Serum High Mobility Group Box 1 Research Articles

Febrile Urinary Tract Infections in Children: The Role of High Mobility Group Box-1.

Differentiating between febrile lower urinary tract infection (LUTI) and acute pyelonephritis (APN) is crucial for prompt clinical management. We investigated whether the high mobility group box-1 (HMGB1) could be a useful biomarker in differentiating between LUTI or APN. We enrolled seventy-four pediatric patients with suspected LUTI/APN, according to the positive or negative renal scintigraphy (DMSA) scan. If the first DMSA findings were abnormal, a second DMSA was performed after six months. Voiding cystourethrography ruled out vesicoureteral reflux (VUR). Higher serum (s) HMGB1 levels characterized the APN group when compared to LUTI patients (13.3 (11.8-14.3) versus 5.9 (5.2-6.8) ng/mL, p: 0.02), whereas there were no differences according to urine (u) HMGB1 values. sHMGB1 correlated with C-reactive protein (CRP) levels (β = 0.47; p: 0.02). Receiver operating characteristic curves identified the best diagnostic profile for detecting APN. sHMGB1 area under the curve was different from CRP (p: 0.01) and white blood cells (p: 0.003). After multivariate analyses, VUR (HR:4.81) and sHMGB1 (HR 1.16; p: 0.006) were independently associated with the risk of renal scarring development. sHMGB1 could represent a marker to differentiate APN from LUTI. Measurement of sHMGB1 could select children for early intervention or long-term follow-up.

Diagnostic value of transpulmonary thermodilution measurements for acute respiratory distress syndrome in a pig model of septic shock

BackgroundNo direct approach assessing pulmonary vascular permeability exists in the current therapeutic strategy for patients with acute respiratory distress syndrome (ARDS). Transpulmonary thermodilution measures hemodynamic parameters such as pulmonary vascular permeability index and extravascular lung water, enabling clinicians to assess ARDS severity. The aim of this study is to explore a precise transpulmonary thermodilution-based criteria for quantifying the severity of lung injury using a clinically relevant septic-ARDS pig model.MethodsThirteen female pigs (weight: 31 ± 2 kg) were intubated, mechanically ventilated under anesthesia, and either assigned to septic shock-induced ARDS or control group. To confirm the development of ARDS, we performed computed tomography (CT) imaging in randomly selected animals. The pulmonary vascular permeability index, extravascular lung water, and other hemodynamic parameters were consecutively measured during the development of septic lung injury. Lung status was categorized as normal (partial pressure of oxygen/fraction of inspired oxygen ≥ 400), or injured at different degrees: pre-ARDS (300–400), mild-to-moderate ARDS (100–300), or severe ARDS (< 100). We also measured serum inflammatory cytokines and high mobility group box 1 levels during the experiment to explore the relationship of the pulmonary vascular permeability index with these inflammatory markers.ResultsUsing CT image, we verified that animals subjected to ARDS presented an extent of consolidation in bilateral gravitationally dependent gradient that expands over time, with diffuse ground-glass opacification. Further, the post-mortem histopathological analysis for lung tissue identified the key features of diffuse alveolar damage in all animals subjected to ARDS. Both pulmonary vascular permeability index and extravascular lung water increased significantly, according to disease severity. Receiver operating characteristic analysis demonstrated that a cut-off value of 3.9 for the permeability index provided optimal sensitivity and specificity for predicting severe ARDS (area under the curve: 0.99, 95% confidence interval, 0.98–1.00; sensitivity = 100%, and specificity = 92.5%). The pulmonary vascular permeability index was superior in its diagnostic value than extravascular lung water. Furthermore, the pulmonary vascular permeability index was significantly associated with multiple parameters reflecting clinicopathological changes in animals with ARDS.ConclusionThe pulmonary vascular permeability index is an effective indicator to measure septic ARDS severity.

Predictive value of serum high-mobility group box 1 levels for checkpoint inhibitor pneumonitis.

