Serum HMGB1 Levels Research Articles

Association between an elevated level of HMGB1 and non-small-cell lung cancer: a meta-analysis and literature review.

BackgroundHMGB1 has been overexpressed in the tissues or serum of patients with non-small-cell lung cancer (NSCLC) in several studies. However, the results remain inconsistent.ObjectiveThe aim of this study was to perform a meta-analysis to investigate the relationship between elevated level of HMGB1 and NSCLC.MethodsAssociated studies were included, and the pooled risk difference and mean difference (MD) together with 95% confidence interval (CI) were calculated.ResultsA total of ten relevant studies on HMGB1 expression were included in this meta-analysis. The pooled results suggested that the expression of HMGB1 in NSCLC tissues was notably higher than those in corresponding nontumor normal tissues by using immu-nohistochemistry (risk difference =0.38, 95% CI: 0.28–0.48, Z=7.67, P<0.00001, I2=0%), Western blot (MD =0.27, 95% CI: 0.06–0.47, Z=2.57, P<0.01), or real-time polymerase chain reaction (MD =15.15, 95% CI: 14.8–15.5, Z=2.08, P=0.04). Serum HMGB1 levels were similarly significantly higher in patients with NSCLC than those in healthy controls. The pooled MDs of HMGB1 in patients with NSCLC compared with healthy controls were 17.54 with 95% CI: 10.99–24.09, Z=5.25, P<0.00001. Two of the included studies were fully reviewed without performing meta-analysis due to the different detection methods used. The protein level of HMGB1 in patients with NSCLC of tumor, nodes, and metastasis (TNM) stages III–IV was higher than that of TNM stages I–II (P<0.047 and P<0.001, respectively).ConclusionThe expression levels of HMGB1 in both tissues and serum of patients with NSCLC were statistically higher than those of normal lung samples, which indicated that elevated levels of HMGB1 can reveal changes that correlated with disease progression, or even the risk of NSCLC disease progression. The elevated level of HMGB1 could also be considered as a potential biomarker for the diagnosis of patients with NSCLC.

The effect of necrostatin-1 on high mobility group protein-B1 in liver of rats with hemorrhagic shock

Objective To investigate the effect and mechanism of necrostatin-1(Hec-1) on the level of HMGB-1 protein in liver of rats with hemorrhagic-traumatic shock. Methods A number of 96 male SD rats were divided into sham-operated group, dimethyl sulfoxide(DMSO) group and Nec-1 group (n=32 in each) by randomized number method. Rat model of hemorrhagic-traumatic shock was made by fracture of femoral bone and tibia bone and exsanguination from femoral vein until 30 mmHg and maintained at 30-40 mmHg for 90 min, then the shed blood was transfused back with Ringer's solution. The rats in sham-operated group were only under anesthesia for separating and ligating blood vessels, without exsanguination to induce hemorrhagic shock and without replenishment with blood. Rats in Nec-1 group were given 1 mg/kg Nec-1 through femoral vein 5 min before replenishment with blood and Ringer's solution, while the rats in DMSO group were given equal volume of DMSO solution instead. Eight rats in each group were sacrificed separately at 2 h, 8 h, 16 h and 24 h after replenishment. The serum and liver tissues of rats in each group were collected to detect serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST), and to observe the pathological changes in liver with hematoxylin-eosin(HE) staining. The level of HMGB-1 in serum was detected by using ELISA. The cytoplasm protein and total protein expressions of HMGB-1 were assessed by using western blot analysis. Results Compared with DMSO group, levels of serum ALT at 8 h(P<0.05), 16 h(P<0.01) and 24 h(P<0.01) in Nec-1 group were significantly lower. Level of serum AST in Nec-1 group were lower compared with DMSO group at 8 h(P<0.01), 16 h(P<0.01) and 24 h(P<0.01). Compared with DMSO group, levels of serum HMGB-1 at 8 h(P<0.05), 16 h(P<0.01) and 24 h(P<0.01) in Nec-1 group were significantly lower. Under light microscopy and transmission electron microscope, hepatic lobule destroyed, the blood extravasated, the immunocyte infiltrated and cellular organelle destroyed were found. Compared with DMSO group, the level of HMGB-1 protein in cytoplasm protein in Nec-1 group were significantly decreased at 8 h(P<0.01), 16 h(P<0.01) and 24 h(P<0.01). The level of HMGB-1 protein in total protein in Nec-1 group were significantly decreased 8 h(P<0.05) and 24 h(P<0.05). Conclusions Nec-1 can remarkably protect the liver of rats with hemorrhagic-traumatic shock, decrease the level of HMGB-1, and protect the hepatocyte effectively. Key words: High mobility group protein B1; Trauma; Shock, Hemorrhagic; Necrostatin-1; Necroptosis

