High High Mobility Group Box 1 Research Articles

Conditional epithelial sodium channel (ENaC) over-expression in C57Bl6 mouse lung triggers innate immune responses via activation of high mobility group box 1 (HMGB1) signaling

Background: One of the more sinister examples of a lung disease borne by chronic inflammation is cystic fibrosis (CF). Inherited mutations in the CFTR protein hinders the secretion of Cl−, depolarizing the membrane potential and enabling excessive Na+ flux across epithelial sodium channels (ENaCs). The mechanism by which these electrochemical imbalances contribute to chronic inflammation are unclear. Based on our preliminary observations, we hypothesize that hyperactive ENaC dysfunction plays a pivotal role in initiating sterile inflammation via activation of HMGB1 cytokine activity. Our research group has shown that high HMGB1 levels in CF sputum predicts incidence and recurrence of future acute pulmonary exacerbation. Methods: In support of this new line of investigation, we generated a conditional lung-ENaC overexpression model ( Dox-Scnn1b), which uniquely allows us to control the timing (and thus severity) of ENaC hyperactive dysfunction in C57Bl6 mice. Bronchoalveolar lavage fluid (BALF) and lung tissue samples were collected from WT and Dox-Scnn1b mice (± 625 mg/kg dox chow) in order to evaluate changes in transcript, protein, immune cell differentials, and lung injury following conditional lung ENaC overexpression. Student’s t-tests; ANOVA followed by post-hoc testing; and multivariate linear regression analysis (SigmaPlot 14.0 Systat Software) were used to evaluate statistical significance and determine whether ENaC feedforward signaling to HMGB1 effects pro-inflammatory signaling in lung epithelia. Results: qRT-PCR indicates that high dox chow (625 mg/kg) increased Scnn1b gene expression (encoding for β-ENaC subunit responsible for hyperactive channel dysfunction) by three-log fold over control fed mice, (n=6; p=0.01). Indeed, increase in Scnn1b transcript corresponded with significant increase in β-ENaC protein as detected by western blot analysis and amiloride sensitive current measurements. Importantly, Scnn1b overexpression correlated positively with increased HMGB1 protein in the lung (by 1.5 fold, p=.01 vs control; n= 6 from 2 independent studies) and % neutrophil migration. Dox induction of ENaC and HMGB1 also resulted in increased lung injury scores (from 0.24±0.1 to 0.45±0.06, n=3; p<.01). Conclusions: Conditional lung ENaC overexpression mediates HMGB1 cytokine activity and closely recapitulates the sterile lung injury phenotype observed in CF patients. Significance: The mechanisms identified through this study can be targeted for new drug therapy, which is highly significant, since there are no effective therapies currently available for reversing lung inflammation. Funding: T35DK103596 (MZ) and R01HL137033 (MH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High-Mobility Group Box 1 Overexpression Predicts a Poor Prognosis and Promotes Epithelial-Mesenchymal Transition in Gastric Cancer by Activating TLR4/NF-κB Signaling

Introduction: The molecular mechanism of high-mobility group box 1 (HMGB1) promoting the epithelial-mesenchymal transition (EMT) of gastric cancer (GC) has not been known well. This study aimed to explore the clinical effects of HMGB1 expression levels on the clinicopathological characteristics of patients with GC and to uncover the potential molecular mechanism which promotes tumor progression. Methods: The expression levels of HMGB1 in 125 patients with GC were detected by immunohistochemistry and Western blotting. Univariate and multivariate analyses were performed to evaluate the relationship between HMGB1 expression and clinical characteristics of patients with GC. Stable overexpression (over-HMGB1) and knockdown (sh-HMGB1) GC cell lines (AGS and MKN-45) were used to determine the effects of HMGB1 on the activation of TLR4/NF-κB signaling. Differences were considered statistically significant at p < 0.05 in two sides. Results: HMGB1 is highly expressed in GC tissues and cell lines. High HMGB1 expression (HR = 1.89, 95% CI: 1.44–2.39, p = 0.001) was an independent risk factor for overall survival in patients with GC. Downregulation of HMGB1 resulted in downregulation of TLR4 and NF-κB subunit (p-p65 and p-IκBα) expression, whereas the upregulated expression of HMGB1 led to increased expression of TLR4 and NF-κB subunits. Overexpression of HMGB1 promotes the upregulation of EMT-TF expression, which enhances the proliferation and migration abilities of GC cell lines. Conclusion: HMGB1 is highly expressed in GC tissues and is associated with a poorer prognosis in patients with GC. HMGB1 activates the TLR4/NF-κB signaling pathway to promote EMT progression in GC cell lines. HMGB1 may be a critical molecule in prognosis prediction and a therapeutic target for patients with GC.