Checkpoint inhibitor pneumonitis (CIP), caused by the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) antibody, can be a fatal adverse event in cancer patients. However, no predictive biomarkers for CIP have been identified. Because high-mobility group box 1 (HMGB1) can aggravate lung injury and potentially increase the immune response, it was investigated as a predictive blood marker. Blood samples, prospectively stored before anti-PD-1/PD-L1 monotherapy between December 2015 and October 2020, were obtained at two university hospitals from 87 and 43 non-small cell lung cancer (NSCLC) patients (discovery and validation cohorts, respectively). We retrospectively evaluated the association of serum HMGB1 levels with the incidence of CIP developed within 3months of initiating anti-PD-1/PD-L1 therapy. CIP was observed in 9 (10.3%) and 6 (14.0%) patients in the discovery and validation cohorts, respectively. In each cohort, serum HMGB1 levels were significantly and reproducibly higher in patients with CIP. In the discovery cohort, an HMGB1 cut-off level of 11.24 ng/ml was identified by receiver operating characteristic analysis. CIP incidence in the HMGB1high subgroup was significantly higher than that in the HMGB1low subgroup in the discovery (41.2% vs. 2.9%) and validation cohorts (36.4% vs. 6.3%). In an exploratory pooled analysis, three patients died of grade 5 CIP; a 19.29 ng/ml HMGB1 cut-off level detected grade 5 CIP with 100% sensitivity and 96.85% specificity. Our results suggest that HMGB1 may be a potential blood marker to predict the development and severity of CIP in NSCLC patients.

Free Light Chains, High Mobility Group Box 1, and Mortality in Hemodialysis Patients.

Background: Uremic toxins are associated with immune dysfunction and inflammation. The inadequate removal by hemodialysis (HD) of serum free light chains (FLCs) determines their accumulation. This study evaluated FLCs in HD patients, analyzing their relations with other biomarkers, such as serum high mobility group box 1 (HMGB1). Methods: FLC and HMGB1 were evaluated in a cohort of 119 HD patients. κFLC and λFLC were summated to give a combined (c) FLC concentration. Patients were followed prospectively until the end of the observation period of four years, or until the endpoint: the patient’s death. Results: cFLC values in HD patients were 244.4 (197.9−273.5) mg/L. We detected a significant reduction in CD8+ cells and a decreased CD4+/CD8+ ratio. HMGB1 levels were 94.5 (55−302) pg/mL. After multivariate analysis, cFLCs correlated with β2-microglobulin and the CD4+/CD8+ ratio. Subjects with cFLC values above 263 mg/L and with sHMGB1 values < 80 pg/mL experienced a significantly faster evolution to the endpoint (mean follow-up time to progression of 27.5 and 28.5 months, respectively; p < 0.001). After an adjusted multivariate Cox analysis, cFLCs were associated with 11% increased risk of death, whereas low sHMGB1 increased this risk by 5%. Conclusions: cFLCs and HMGB1 reflect the inflammation and immune dysfunction in HD patients representing two strong and independent risk markers of mortality.

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.

Serum high mobility group box-1 levels associated with cardiovascular events after lower extremity revascularization: a prospective study of a diabetic population

BackgroundPeripheral arterial disease (PAD) is one of the most disabling cardiovascular complications of type 2 diabetes mellitus and is indeed associated with a high risk of cardiovascular and limb adverse events. High mobility group box-1 (HMGB-1) is a nuclear protein involved in the inflammatory response that acts as a pro-inflammatory cytokine when released into the extracellular space. HMBG-1 is associated with PAD in diabetic patients.The aim of this study was to evaluate the association between serum HMGB-1 levels and major adverse cardiovascular events (MACE) and major adverse limb events (MALE) after lower-extremity endovascular revascularization (LER) in a group of diabetic patients with chronic limb-threatening ischemia (CLTI).MethodsWe conducted a prospective observational study of 201 diabetic patients with PAD and CLTI requiring LER. Baseline serum HMGB-1 levels were determined before endovascular procedure. Data on cardiovascular and limb outcomes were collected in a 12-month follow-up.ResultsDuring the follow-up period, 81 cases of MACE and 93 cases of MALE occurred. Patients who subsequently developed MACE and MALE had higher serum HMGB-1 levels. Specifically, 7.5 ng/mL vs 4.9 ng/mL (p < 0.01) for MACE and 7.2 ng/mL vs 4.8 ng/mL (p < 0.01) for MALE. After adjusting for traditional cardiovascular risk factors, the association between serum HMGB-1 levels and cardiovascular outcomes remained significant in multivariable analysis. In our receiver operating characteristic (ROC) curve analysis, serum HMGB-1 levels were a good predictor of MACE incidence (area under the curve [AUC] = 0.78) and MALE incidence (AUC = 0.75).ConclusionsThis study demonstrates that serum HMGB-1 levels are associated with the incidence of MACE and MALE after LER in diabetic populations with PAD and CLTI.

Serum Sirtuin-1, HMGB1-TLR4, NF-KB and IL-6 Levels in Alzheimer's: The Relation Between Neuroinflammatory Pathway and Severity of Dementia.