Effect of ischemia-reperfusion induced HMGB1 release on P38 MAPK signaling pathway in mouse liver

Objective To explore the effect of HMGB1 release on P38 MAPK signaling pathway induced by ischemia-reperfusion (IR) in mouse liver. Methods C57BL/6 mice included sham operation group (Sham), IR group (IR) and HMGB1 release inhibitor group (GA). The serum AST, TNF-α and HMGB1 level of the mice were determined using a commercial assay kit. Histopathological changes were observed in mice livers by HE staining. HMGB1, p-P38, P38 and Caspase-3 expression were detected by immunohistochemistry and Western blot, while cell apoptosis was detected by TUNEL assay. Results Compared with Sham group, serum ALT (423.4±99.6), TNF-α (84.3±21.4) and HMGB1 (0.79±0.04) levels were increased in IR group, but decreased in GA group (P<0.05). The histological changes in the livers of the IR group included hepatocyte swelling, hepatic sinusoids narrowing and hepatocyte necrosis, which were alleviated in GA group. Compared with Sham and GA groups, there was a significant increase on HMGB1 transposition and release, and cell apoptosis [(59.3±9.1)%] in IR group (P<0.05), but GA decreased the HMGB1 level in hepatocyte. The expression of HMGB1, p-P38 and Caspase-3 were up-regulated in IR group compared with those in Sham and GA groups (P<0.05). Conclusion The release of HMGB1 induced by IR can cause hepatic cell damage probably by stimulating P38 MAPK signaling pathway. Key words: Ischemia-reperfusion; Hepatocyte; Protein kinases, P38 MAPK; High mobility group, HMGB1

Protective Effect of Brown Alga Phlorotannins against Hyper-inflammatory Responses in Lipopolysaccharide-Induced Sepsis Models.

Brown algae have been recognized as a food ingredient and health food supplement in Japan and Korea, and phlorotannins are unique marine phenol compounds produced exclusively by brown algae. Sepsis is a whole-body inflammatory condition with a mortality rate of 30-40%. Here, we investigated the effects of a phlorotannin-rich extract of the edible brown alga Ecklonia cava against hyper-inflammatory response in LPS-induced septic shock mouse model. E. cava extract significantly increased the survival rate and attenuated liver and kidney damage in the mice. In addition, E. cava attenuated serum levels of NO, PGE2, and HMGB-1. In macrophages, treatment with E. cava extract down-regulated iNOS, COX-2, TNF-α, IL-6, and HMGB-1. In addition, E. cava suppressed the NIK/TAK1/IKK/IκB/NFκB pathway. Moreover, E. cava increased Nrf2 and HO-1 expression. HO-1 knockdown using siRNA restored the extract-suppressed NO and PGE2 production. Dieckol, a major compound in the extract, reduced mortality, tissue toxicity, and serum levels of the inflammatory factors in septic mice. These data suggest that brown algae phlorotannins suppress septic shock through negative regulation of pro-inflammatory factors via the NIK/TAK1/IKK/IκB/NFκB and Nrf2/HO-1 pathways.