High mobility group box 1 levels as potential predictors of asthma severity.

High mobility group box 1 levels as potential predictors of asthma severity.

HMGB1 Is a Prognostic Factor for Mortality in Acute Kidney Injury Requiring Renal Replacement Therapy

Instruction: High mobility group box 1 (HMGB1) is a pro-inflammatory cytokine that reportedly causes kidney injury and other organ damage in rodent acute kidney injury (AKI) models. However, it remains unclear whether HMGB1 is associated with clinical AKI and related outcomes. This study aimed to evaluate the association with HMGB1 and prognosis of AKI requiring continuous renal replacement therapy (CRRT). Methods: AKI patients treated with CRRT in our intensive care unit were enrolled consecutively during 2013–2016. Plasma HMGB1 was measured on initiation. Classic initiation was defined as presenting at least one of the following conventional indications: hyperkalemia (K ≥6.5 mEq/L), severe acidosis (pH <7.15), uremia (UN >100 mg/dL), and diuretics-resistant pulmonary edema. Early initiation was defined as presenting no conventional indications. The primary outcome was defined as 90-day mortality. Results: A total of 177 AKI patients were enrolled in this study. HMGB1 was significantly associated with the primary outcome (hazard ratio, 1.06; 95% CI, 1.04–1.08). When the patients were divided into two-by-two groups by the timing of CRRT initiation and the HMBG1 cutoff value obtained by receiver operating curve (ROC) analysis, the high HMGB1 group (>10 ng/mL) with classic initiation was significantly associated with the primary outcome compared with the others, even after adjusting for other factors including the nonrenal serial organ failure assessment (SOFA) score. Conclusion: HMGB1 was associated with 90-day mortality in AKI patients requiring CRRT. Notably, the highest mortality was observed in the high HMGB1 group with classic initiation. These findings suggest that CRRT should be considered for AKI patients with high HMGB1, regardless of the conventional indications.

A pan-cancer analysis of high mobility group box 1 and its role in human tumorigenesis

Understanding the specific and co-driving mechanisms of carcinogenesis in human tumors is indispensable for cancer research and can guide the development of effective treatment methods for tumors. High mobility group box 1 (HMGB1) participates in a variety of physiological processes of the body and has an inseparable relationship with tumors. In this study, The Cancer Genome Atlas, Gene Expression Omnibus database, Human Protein Atlas, and bioinformatic tools were used to conduct pan-cancer analysis of HMGB1 in various cancers so as to elucidate its role in human tumorigenesis. We analyzed and evaluated the expression of HMGB1 in tumors, and discovered that overexpression of HMGB1 usually indicated poor overall survival of adrenocortical carcinoma (P &lt; 0.01) and lung adenocarcinoma (LUAD) (P &lt; 0.05). High HMGB1 expression is also associated with unfavorable disease-free survival for patients with adrenocortical carcinoma (P &lt; 0.001), cervical squamous cell carcinoma and endocervical adenocarcinoma (P &lt; 0.01), head and neck squamous cell carcinoma (P &lt; 0.05), LUAD (P &lt; 0.05), and sarcoma (P &lt; 0.05). The potential mechanism of HMGB1-mediated tumorigenesis is also discussed. In conclusion, our pan-cancer analysis offers a comprehensive description of the carcinogenic roles of HMGB1 in a variety of human cancers.