In this study, serum Sirtuin-1(SIRT-1), High Mobility Group Box 1 (HMGB1), Toll-Like Receptor-4 (TLR4), Nuclear Factor Kappa B (NF-kB), Interleukin-6 (IL-6), Amyloid βeta-42 (Aβ- 42), and p-tau181 levels in patients diagnosed with AD according to NINCS-ADRA criteria were studied. We investigated the inflammatory pathways that lead to progressive neuronal loss and highlight their possible relationship with dementia severity in the systemic circulation. Patients over 60 years of age were grouped according to their Standard Mini Mental Test results, MRI, and/or Fludeoxyglucose positron emission tomography or according to their CT findings as Control n:20; AD n:32; Vascular Dementia (VD) n:17; AD + VD; n = 21. Complete blood count, Glucose, Vitamin B12, Folic Acid, Enzymes, Urea, Creatinine, Electrolytes, Bilirubin, and Thyroid Function tests were evaluated. ELISA was used for the analysis of serum SIRT1, HMGB1, TLR4, NF-kB, IL-6, Aβ-42, and p-tau181 levels. Levels of serum Aβ-42, SIRT1, HMGB1, and IL-6 were significantly higher (p< 0.001, p< 0.01, p< 0.001, and p< 0.001, respectively), and TLR4 levels were significantly lower (p< 0.001) in the dementia group than in the control group. No significant difference was observed between dementia and control groups for serum NF-kB and p-tau181 levels. Our results show that the levels of the Aβ42, SIRT 1, HMGB1, and TLR4 pathways are altered in AD and VD. SIRT 1 activity plays an important role in the inflammatory pathway of dementia development, particularly in AD.

High mobility group box 1 and Dickkopf-related protein 1 as biomarkers of glucose toxicity, atherogenicity, and lower β cell function in patients with type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is associated with increased atherogenicity and inflammatory responses, which may be related to high mobility group box 1 (HMGB1) and Dickkopf-related protein 1 (DKK1). The role of HMGB1 and DKK1 in T2DM is examined in association with lipid and insulin profiles. Serum HMGB1 and DKK1 were measured in T2DM with and without hypertension and compared with controls. The results showed that HMGB1 and DKK1 are higher in T2DM irrespective of hypertension. A large part of the variance in the β-cell index and glucose toxicity was explained by the combined effects of HMGB1 and DKK1. In conclusion, both HMGB1 and DKK1 may contribute to increased atherogenicity in T2DM. Moreover, both biomarkers may cause more deficits in β-cell function and increase glucose toxicity leading to the development of more inflammation and diabetic complications. HMGB1 and the Wnt pathways are other drug targets in treating T2DM.

E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation

Necroinflammation plays an important role in disease settings such as acute kidney injury (AKI). We and others have elucidated that prostaglandins, which are critically involved in inflammation, may activate E-prostanoid 3 receptor (EP3) at low concentrations. However, how EP3 blockade interacts with regulated cell death and affects AKI remains unknown. In this study, AKI was induced by ischemia-reperfusion (30 minutes/24 hours) in Ep3 knockout (Ep3-/-), bone marrow chimeric, myeloid conditional EP3 knockout and corresponding control mice. The production of prostaglandins E2 and I2 was markedly increased after ischemia-reperfusion, and either abrogation or antagonism of EP3 ameliorated the injury. EP3 deficiency curbed inflammatory cytokine release, neutrophil infiltration and serum high-mobility group box 1 levels, but additional TLR4 inhibition with TAK-242 did not offer further protection against the injury and inflammation. The protection of Ep3-/- was predominantly mediated by suppressing Mixed Lineage Kinase domain-Like-dependent necroptosis, resulting from the inhibition of cytokine generation and the switching of cell death modality from necroptosis to apoptosis through caspase-8 up-regulation, in part due to the restraint of IL-6/JAK2/STAT3 signaling. EP3 deficiency failed to further alleviate the injury when necroptosis was inhibited. Ep3-/- in bone marrow-derived cells, particularly that in myeloid cells, protected kidneys to the same extent as that of global EP3 deletion. Thus, our results demonstrate that EP3 deficiency especially that on myeloid cells, ameliorates ischemic AKI via curbing inflammation and breaking the auto-amplification loop of necroinflammation. Hence, EP3 may be a promising target for the prevention and/or treatment of AKI.

Predictive role of circulatory levels of high-mobility group box 1 for radiation pneumonitis in patients with non-small cell lung cancer treated with definitive thoracic radiotherapy.