Significance of P53 and high mobility group box 1 protein in different levels of liver fibrosis in chronic hepatitis B

To investigate the role of P53 and high mobility group protein 1 (HMGB1) protein expression in liver fibrosis stages in chronic hepatitis B patients. According to the pathological grades, 103 patients were divided into 3 groups: no fibrosis group (n=18), low fibrosis group (n=49) or high fibrosis group (n=36). Serum HMGB1 levels were determined and receiver operating characteristic (ROC) curve was made based on the HMGB1 level and liver fibrosis score. Liver fibrosis model was developed by CCl4 in 60 male SD rats, which were sacrificed 6 or 12 weeks later. The degree of fibrosis was examined by Masson staining; HMGB1 and P53 protein expression were analyzed by Western blot; histone deacetylase (HDAC) activity, TNF-α, IL-1β and IL-6 levels in serum were measured. The serum levels of HMGB1 level in low and high fibrosis groups were significantly higher than that in no fibrosis group (P<0.01, respectively). ROC curve showed that serum HMGB1 in the diagnosis of hepatic fibrosis with cut off at 74 pg/mL, specificity at 65% and sensitivity at 87%. Compared with the control group, HMGB1 expression in both low and high fibrosis group was decreased in nucleus but was increased in cytoplasm, accompanied by the elevated P53 expression, increased HDAC activity and inflammatory cytokine levels (all P<0.01, respectively). P53 and HMGB1 expression was significantly increased in chronic hepatitis B patients with liver fibrosis; serum HMGB1 level was positively correlated with the degree of liver cirrhosis and HMGB1 could be used as a sensitive and specific index for liver fibrosis prognosis.

Abstract A36: Novel therapeutic approaches for human malignant mesothelioma

Abstract Human malignant mesothelioma (MM) is an aggressive and highly lethal cancer that has been linked to asbestos and erionite exposure. MM causes about 3,200 deaths per year in the US and more than 100,000 deaths per year worldwide. We previously found that high-mobility group box-1 protein (HMGB1), a prototypic damage-associated molecular pattern (DAMP), plays a critical role in the early events of HM malignant transformation and MM development. More recently we showed that MM cells are “addicted” to HMGB1 that supports the malignant phenotype by promoting proliferation and invasiveness of MM cells. We demonstrated that MM growth is inhibited by targeting HMGB1 using HMGB1 neutralizing antibody or BoxA, a HMGB1 antagonist. Ethyl pyruvate (EP) is the ethyl ester of pyruvic acid, known to suppress oxygen radical formation and HMGB1 secretion. Here we show that EP impaired motility, survival and proliferation of MM cells in vitro. Both BoxA and EP inhibited the activity of the pro-inflammatory transcription factor NF-kappaB, as well as reduced HMGB1 serum levels and the growth of MM xenografts in SCID mice. Taken together, our results provide a preclinical proof-of-principle that inhibition of HMGB1 activity using either HMGB1 antibody, BoxA or EP offers novel therapeutic approaches for MM treatment. Citation Format: Haining Yang, Sandro Jube, Michele Carbone. Novel therapeutic approaches for human malignant mesothelioma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A36.

Effect of dexmedetomidine on high-mobility group box 1 protein in rats with sepsis

To explore the effect of dexmedetomidine (DEX) on high-mobility group box 1 protein (HMGB1) in the serum and spleen in rats with sepsis and the underlying mechanisms. A total of 100 male Wistar rats were randomly divided into five groups: a control group, a sepsis group, a DEX group, an α-bungarotoxin- tetramethylrhodamine (α-BGT) plus DEX group and an α-BGT group (n=20 in each group). In the control group, same volume of normal saline (NS) was administrated, while lipopolysaccharide (LPS) was injected to the vein to develop a classic sepsis model. At the 48th h after LPS injection, the rats were sacrificed, and the blood and spleen were collected. The content of tumor necrosis factor-α (TNF-α) and HMGB1 in blood serum were detected by enzyme-linked immuno sorbent assay (ELISA), and the HMGB1 in the spleen was examined by Western blot. Among the 5 groups, there were statistical significance in the mortality, the serum level of TNF-α and HMGB1, and the content of secreting type of HMGB1 in spleen (all P<0.05), and the serum level of HMGB1 was positively correlated with the content of secreting type of HMGB1 (r=0.863, P<0.05). DEX exert late anti-inflammatory effects in the serum and spleen in rats with sepsis, which is related to the activation of the cholinergic anti-inflammatory pathway.