CircRTN1 stimulates HMGB1 to regulate the malignant progression of papillary thyroid cancer by sponging miR-101-3p.

The important role played by circular RNA (circRNA) in promoting the progression of papillary thyroid cancer (PTC) is attracting ever more attention among medical researchers. However, what the precise contribution is of circRTN1 in PTC progression remains unclear. The study was designed to analyze the role and mechanism of circRTN1 in regulating PTC progression. Human PTC cell lines (TPC-1 and IHH-4) and human thyroid normal cells (Nthy-ori 3-1) were used for in vitro assays. mRNA or protein expression of circRTN1, miR-101-3p, and high mobility group box 1 (HMGB1) were detected by quantitative real-time polymerase chain reaction or western blot. Cell proliferation was investigated by cell counting kit-8 assay, cell colony formation assay, and 5-ethynyl-2'-deoxyuridine assay. Wound-healing assay and transwell invasion assay were conducted to evaluate cell migration and invasion. Dual-luciferase reporter assay and RNA immunoprecipitation assay were applied to verify the target relations between circRTN1, miR-101-3p, and HMGB1. A xenograft tumor model was established to demonstrate the effect of circRTN1 on tumor formation in vivo. An immunohistochemistry assay was used to detect protein expression of HMGB1, ki-67, E-cadherin, and vimentin. In comparison with healthy thyroid tissues and cells, PTC tissues and cells displayed high circRTN1 RNA expression and high HMGB1 mRNA and protein expression but low miR-101-3p expression. Silencing of circRTN1 suppressed PTC cell proliferation, migration, and invasion in vitro. MiR-101-3p was a target of circRTN1, and the knockdown of miR-101-3p relieved circRTN1 absence-mediated suppressive effects on PTC cell malignancy. HMGB1 was identified as a target gene of miR-101-3p, and overexpressed HMGB1 almost reverted the inhibitory impacts induced by miR-101-3p mimic in PTC cells. Moreover, circRTN1 silencing hampered tumor formation in vivo. CircRTN1 depletion impeded PTC cell malignancy via the miR-101-3p/HMGB1 pathway, which provided a possible circRNA-targeted therapeutic strategy for PTC.

Effects of AGEs, sRAGE and HMGB1 on Clinical Outcomes in Multiple Myeloma.

The receptor for advanced glycation end products (RAGE) upregulated during the onset and progression of cancer and bone-related pathologies. In this study, we aimed to investigate the role of serum advanced glycation end products (AGEs), soluble RAGE (sRAGE) and high mobility group box 1 (HMGB1), in multiple myeloma (MM). AGEs, sRAGE and HMGB1 concentrations of 54 newly diagnosed MM patients and 30 healthy volunteers were measured by ELISA. The estimations were done only once at diagnosis. The medical records of the patients were evaluated. There was no significant difference between the AGEs and sRAGE levels between the patient and control groups (p = 0.273, p = 0.313). In ROC analysis, a HMGB1 cutoff value of > 9170 pg/ml accurately discriminated MM patients (AUC = 0.672, 95% CI 0.561-0.77, p = 0.0034). AGEs level was found to be significantly higher in early-stage disease and HMGB1 in advanced disease (p = 0.022, p = 0.026). High HMGB1 levels were detected in patients whose with better first-line treatment response (p = 0.019). At 36 months, 54% of patients with low AGE were alive, compared to 79% of patients with high AGE (p = 0.055). Patients with high HMGB1 levels tended to have a longer PFS (median 43 mo [95% CI; 20.68-65.31] ) compared to patients with low HMGB1 levels (median 25 mo [95% CI; 12.39-37.6], p = 0.054). In this study, a significant elevation of serum HMGB1 level was found in MM patients. In addition, the positive effects of RAGE ligands on treatment response and prognosis were determined.

Platelet dysfunction after trauma: From mechanisms to targeted treatment.

Platelet dysfunction after trauma: From mechanisms to targeted treatment.

