invasion of LoVo cells. In vivo experiments demonstrated that the over-expression of TCTP in nude mice promoted the development and spread of xenografted tumors, and concurrently enhanced the expression of HMGB1 in tumor tissues. Collectively, these findings suggested that TCTP promotes CRC metastasis through regulating the behaviors of HMGB1 and the downstream activation of the NF-κB signaling pathway.

Assessment of HMGB-1 concentration in tick-borne encephalitis and neuroborreliosis

BackgroundThe aim of this study was to determine the concentration of HMGB-1 (high mobility group box 1) in the serum and cerebrospinal fluid (CSF) of patients suffering from tick-borne encephalitis (TBE) and neuroborreliosis (NB). Focus was placed on HMGB-1 measurement in the CSF or serum in order to establish whether this could help to differentiate between NB and TBE. MethodsEighty patients with meningitis and meningoencephalitis were enrolled in the study. The patients were divided into two groups: group I comprised patients with NB (n=40) and group II comprised patients with TBE (n=40). The diagnosis was made based on the clinical picture, CSF examination, and the presence of specific antibodies in the serum and CSF. The control group for the evaluation of the parameters in serum were healthy blood donors (n=25), while the control group for the evaluation of parameters in the CSF were patients in whom a central nervous system (CNS) inflammatory process was excluded. The concentrations of HMGB-1 were measured by ELISA method using a commercial kit (HMGB-1 ELISA Kit; EIAab, China). The results were analyzed using Statistica 10, Gretl, receiver operating characteristics curve (ROC), and the Pearson correlation coefficient. Results and conclusionsHMGB-1 is associated with the development of inflammatory processes in the CNS caused by both tick-borne pathogens: viral (TBE) and bacterial (Lyme borreliosis). Measurement of the serum HMGB-1 concentration in the early stages of both diseases of the CNS may contribute to the differentiation between TBE and NB, which may have a clinical impact for patients bitten by ticks.

Erratum to: Serum HMGB1 concentrations at 4weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy.

Background Biomarkers predicting the response to the anticancer treatment and prognosis in patients with advanced hepatocellular carcinoma (HCC) are required. Recently, high mobility group box 1 (HMGB1) was reported to promote HCC progression and be associated with poor prognosis for patients with HCC. The purpose of this study was to assess serum HMGB1 concentrations before and during sorafenib treatment or hepatic arterial infusion chemotherapy (HAIC) and to explore the ability of serum HMGB1 concentrations to predict prognosis.

Serum HMGB1 concentrations at 4\xa0weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy

BackgroundBiomarkers predicting the response to the anticancer treatment and prognosis in patients with advanced hepatocellular carcinoma (HCC) are required. Recently, high mobility group box 1 (HMGB1) was reported to promote HCC progression and be associated with poor prognosis for patients with HCC. The purpose of this study was to assess serum HMGB1 concentrations before and during sorafenib treatment or hepatic arterial infusion chemotherapy (HAIC) and to explore the ability of serum HMGB1 concentrations to predict prognosis.MethodsSerum HMGB1 concentrations were measured in 71 and 72 patients with advanced HCC treated with sorafenib and HAIC, respectively, to assess their usefulness for prediction of the response to the treatment and prognosis.ResultsMultivariate analysis identified high HMGB1 at 4 weeks (P = 0.001), high α-fetoprotein (AFP) at baseline (P = 0.025), tumor liver occupying rate (P = 0.009) and modified RECIST (mRECIST, P < 0.0001) as independent predictors of poor overall survival in sorafenib treatment. High HMGB1 at 4 weeks (P = 0.025), vascular invasion to the hepatic vein (Vv) (P = 0.009), mRECIST (P < 0.0001) and Child-Pugh B (P = 0.004) were identified as independent predictors of poor overall survival in HAIC treatment. The concentrations of HMGB1 at baseline and 4 weeks were not correlated with conventional tumor markers and progressive disease assessed by mRECIST at 8 weeks.ConclusionsThese results suggest that serum HMGB1 at 4 weeks after the start of treatment might be a useful biomarker with added value to the conventional tumor marker and radiologic responses to predict poor overall survival in patients with advanced HCC treated with sorafenib or HAIC.

SIRT1 inhibits releases of HMGB1 and HSP70 from human umbilical vein endothelial cells caused by IL-6 and the serum from a preeclampsia patient and protects the cells from death.

Preeclampsia (PE), a pregnancy-specific disorder, is associated with inappropriate maternal inflammatory response, oxidative stress, and vascular endothelial cell dysfunction and damage. Releases of high mobility group box-1 (HMGB1) and heat-shock protein 70 (HSP70) into serum are considered to participate in the pathogenesis of PE. The deacetylase, sirtuin 1 (SIRT1), has protective effects against inflammation, apoptosis, and oxidative stress in various pathological conditions. We established a PE mouse model by injection of phosphatidylserine/dioleoyl-phosphatidycholine compounds, followed by measurement of the SIRT1 protein level in the placenta via Western blotting and the serum HMGB1 and HSP70 concentrations via enzyme-linked immunosorbent assay (ELISA). SIRT1 was down-regulated in the placenta of PE mice, in accompany with increased serum HMGB1 and HSP70 concentrations. We incubated human umbilical vein endothelial cells (HUVECs) with IL-6 and the serum from a PE patient individually to mimic status of vein endothelial cells in PE. Western blot and Immunofluorescent assays showed that HMGB1 and HSP70 protein levels were decreased in the cells, but they were increased in the cell medium based on ELISA. These suggested that HMGB1 and HSP70 were forced to be released from the cells. SIRT1 knockdown promoted the releases of HMGB1 and HSP70, whereas its over-expression inhibited the releases. Moreover, SIRT1 protected the cells from death. Collectively, SIRT1 inhibits the releases of HMGB1 and HSP70 from HUVECs caused by IL-6 and the serum from PE patient and protects the cells from death, thus SIRT1 is probably a potentially protective factor in placenta against PE.

Adeno-associated virus-mediated colonic secretory expression of HMGB1 A box attenuates experimental colitis in mice.

Extracellular high mobility group box 1 (HMGB1) is crucially implicated in the pathogenesis of inflammatory bowel diseases (IBDs). A box domain of HMGB1 has been identified as a specific antagonist of HMGB1. In the present study, we tested the effects of adeno-associated virus (AAV)-mediated colonic secretory expression of HMGB1 A box on murine experimental colitis. Self-complementary AAV-2 carrying mouse immunoglobin Gκ leader-human HMGB1 A box (AAV-HMGB1 A box) was constructed. The effects of intracolonically administered AAV-HMGB1 A box on dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis were assessed by the disease activity index (DAI), colon length, macroscopic and histological scoring, myeloperoxidase (MPO) activity, and epithelial apoptosis and complementary proliferation. Colonic immune cell infiltrates, mucosal malondialdehyde content and superoxide dismutase activity, colonic tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-10 levels, serum HMGB1 concentration, and colonic HMGB1 release were determined to investigate the underlying mechanisms. Intracolonically administered AAV-HMGB1 A box efficiently mediated secretory expression of HMGB1 A box and led to significant decreases in DAI, macroscopic and histological scores and colonic epithelial apoptosis in both DSS- and TNBS-treated mice. Modulating inflammation-associated cytokines, such as inhibiting colonic TNF-α and IL-1β expression, decreasing HMGB1 release, and restoring colonic IL-10 levels, and thereby inhibiting inflammatory cell infiltration and alleviating oxidant damage, might be the underlying mechanism. Intracolonic application of AAV-HMGB1 A box is effective in alleviating murine colitis and has therapeutic potential in human IBDs.