Effect of dexmedetomidine on inflammatory mediators in different periods of sepsis in rats

Objective To investigate the effect of dexmedetomidine (DEX) on inflammatory mediators in different periods of sepsis and its impact on survival rate of rats with sepsis. Methods Ninety male Wistar rats were randomly divided into three groups: control group (group C) , sepsis model group (group S) , and DEX treatment group (group D). Lipopolysaccharide (LPS) was injected to the vein to reproduce a classic sepsis model, while in control group, equivalent volume of NS was used instead. Different treatments were given to the corresponding groups, and then venous blood was taken at given intervals. Behavioral changes and mortality rate of rats within 48 hours after experiment were recorded. The levels of the early inflammatory mediators such as tumor necrosis factor-α (TNF-α) , interleukin-6 (IL-6) and the late inflammatory mediators such as high-mobility group boxl protein (HMGB1) in blood serum were detected by ELISA. Results Among three groups, there were significant differences in mortality rate of rats, the serum level of TNF-α, IL-6 and HMGB1 (all P<0.05). Conclusion DEX has a certain anti-inflammatory effects on early and late stages of sepsis in rats with sepsis, and can also reduce the mortality rate. Key words: Dexmedetomidine; Sepsis; Inflammatory mediators; High-mobility group boxl protein

Individuals with Primary Sclerosing Cholangitis Have Elevated Levels of Biomarkers for Apoptosis but Not Necrosis.

Hepatocyte apoptosis or necrosis from accumulation of bile salts may play an important role in the disease progression of primary sclerosing cholangitis (PSC). The aim of the current study was to measure serum markers of hepatocyte apoptosis (cytokeratin-18 fragments--K18) and necrosis (high-mobility group protein B1--HMGB1) in adults with PSC and examine the relationship with disease severity. We measured serum levels of K18 and HMGB1 in well-phenotyped PSC (N = 37) and 39 control subjects (N = 39). Severity of PSC was assessed biochemically, histologically, and PSC Mayo risk score. Quantification of hepatocyte apoptosis was performed using TUNEL assay. The mean age of the study cohort was 49.7 ± 13.3 years and comprised of 67% men and 93% Caucasian. Serum K18 levels were significantly higher in the PSC patients compared to control (217.4 ± 78.1 vs. 157.0 ± 58.2 U/L, p = 0.001). However, HMGB1 levels were not different between the two groups (5.38 ± 2.99 vs. 6.28 ± 2.85 ng/mL, p = 0.15). Within the PSC group, K18 levels significantly correlated with AST (r = 0.5, p = 0.002), alkaline phosphatase (r = 0.5, p = 0.001), total bilirubin (r = 0.61, p ≤ 0.001), and albumin (r = -0.4, p = 0.02). Serum K18 levels also correlated with the level of apoptosis present on the liver biopsy (r = 0.8, p ≤ 0.001) and Mayo risk score (r = 0.4, p = 0.015). Serum K18 but not HMGB1 levels were increased in PSC and associated with severity of underlying liver disease and the degree of hepatocyte apoptosis.

Biomarkers of oxidation stress, inflammation, necrosis and apoptosis are associated with hepatitis B-related acute-on-chronic liver failure

Hepatitis B virus related acute-on-chronic liver failure is a serious condition with a high mortality. Oxidative stress, inflammation, necrosis and apoptosis may play an important role in it. This study is to investigate whether serum AOPP, S100A12, HMGB1 and sRAGE can provide diagnostic or prognostic information in HBV-related ACLF. We measured serum S100A12, HMGB1 and sRAGE levels in 50 patients with HBV-related ACLF, 35 patients with liver cirrhosis (LC), 35 patients with chronic hepatitis B (CHB) and 35 healthy controls by enzyme-linked immunosorbent assay. AOPP measured by spectrophotometry. Significantly higher AOPP, S100A12, HMGB1 and sRAGE levels on admission were found in patients with ACLF compared with LC, CHB and healthy controls (P<0.001). In ACLF patients, they were higher in nonsurvivors than survivors (P<0.001). They had a positive relationship with total bilirubin and MELD scores. AOPP, S100A12 and HMGB1 concentrations continually declined in survivors while increased in nonsurvivors, sRAGE concentrations did not change in survivors, but gradually increased in nonsurvivors during hospitalization. ROC curve analysis showed that the four biomarkers had a higher AUC than TBIL. Multivariate Cox regression analysis demonstrated that S100A12, AOPP and sRAGE were independent risk factors for poor prognosis. Serum AOPP, S100A12 and sRAGE maybe reflect the oxidation stress, inflammation levels in HBV-related acute-on-chronic liver failure. Increased AOPP, S100A12 and sRAGE may serve as important biological markers of worse outcome.