High-mobility group box 1 (HMGB1) is a pro-inflammatory protein associated with the pathophysiology of lung injury and lung tumorigenesis. Here, we investigated the predictive potential of serum HMGB1 levels for radiation pneumonitis in patients with lung cancer. This was a retrospective biomarker study of 73 patients with non-small cell lung cancer treated with definitive thoracic radiotherapy between August 2007 and January 2021. We measured HMGB1 levels in serum stored before treatment, and analyzed its association with the development of grade ≥ 2 or grade ≥ 3 radiation pneumonitis. Additionally, baseline characteristics affecting HMGB1 levels were identified. Of the 73 patients, 21 (28.8%) and 6 (8.2%) patients experienced grade 2 and ≥ 3 radiation pneumonitis, respectively. Univariate and multivariate logistic regression analyses revealed that higher baseline levels of serum HMGB1 were significantly associated with a higher risk of grade ≥ 3, but not grade ≥ 2, radiation pneumonitis. The incidence of grade ≥ 3 radiation pneumonitis was higher in patients with HMGB1 levels ≥ 6.2ng/mL than in those with levels < 6.2ng/mL (25.0% vs. 3.5%, p = 0.019). Baseline serum levels of HMGB1 were independently and positively associated with gross tumor volume. Higher serum HMGB1 levels were significantly associated with the risk of grade ≥ 3 radiation pneumonitis in patients with lung cancer, and therefore, HMGB1 could be a potential blood biomarker for predicting severe radiation pneumonitis.

Accuracy and sensitivity of high mobility group box 1 (HMGB1) in diagnosis of acute kidney injury caused by sepsis and relevance to prognosis

ObjectiveThe diagnostic value of high mobility group box 1 (HMGB1) levels in patients with acute kidney injury (AKI) caused by sepsis and its relationship with disease prognosis were investigated to improve patient survival. MethodsA total of 120 patients diagnosed with sepsis by comprehensive clinical examination were selected as the research subjects. According to the presence or absence of concurrent AKI, all patients were divided into SIAKI (50 cases with concurrent AKI) and N-AKI groups (70 cases without concurrent AKI). Sixty normal people receiving a physical examination in our hospital during the same period were divided into the control group. The diagnostic efficacy and the influences of HMGB1 on prognosis were assessed. ResultsHMGB1 levels in the serum and urine of the control group (3.43 ± 0.73 pg/mL, 343.13 ± 51.03 pg/mL) were both lower than those of the SIAKI (14.76 ± 2.44 pg/mL, 1109.76 ± 225.66 pg/mL) and N-AKI groups (7.99 ± 1.84 pg/mL, 890.54 ± 97.76 pg/mL) (P < 0.05). HMGB1 in the serum of the SIAKI group was higher than that of the N-AKI group (P < 0.05). The sensitivity (88%), specificity (87%), accuracy (88%), and area under the curve (AUC) (0.891) of the joint diagnosis of HMGB1 in blood and urine were superior to the diagnostic effects of HMGB1 in serum (70%, 70%, 70%, and 0.701) and HMGB1 in urine (59%, 57%, 58%, and 0.677) (P < 0.05). The proportion of HMGB1 in the nonsurvivors was higher than that in the survivors (85%) and was obviously higher than that in the survivors (15%) (P < 0.05). ConclusionAs a diagnostic marker of sepsis complicated with AKI, HMGB1 in serum and urine showed good application value. Serum HMGB1 could be used to assess disease prognosis with good clinical promotion.

Roles of Vitamin-K-dependent Factors Protein S and GAS6 With TAM Receptors and HMGB1 in Pediatric COVID-19 Disease.

This study was designed to evaluate serum high-mobility group box 1 (HMGB1), protein S (PS), growth arrest-specific gene 6 (GAS6), and TAM receptor (TYRO3, AXL, and MERTK) levels in children with COVID-19 disease. A prospective case-control study was conducted in our pediatric emergency department and 57 patients with SARS-CoV-2 polymerase chain reaction (PCR) positivity, 6 patients with multisystem inflammatory syndrome in children (MIS-C), and 17 healthy children were included. Demographic data, clinical findings, laboratory and radiologic data, the need for hospitalization, and prognosis were recorded. Serum HMGB1, PS, GAS6, and TAM receptor levels were studied by enzyme-linked immunosorbent assay method. While SARS-CoV-2 PCR-positive patients and healthy controls were similar in terms of gender and age, GAS6 and MERTK levels were significantly lower in SARS-CoV-2 PCR-positive patients compared with healthy controls. Among SARS-CoV-2 PCR-positive patients, no difference was found in terms of serum markers in those with and without gastrointestinal or respiratory system symptoms. However, in patients with respiratory distress at admission, PS and TYRO3 levels were significantly lower. AXL levels were lower in patients diagnosed with MIS-C compared with healthy controls. Activated partial thromboplastin time was negatively correlated with HMGB1, PS, GAS6, and AXL levels. Our results suggest that such measurements may be informative and warranted in children with COVID-19 who show evidence of coagulopathy and respiratory distress. Further studies are needed to clarify the roles of these markers in diagnosis, to predict clinical severity, and to evaluate their roles in treatment approaches for COVID-19 disease.