Involvement of High Mobility Group Box 1 Protein in Optic Nerve Damage in Diabetes.

IntroductionDiabetic patients routinely have high levels of high mobility group box 1 (HMGB1) protein in their plasma, vitreous and ocular membranes, which is strongly correlated with subclinical chronic inflammation in the eye. Our previous work has suggested that high HMGB1 in diabetes plays a role in retinal inflammation and angiogenesis, but its role in the optic nerve damage is unclear. Therefore, our goal is to examine the role of HMGB1 in optic nerve damage in diabetes.MethodsGene expression of HMGB1 was quantified in the optic nerve from streptozotocin-induced diabetic mice by qRT-PCR, and their protein expressions by Western blot analysis and immunofluorescence staining. Using immunohistochemical technique, expression of reactive astrogliosis (indicator of neuroinflammation) and nerve demyelination/damage were determined by quantifying glial fibrillary acid protein (GFAP) and myelin basic protein (MBP), respectively. The role of HMGB1 in the optic nerve damage and alteration visual pathways was confirmed in mice receiving glycyrrhizin, a HMGB1 inhibitor. Similar parameters were measured in the optic nerve from human donors with diabetes.ResultsCompared to normal mice, diabetic mice exhibited increased levels of HMGB1, higher GFAP expression, and decreased MBP in the optic nerve. Double immunofluorescence microscopy revealed that diabetes induced increased HMGB1 immunoreactivities were significantly colocalized with GFAP in the optic nerve. Glycyrrhizin supplementation effectively reduced HMGB1 and maintained normal axonal myelination and visual conduction. Results from mice optic nerve confirmed the results obtained from human donors with diabetes.DiscussionsThus, diabetes-induced HMGB1 upregulation promotes optic nerve demyelination and inflammation. The regulation of HMGB1 activation has potential to protect optic nerve damage and the abnormalities of visual pathways in diabetic patients.

Decreased levels of histidine-rich glycoprotein and increased levels of high-mobility group box 1 are risk factors for refractory Kawasaki disease.

Histidine-rich glycoprotein (HRG) and high-mobility group box 1 (HMGB1) regulate the activation of neutrophils and vascular endothelium. The aim of this study was to quantify HRG and HMGB1 levels in patients with Kawasaki disease (KD) and evaluate their use in the clinical management of KD. This study was prospectively performed. Patients were divided into two groups and analysed depending on whether KD symptoms improved by Day 10 of illness. HRG, HMGB1, and other laboratory variables were measured before the first treatment in all cases and, in most cases, afterwards for assessing trends. In this prospective study, we enrolled 60 patients with KD and 48 healthy controls. The HRG level in the KD group was significantly lower than that in the healthy control group; HMGB1 levels showed no obvious differences. In the KD group, HRG levels were negatively correlated with white blood cell and neutrophil counts. In the poor responders and responders groups, a tendency for a decrease in HRG and HMGB1 levels, respectively, was observed from pretreatment to post-treatment. HRG and HMGB1 are related to the pathogenesis of KD; low HRG and high HMGB1 levels cause resistance against KD treatment.

High-mobility group box 1 (HMGB1) in COVID-19: extrapolation of dangerous liaisons.