High-mobility group box 1 in multiple sclerosis.

This study is one in series determining the potential of RAGE axis (receptor for advanced glycation end products, isoforms, ligands) as a biomarker in multiple sclerosis (MS). We evaluated serum levels of RAGE ligand, the high-mobility group box (HMGB)1 in MS patients, and assessed the correlation between HMGB1 serum levels and the use of disease-modifying drugs (DMDs), and between HMGB1 serum levels and indicators of MS disease severity. HMGB1 serum levels were compared between 96 (23 males) MS patients and 34 age- and gender-matched healthy controls (HCs) using enzyme-linked immunosorbent assays. DMD-naïve MS patients had significantly higher HMGB1 serum levels compared with DMD-treated (P = 0.04) and compared with HCs (P = 0.01). HMGB1 serum levels were not significantly different between total MS patients (DMD-naïve plus DMD-treated) and HCs (P = 0.09). DMD-naïve MS patients in clinical relapse tended to have lower HMGB1 serum levels than clinically stable RRMS patients (P = 0.07). HMGB1 serum levels showed 0.65 area under the curve (95 % CI 0.55-0.95) sensitivity/specificity for MS clinical relapse. The role of HMGB1 in MS disease pathology and DMD modulation of this protein warrant further investigations.

Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is becoming a pandemic. While multiple ‘hits’ have been reported to contribute to NAFLD progression to non-alcoholic steatohepatitis (NASH), fibrosis and liver cancer, understanding the natural history of the specific molecular signals leading to hepatocyte damage, inflammation and fibrosis, is hampered by the lack of suitable animal models that reproduce disease progression in humans. The purpose of this study was first, to develop a mouse model that closely mimics progressive NAFLD covering the spectrum of immune, metabolic and histopathologic abnormalities present in human disease; and second, to characterize the temporal relationship between sterile/exogenous danger signals, inflammation, inflammasome activation and NAFLD progression.MethodsMale C57Bl/6 mice were fed a high fat diet with high cholesterol and a high sugar supplement (HF–HC–HSD) for 8, 27, and 49 weeks and the extent of steatosis, liver inflammation, fibrosis and tumor development were evaluated at each time point.ResultsThe HF–HC–HSD resulted in liver steatosis at 8 weeks, progressing to steatohepatitis and early fibrosis at 27 weeks, and steatohepatitis, fibrosis, and tumor development at 49 weeks compared to chow diet. Steatohepatitis was characterized by increased levels of MCP-1, TNFα, IL-1β and increased liver NASH histological score. We found increased serum levels of sterile danger signals, uric acid and HMGB1, as early as 8 weeks, while endotoxin and ATP levels increased only after 49 weeks. Increased levels of these sterile and microbial danger signals paralleled upregulation and activation of the multiprotein complex inflammasome. At 27, 49 weeks of HF–HC–HSD, activation of M1 macrophages and loss of M2 macrophages as well as liver fibrosis were present. Finally, similar to human NASH, liver tumors occurred in 41% of mice in the absence of cirrhosis and livers expressed increased p53 and detectable AFP.ConclusionsHF–HC–HSD over 49 weeks induces the full spectrum of liver pathophysiologic changes that characterizes the progression of NAFLD in humans. NAFLD progression to NASH, fibrosis and liver tumor follows progressive accumulation of sterile and microbial danger signals, inflammasome activation, altered M1/M2 cell ratios that likely contribute to NASH progression and hepatic tumor formation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0552-7) contains supplementary material, which is available to authorized users.

High mobility group box 1 protein polymorphism affects susceptibility to recurrent pregnancy loss by up-regulating gene expression in chorionic villi.