The HMGB1-RAGE axis induces apoptosis in acute respiratory distress syndrome through PERK/eIF2α/ATF4-mediated endoplasmic reticulum stress.

Apoptosis plays a major role in the progression of acute respiratory distress syndrome (ARDS) that may involve the interaction of the high mobility group box 1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). However, the underlying mechanism remains unclear. Thus, we aimed to explore the mechanisms of HMGB1-RAGE axis-induced apoptosis in ARDS. Blood samples from ARDS patients and healthy volunteers were collected to investigate the correlation between serum HMGB1 levels and the severity of ARDS in patients. Mouse models of ARDS induced by caecal ligation and perforation and A549 cell models established by stimulation with recombinant human HMGB1 (rHMGB1) were designed to explore lung inflammatory injury and apoptosis. Serum HMGB1 levels were significantly increased in ARDS patients compared to controls, and HMGB1 levels in the Severe group and Nonsurvival group were significantly higher than those in the Mild and Moderate group and Survival group. In vivo, compared to sham mice, ARDS mice showed significant lung inflammatory injury and apoptosis as well as upregulation of HMGB1 and RAGE and endoplasmic reticulum stress (ERs) protein expression. All injury was attenuated by treatment with an HMGB1 inhibitor GA, a RAGE blocker FPS-ZM1, and an ERs inhibitor 4-PBA. In vitro, A549 cells challenged with rHMGB1 exhibited significant increases in the levels of proteins in the RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2alpha (eIF2α)/activating transcription factor 4 (ATF4) pathway and in apoptosis, all of which were significantly inhibited by pre-treatment with lenti-shPERK and an anti-RAGE antibody. The HMGB1-RAGE axis induces apoptotic injury during ARDS, possibly through PERK/eIF2α/ATF4-mediated ERs.

HMGB1 induced endothelial to mesenchymal transition in liver fibrosis: The key regulation of early growth response factor 1

BackgroundLiver fibrosis has been the focus and difficulty of medical research in the world and its concrete pathogenesis remains unclear. This study aims to observe the high-mobility group box 1 (HMGB1)-induced hepatic endothelial to mesenchymal transition (EndoMT) during the development of hepatic fibrosis, and further to explore the crucial involvement of Egr1 in this process. MethodsCarbon tetrachloride (CCl4), diosbulbin B (DB), N-acetyl-p-aminophenol (APAP) and bile duct ligation (BDL) were used to induce liver fibrosis in mice. Serum HMGB1 content, the occurrence of EndoMT and the production of extracellular matrix (ECM) in vitro and in vivo were detected by Western-blot. ResultsThe elevated serum HMGB1 content, the occurrence of EndoMT, the production of ECM and the activation of Egr1 were observed in mice with liver fibrosis induced by CCl4, DB, APAP or BDL. HMGB1 induced EndoMT and ECM production in human hepatic sinusoidal endothelial cells (HHSECs), and then HHSECs lost the ability to inhibit the activation of hepatic stellate cells (HSCs). The hepatic deposition of collagen, the increased serum HMGB1 content and hepatic EndoMT were further aggravated in Egr1 knockout mice. Natural compound silymarin attenuated liver fibrosis in mice induced by CCl4 via increasing Egr1 nuclear accumulation, decreasing serum HMGB1 content and inhibiting hepatic EndoMT. ConclusionEgr1 regulated the expression of HMGB1 that induced hepatic EndoMT, which plays an important role in the development of liver fibrosis.General significance:This study provides a novel therapeutic strategy for the treatment of liver fibrosis in clinic.