High-mobility group box 1 (HMGB1), a multifunctional nuclear protein, exists mainly within the nucleus of all mammal eukaryotic cells. It is actively secreted by the necrotic cells as a response to the inflammatory signaling pathway. HMGB1 binds to receptor ligands as RAGE, and TLR and becomes a pro-inflammatory cytokine with a robust capacity to trigger inflammatory response. It is a critical mediator of the pathogenesis of systemic inflammation in numerous inflammatory disorders. Release of HMGB1 is associated with different viral infections and strongly participates in the regulation of viral replication cycles. In COVID-19 era, high HMGB1 serum levels were observed in COVID-19 patients and linked with the disease severity, development of cytokine storm (CS), acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). SARS-CoV-2-induced cytolytic effect may encourage release of HMGB1 due to nuclear damage. Besides, HMGB1 activates release of pro-inflammatory cytokines from immune cells and up-regulation of angiotensin I-converting enzyme 2 (ACE2). Therefore, targeting of the HMGB1 pathway by anti-HMGB1 agents, such as heparin, resveratrol and metformin, may decrease COVID-19 severity. HMGB1 signaling pathway has noteworthy role in the pathogenesis of SARS-CoV-2 infections and linked with development of ALI and ARDS in COVID-19 patients. Different endogenous and exogenous agents may affect release and activation of HMGB1 pathway. Targeting of HMGB1-mediated TLR2/TLR4, RAGE and MAPK signaling, might be a new promising drug candidate against development of ALI and/or ARDS in severely affected COVID-19 patients.

Serum Level of High-Mobility Group Box Protein 1 as a Potential Treatment Target in Egyptian Sickle Cell Disease Patients

Background:&#x0D; During tissue injury, high mobility group box 1 (HMGB1) is passively released from necrotic cells and actively secreted by inflammatory cells. Extracellular HMGB1 acts as an amplifier of Toll-Like Receptor (TLR)-dependent inflammation rather than a primary trigger of inflammation. We studied HMGB1 quantitative trait locus reference sequence 2249825 (rs2249825) and its serum level in both sickle cell disease (SCD) patients and healthy subjects to explore its possible role in the pathogenesis of vaso-occlusive crises (VOCs).&#x0D; Methods:&#x0D; HMGB1 rs2249825 was assayed in peripheral blood samples using real-time polymerase chain reaction (RT-PCR). While the serum level was assayed using a two-site enzyme-linked immunosorbent technique (ELISA).&#x0D; Results:&#x0D; Both the SCD patients and the control group had comparable HMGB1 rs2249825 genotype frequencies (P-value &gt;0.05). SCD patients at their steady-state showed statistically significantly higher serum HMGB1 levels than the healthy controls, a median of 0.6 ng/ml with a range of 0.1- 85 ng/ml versus a median of 0.3 ng/ml and a range of 0.1-3 ng/ml (P-value &lt;0.001), respectively. Statistically significant skewed high serum HMGB1 in the VOC samples in contrast to the steady-state samples was observed in the SCD patients with a median of 3.2 ng/ml and a range of 0.3-76.4 ng/ml versus a median of 0.2 ng/ml and a range 0.2-7.4 ng/ml (P-value &lt;0.0001), respectively.&#x0D; &#x0D; &#x0D; Conclusion:&#x0D; HMGB1 could have a role in the VOC pathogenesis, hence it is suggested as a potential additive therapeutic target in SCD in general and in vaso-occlusions in specific.&#x0D; Keywords:&#x0D; Sickle cell disease, HMGB1, Hemoglobin S

Role of Extracellular High-Mobility Group Box-1 as a Therapeutic Target of Gastric Cancer.

Background: High-mobility group box-1 (HMGB1) is involved in the tumorigenesis and metastasis of various cancers. The present study investigated the roles of extracellular HMGB1 in the progression of gastric cancer (GC) and the therapeutic effects of recombinant human soluble thrombomodulin (rTM) targeting HMGB1. Methods: The effects of extracellular HMGB1 and rTM on GC cells were assessed using proliferation and Transwell assays. Their effects on local tumor growth and metastasis were evaluated using subcutaneous tumor and liver metastasis mouse models, respectively. Plasma HMGB1 concentrations in GC patients were measured using ELISA. The relationships between plasma HMGB1 concentrations and the prognosis and clinicopathological factors of patients were also investigated. Results: GC proliferation, migration, and invasion abilities were promoted by increases in extracellular HMGB1 concentrations and alleviated by rTM. In the subcutaneous tumor model, local tumor growth was promoted by the addition of rhHMGB1 and alleviated by rTM. Similar changes occurred in the liver metastasis model. Recurrence-free survival (p < 0.01) and overall survival (p = 0.01) were significantly worse in patients with high plasma HMGB1 concentrations. Conclusion: Plasma HMGB1 concentrations are a prognostic marker in GC patients. Extracellular HMGB1 promotes cancer progression and has potential as a novel treatment target in GC cells for rTM.