Inflammation in chorionic villi is involved in the development of recurrent pregnancy loss (RPL). High mobility group box 1 protein (HMGB1) plays critical roles in inflammation and expression of the protein can be found in chorionic villi. The purpose of the study was to investigate the association between HMGB1 genetic polymorphisms and susceptibility to RPL and to examine the mechanism underlying this correlation. Two HMGB1 polymorphisms, rs2249825C/G and rs1412125T/C, were examined in 112 RPL patients and 118 healthy controls by the polymerase chain reaction-restriction fragment length polymorphism assay. Percentage of rs2249825GG was significantly increased in patients than in controls (Odd ratio [OR] =2.33, 95 % confidence interval [CI]: 1.18-4.58, P = 0.013). Also, prevalence of rs2249825G allele was significantly higher in RPL cases (OR = 1.77, 95 % CI: 1.20-2.62, P = 0.004). Function analysis of rs2249825C/G revealed that the polymorphism did not affect serum level of HMGB1. Interestingly, we found significantly increased level of HMGB1 in chorionic villi from RPL patients. Moreover, patients with rs2249825GG genotype presented significantly elevated level of HMGB1 in chorionic villi compared to those with CG or CC genotypes. These results suggest that HMGB1 rs2249825C/G polymorphism is associated with increased risk of RPL and can elevate gene expression in chorionic villi.

Response to letter regarding “Increased serum HMGB1 level may predict the fatal outcomes in patients with chronic heart failure”

Response to letter regarding “Increased serum HMGB1 level may predict the fatal outcomes in patients with chronic heart failure”

Endothelial cell is critical in HMGB1 mediated cardiac impairment in ischemic heart disease

We have recently read with great interest the clinical report by Liu T and colleagues [1] concerning “Increased serum HMGB1 level may predict the fatal outcomes in patients with chronic heart failure”. They indicate that serum HMGB1 levels were inversely correlated with LVEF and positively correlated with NT-pro-BNP and may be an alternative indicator in the risk stratification of patients with chronic HF (heart failure).

Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients

Chronic obstructive pulmonary disease (COPD) is a severe and progressive lung disease characterised by destruction of lung parenchyma and chronic airway inflammation [1]. A major cause of COPD is chronic exposure to noxious gases and particles, including cigarette smoke. During exacerbation, COPD patients experience a worsening of symptoms that coincides with increased inflammation and accelerated decline in lung function, resulting in a decrease in quality of life and increased healthcare costs. Approximately half of the COPD exacerbations causing hospitalisation are associated with respiratory viral and/or bacterial infections [2]. However, the underlying mechanisms causing COPD exacerbations are unknown [3]. Molecules derived from viruses and bacteria during airway infection can trigger the activation of pattern recognition receptors (PRRs) on lung structural and innate immune cells, and may thus contribute to the aggravation of inflammation during COPD exacerbations [1]. Interestingly, damage-associated molecular patterns (DAMPs) released from damaged or necrotic cells are also known to activate PRRs, including Toll-like receptors (TLRs) and the receptor for advanced glycation end-products (RAGE) [4]. A role for DAMPs has been proposed in the pathogenesis of COPD, as various DAMPs have been found to be increased in lung fluids and serum of COPD patients [5, 6]. Furthermore, Ager , the gene encoding RAGE, has been identified by genome-wide association studies as a susceptibility gene for COPD [7, 8]. Moreover, the serum levels of soluble RAGE (sRAGE), a decoy receptor for RAGE, were shown to be significantly lower in COPD patients, while the RAGE ligand EN-RAGE (also known as S100 calcium-binding protein (S100)A12) was significantly higher in COPD patients compared with smoking and nonsmoking controls [9]. It is currently unknown, however, whether DAMPs play a role in COPD exacerbations. Here, we hypothesised that the release of DAMPs is increased during exacerbations of COPD. Serum levels of the RAGE-activating DAMPs LL37, HMGB1 and S100A9 are increased during exacerbation in COPD patients http://ow.ly/Idh3r

Increased serum HMGB1 level may predict the fatal outcomes in patients with chronic heart failure

A total of 94 patients with chronic heart failure (HF) due to ischemic cardiomyopathy enrolled between Jan. 2009 and Dec. 2011 were included in the study, including 34 patients with New York Heart Association (NYHA) class II, 31 with class III and 29 with class IV. There were no statistically significant differences among the groups in age, gender, hypertension, or diabetics (p > 0.05). Compared with the control group, a higher proportion of patients in the HF group were treated with diuretics, angiotensin converting enzyme inhibitors (ACEIs), beta-blockers or digoxin (p < 0.05).

Correlation between serum levels of high mobility group box-1 protein and pancreatitis: a meta-analysis.

Background. Aberrant expression of high mobility group box-1 protein (HMGB1) contributes to the progression of various inflammatory diseases. This meta-analysis focused on the clinical significance of serum HMGB1 levels in pancreatitis patients, with the goal of building a novel diagnostic score model. Method. We conducted a meta-analysis by searching in the PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, China BioMedicine (CBM), and China National Knowledge Infrastructure (CNKI) databases without any language restrictions. Studies were pooled and standard mean difference (SMD) and its corresponding 95% confidence intervals (95% CIs) were calculated. Version 12.0 STATA software was used for statistical analysis. Results. We performed a final analysis of 841 subjects from 12 clinical case-control studies. The meta-analysis results showed a positive association between serum HMGB1 levels and the progression of pancreatitis. In the subgroup analysis by country, high serum level of HMGB1 may be related to pancreatitis progression in China, Korea, Hungary, and Japan populations (all P < 0.05). Conclusion. The present meta-analysis indicated that serum HMGB1 level was statistically elevated in patients with pancreatitis, and thus serum levels of HMGB1 could be determined to be a useful biomarker for pancreatitis patients.

Expression of ATF3 in mouse protects the liver against sepsis via inhibiting HMGB expression

Lipopolysaccharides are components of Gram-negative enterobacteria that cause septic shock in mammals and triggers innate immunity mainly via TLR4 signaling. HMGB1 play a critical role in regulating innate immunity-induced sepsis. ATF3 is a negative regulator of TLR4 signaling and the mechanism of HMGB1 induced liver injury after sepsis are incompletely understood. In this study, we investigated the protective effects of ATF3 after LPS injection. Adult (4-6 months) C57/BL6 mice and ATF3 knockout mice were treated with a low dose of LPS (0.5 mg/kg, iv) for 6, 12 hrs. Liver enzymes and cytokines (TNF-α, IL-1β and IL-6) are assessed. The neutrophil and mononuclear cells in the liver tissue were examined using immunofluorescent staining. We found that serum HMGB1 levels were 8-fold higher in C57/BL6 mice with sepsis than ATF3 knockout with greater densities of neutrophils and mononuclear cells in the liver tissue, and higher levels of TNF-α, IL-1β and IL-6 in the circulation and liver tissue as well as associated with an increase in the mortality rate. In conclusion, upregulation of ATF3 contributes to the reduced release of HMGB1, and increased the survival rate of mice after LPS treated. Therefore, suppressing LPS-induced inflammation with ATF3 induction may be an important strategy for sepsis therapy.

Hypoxic trophoblast HMGB1 induces endothelial cell hyperpermeability via the TRL-4/caveolin-1 pathway.

High mobility group box 1 (HMGB1) plays an important role in the pathologic processes of endothelial permeability under oxidative stress. Trophoblast oxidative stress has been implicated in the pathophysiology of preeclampsia (PE). HMGB1 serum levels are increased in PE. However, the potential roles of HMGB1 in endothelial permeability in PE remain unclear. We assessed the effects of the hypoxic trophoblast on the permeability of the endothelial monolayer. Our results showed that the hypoxic trophoblast displayed higher HMGB1 mRNA, intracellular HMGB1 protein, and HMGB1 in conditioned medium than those of the normoxic trophoblast did. The hypoxic trophoblast conditioned medium increased the endothelial monolayer permeability and increased TLR 4 and caveolin-1 (CAV-1) protein expression in endothelial cells, which was inhibited by glycyrrhizic acid and HMGB1 small interfering RNA transfection to trophoblasts before hypoxia. The increased endothelial permeability induced by hypoxic trophoblast conditioned medium could be inhibited with TLR4 or CAV-1 gene silencing in endothelial cells. Immunoprecipitation showed that CAV-1 and TLR4 are colocalized in HUVECs and C57BL/6 mouse kidney. TLR4 small interfering RNA suppressed CAV-1 protein expression in endothelial cells upon stimulation of hypoxic trophoblast conditioned medium or HMGB1. We conclude that hypoxic trophoblasts play an important role in the mechanism of general edema (including protein urine) in PE via increasing endothelial monolayer permeability through the HMGB1/TLR4/CAV-1 pathway.