Mortality at 180-days is affected by serum haptoglobin levels in septic patients with high magnitude serum high mobility group box-1 levels.

AimHigh mobility group box‐1 (HMGB1) is a lethal mediator of sepsis that binds to haptoglobin (Hp) and is associated with its prognosis. We investigated the effect of the combination of HMGB1 and Hp on sepsis prognosis.MethodsThis single‐center, retrospective study registered 78 patients with sepsis according to Sepsis‐3 criteria on day 1 of diagnosis from July 2016 to November 2018. We divided the patients into four groups according to the serum concentration of 6.2 ng/mL HMGB1 and the median value of Hp. The 180‐day mortality rates and cytokine concentrations of the low and high HMGB1 groups were compared.ResultsThere was no difference in the 180‐day mortality rate between the low Hp group and the high Hp group in the low HMGB1 group (P = 0.691). In the high HMGB1 group, a statistically significant difference was found between the low Hp group and the high Hp group (P = 0.002). In the high HMGB1 group, high Hp was associated with a better prognosis in univariate analysis (odds ratio, 0.131; 95% confidence interval [CI], 0.027–0.629; P = 0.011), and multivariate analysis (adjusted odds ratio, 0.086; 95% CI, 0.013–0.582; P = 0.009). In addition, in the high HMGB1 group, interleukin‐8 levels were significantly higher in the low Hp group than in the high Hp group (P = 0.004).ConclusionPatients with sepsis‐induced high serum HMGB1 levels and low serum Hp levels could have a poor long‐term prognosis.

Evaluation of RUNX2 and HMGB1 expression as markers of tumor aggressiveness in urothelial carcinoma

Aim To investigate the expression and the clinical significance of runt-related transcription factor (RUNX2) and high-mobility group box 1 (HMGB1) in urothelial carcinoma of the urinary bladder. The correlation between RUNX2 and HMGB1 expression and the clinicopathological features was analyzed. Patients and methods RUNX2 and HMGB1 expression was examined by immunohistochemistry in 62 urothelial carcinoma and 20 nonneoplastic bladder tissues as control group. Results High RUNX2 and HMGB1 protein expression was observed in 67.7 and 56.5% of cases of urothelial carcinoma, respectively, and showed predominantly nuclear expression. The expression of RUNX2 and HMGB1 in urothelial carcinoma was significantly higher than that in nonneoplastic urothelial tissues (P<0.001 for each). Moreover, high RUNX2 expression was significantly associated with high tumor grade (P=0.003), advanced tumor stage (P=0.011), lymph-node metastasis (P=0.045), and the presence of concomitant carcinoma in situ (P=0.01). HMGB1 showed higher expression with high-grade tumors (P=0.007), advanced tumor stage (P=0.002), and the presence of necrosis (P<0.001). A significant direct relationship was detected between RUNX2 and HMGB1 expression (P<0.001). Conclusion Our data suggest that RUNX2 and HMGB1 overexpression may contribute to urothelial carcinoma tumorigenesis and was associated with aggressive clinicopathologic features. RUNX2 and HMGB1 could be promising potential biomarkers for urothelial carcinoma.

Peritumoral B cells drive proangiogenic responses in HMGB1-enriched esophageal squamous cell carcinoma

Several B-cell subsets with distinct functions and polarized cytokine profiles that extend beyond antibody production have been reported in different cancers. Here we have demonstrated that proliferating B cells were predominantly found in the peritumoral region of esophageal squamous cell carcinoma (ESCC). These B cells were enriched in tumor nests with high expression of high-mobility group box 1 (HMGB1). High densities of peritumoral proliferating B cells and concomitantly high intratumoral HMGB1 expression showed improved prognostic significance, surpassing prognostic stratification of ESCC patients based on HMGB1 positivity alone. This striking association led us to set up models to test whether cancer-derived HMGB1 could shape tumor microenvironment via modulation on B cells. Overexpression of HMGB1 in ESCC cell lines (KYSE510 and EC18) enhanced proliferation and migration of B cells. Transcriptomic analysis showed that migratory B cells exhibited high enrichment of proangiogenic genes. VEGF expression in proliferating B cells was induced upon co-culture of HMGB1-overexpressing tumor cells and B cells. Secretome array profiling of conditioned media (CM) from the co-culture revealed rich expression of proangiogenic proteins. Consequently, incubation of human umbilical vein endothelial cells with CM promoted angiogenesis in tube formation and migration assays. HMGB1 inhibitor, glycyrrhizin, abolishes all the observed proangiogenic phenotypes. Finally, co-injection of B cells and CM with HMGB1-overexpressing tumor cells, but not with glycyrrhizin, significantly enhanced tumor growth associated with increased microvascular density in ESCC xenograft mice model. Our results indicate that cancer-derived HMGB1 elevates angiogenesis in ESCC by shifting the balance toward proangiogenic signals in proliferating B cells.

Correlation of blood high mobility group box-1 protein with mortality of patients with sepsis: A meta-analysis

BackgroundThe role of blood high mobility group box-1 (HMGB-1) protein in predicting mortality of sepsis remains controversial. ObjectiveHere we conducted a meta-analysis to seek evidence for the association between blood HMGB-1 concentrations and mortality in patients with sepsis. MethodsEligible studies were identified by a comprehensive search of six digital databases, supplemented by a manual search of related references. Standardized mean differences (SMDs) and corresponding 95% confidence intervals (CIs) were calculated as effect estimates. ResultsA total of eighteen studies, covering 1163 patients with sepsis, were included. Compared with survival groups of sepsis, non-survival groups had significantly higher blood HMGB-1 concentrations at enrollment (SMD: 0.45, 95% CI: 0.21–0.69). Subgroup analyses showed that no significant differences were found between two groups among patients with more severe sepsis (SMD: 0.18, 95% CI: -0.02–0.38). A significant association between initial HMGB-1 levels and ≤30-day mortality remained (SMD: 0.43, 95% CI: 0.09–0.78). Besides, HMGB-1 levels were observed to be more significantly higher in non-survival groups after the third day of admission (SMD: 1.33, 95% CI: 1.05–1.62) but two groups attained comparable HMGB-1 levels on day 7 (SMD: 1.01, 95% CI: -0.31–2.33). ConclusionsInitial high blood HMGB-1 levels are significantly associated with short-term (≤30 days) mortality of patients with sepsis, and the association may be affected by the severity of sepsis. Subsequent monitoring of HMGB-1 levels, on the third and seventh day after admission, is encouraged for better evaluation of HMGB-1 as a prognostic marker of mortality in sepsis.

High Mobility Group Box 1 Release by Cholangiocytes Governs Biliary Atresia Pathogenesis and Correlates With Increases in Afflicted Infants.

Background and AimsBiliary atresia (BA) is a devastating cholangiopathy of infancy. Upon diagnosis, surgical reconstruction by Kasai hepatoportoenterostomy (HPE) restores biliary drainage in a subset of patients, but most patients develop fibrosis and progress to end‐stage liver disease requiring liver transplantation for survival. In the murine model of BA, rhesus rotavirus (RRV) infection of newborn pups results in a cholangiopathy paralleling that of human BA. High‐mobility group box 1 (HMGB1) is an important member of the danger‐associated molecular patterns capable of mediating inflammation during infection‐associated responses. In this study, we investigated the role of HMGB1 in BA pathogenesis.Approach and ResultsIn cholangiocytes, RRV induced the expression and release of HMGB1 through the p38 mitogen‐activated protein kinase signaling pathway, and inhibition of p38 blocked HMGB1 release. Treatment of cholangiocytes with ethyl pyruvate suppressed the release of HMGB1. Administration of glycyrrhizin in vivo decreased symptoms and increased survival in the murine model of BA. HMGB1 levels were measured in serum obtained from infants with BA enrolled in the PROBE and START studies conducted by the Childhood Liver Disease Research Network. High HMGB1 levels were found in a subset of patients at the time of HPE. These patients had higher bilirubin levels 3 months post‐HPE and a lower survival of their native liver at 2 years.ConclusionsThese results suggest that HMGB1 plays a role in virus induced BA pathogenesis and could be a target for therapeutic interventions in a subset of patients with BA and high HMGB1.

Identification of High-Mobility Group Box 1 (HMGB1) Expression as a Potential Predictor of Rejection and Poor Prognosis After Liver Transplantation.

BackgroundAcute cellular rejection (ACR) frequently occurs after liver transplantation (LT) and can result in permanent damage of the liver allograft. Specific and sensitive biomarkers for predicting and monitoring ACR are vital for guiding post-transplantation care. In the present study, we aimed to investigate the function of high-mobility group box 1 (HMGB1) in predicting ACR and prognosis after LT.Material/MethodsA total of 113 LT recipients were enrolled in the study, including 62 patients in an ACR group and 51 patients in a non-rejection group. Using tissues from the 113 patients, HMGB1 expression was examined by immunohistochemistry, and the total score for HMGB1 expression was calculated by multiplying the percentage of immunoreactive cells score and the staining intensity score. We then analyzed the association between HMGB1 expression and clinical features. Finally, the function of HMGB1 in predicting the prognosis of LT was determined using Kaplan-Meier (K-M) survival and Cox multivariate analyses.ResultsImmunohistochemical staining results demonstrated that the expression of HMGB1 was significantly increased in the ACR group, compared with that in the non-rejection group (P<0.05). Clinical characteristic analysis revealed that high HMGB1 levels were related to ACR (P<0.05). Moreover, K-M survival analysis showed that patients with high HMGB1 expression displayed poorer prognosis (P<0.05). Cox multivariate analysis demonstrated that HMGB1 was an independent prognostic predictor for post-LT survival (odds ratio, 3.283; P=0.008).ConclusionsLT recipients’ HMGB1 levels may be a useful and noninvasive biomarker for the prediction of ACR and prognosis after LT.

Association of plasma level of high-mobility group box-1 with necroptosis and sepsis outcomes

The role of high-mobility group box-1 (HMGB1) in outcome prediction in sepsis is controversial. Furthermore, its association with necroptosis, a programmed cell necrosis mechanism, is still unclear. The purpose of this study is to identify the association between the plasma levels of HMGB1 and the severity and clinical outcomes of sepsis, and to examine the correlation between HMGB1 and key executors of necroptosis including receptor-interacting kinase 3 (RIPK3) and mixed lineage kinase domain-like- (MLKL) proteins. Plasma HMGB1, RIPK3, and MLKL levels were measured with the enzyme-linked immunosorbent assay from the derivation cohort of 188 prospectively enrolled, critically-ill patients between April 2014 and December 2016, and from the validation cohort of 77 patients with sepsis between January 2017 and January 2019. In the derivation cohort, the plasma HMGB1 levels of the control (n = 46, 24.5%), sepsis (n = 58, 30.9%), and septic shock (n = 84, 44.7%) groups were significantly increased (P < 0.001). A difference in mortality between high (≥ 5.9 ng/mL) and low (< 5.9 ng/mL) HMGB1 levels was observed up to 90 days (Log-rank test, P = 0.009). There were positive linear correlations of plasma HMGB1 with RIPK3 (R2 = 0.61, P < 0.001) and MLKL (R2 = 0.7890, P < 0.001). The difference in mortality and correlation of HMGB1 levels with RIPK3 and MLKL were confirmed in the validation cohort. Plasma levels of HMGB1 were associated with the severity and mortality attributed to sepsis. They were correlated with RIPK3 and MLKL, thus suggesting an association of HMGB1 with necroptosis.