Effects of intermittent pneumatic compression on serum HMGB1 levels of deep venous thrombosis of lower extremity in severe traumatic brain injury patients

Objective: To investigate the efficacy of intermittent pneumatic compression (IPC) in prevention of deep venous thrombosis (DVT) in severe traumatic brain injury (TBI) patients and to observe the effects of IPC on hemorheological and coagulation indices, as well as high-mobility group box 1 (HMGB1) in severe TBI patients. Methods: The present prospective open randomized controlled research recruited 332 severe TBI cases seen during May 2017~November 2019. All patients were randomly divided into two groups, with 166 cases in the control group and 166 cases in the IPC group. The serum levels of HMGB1 were determined using an enzyme linked immunosorbent assay (ELISA). The flow velocity of common femoral vein was also evaluated using Doppler ultrasound before treatment, as well as at 1 d, 3 d, 7 d and 14 d after admission. Levels of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB) and D-Dimer (D-D) were also evaluated before treatment, as well as at 7 d and 14 d after admission. Results: DVT occurred in a total of 35 (10.54%) cases of all patients, with 6 (3.61%) cases in IPC group, which was significantly lower than 29 (17.47%) cases in the control group. Serum FIB levels were significantly lower in the IPC group at 7 d and 14 d after treatment compared with the control. At 3 d, 7 d and 14 d after treatment, the levels of flow velocity of common femoral vein were markedly higher in IPC group compared with the control and after 3 d treatment, the levels of HMGB1 at 1 d, 3 d, 7 d and 14 d were all markedly lower in IPC group than the control. After admission, the serum levels of HMGB1 were markedly higher in DVT patients compared with the non-DVT patients at 1 d, 3 d, 7 d and 14 d and were negatively correlated with the flow velocity of common femoral vein at 3 d, 7 d and 14 d. Conclusion: IPC treatment could prevent DVT in severe TBI patients, which was associated with increased velocity of common femoral vein and decreased FIB and HMGB1 levels. HMGB1 may be useful as a potential biomarker for DVT in severe TBI patients.

Oxidized high mobility group B-1 enhances metastability of colorectal cancer via modification of mesenchymal stem/stromal cells.

High mobility group box‐1 (HMGB1) is known to be a chemotactic factor for mesenchymal stem/stromal cells (MSCs), but the effect of post‐translational modification on its function is not clear. In this study, we hypothesized that differences in the oxidation state of HMGB1 would lead to differences in the function of MSCs in cancer. In human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three‐fold fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM‐MSCs) and induced differentiation into osteoblasts and vascular pericytes, whereas oxidized HMGB1 promoted proliferation and increased stemness, and no differentiation was observed. When BM‐MSCs pretreated with oxidized HMGB1 were co‐cultured with syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased, and tumorigenesis and drug resistance were promoted. In contrast, co‐culture with reduced HMGB1‐pretreated BM‐MSCs did not enhance stemness. In an animal orthotopic transplantation colorectal cancer model, oxidized HMGB1, but not reduced HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore, oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized HMGB1–MSC axis may be an important target for cancer therapy.

Second-trimester serum high mobility group box-1 and uterine artery Doppler to predict preeclampsia

The objective of this study was to identify the predictive value for preeclampsia of second-trimester serum high mobility group box-1 (HMGB1) and uterine artery Doppler in singleton pregnancies. Between April 2020 and April 2021, a prospective study was conducted on singleton pregnancies with a gestational age of 16–20+6 weeks at King Chulalongkorn Memorial Hospital, Department of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Maternal characteristics, uterine artery Doppler, and serum HMGB1 were collected. Serum HMGB1 levels and mean uterine artery pulsatility index (UAPI) were combined to calculate the predictive value for preeclampsia. A total of 393 pregnant women were analyzed, with 25 cases (6.4%) developing preeclampsia and 5 cases (1.3%) developing early-onset preeclampsia. Baseline characteristics of preeclampsia and normal pregnant women were comparable. Preeclamptic pregnant women had significantly higher mean serum HMGB1 levels than normal pregnant women (1112.8 ± 363.1 ng/mL vs 910.8 ± 486.1 ng/mL, p = 0.013). There was no difference in the mean UAPI. Any early-diastolic notching was found more frequently in the preeclampsia group (32.0% vs 12.5%, p = 0.013). The cut-off value for serum HMGB1 levels above 1.04 MoM as abnormal value to predict preeclampsia had sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 88.0%, 53.5%, 11.4% and 98.5%, respectively. When using abnormal serum HMGB1 levels combined with mean UAPI above 95th percentile, the sensitivity, specificity, PPV and NPV to predict preeclampsia were 88.0%, 50.8%, 10.8% and 98.4%, respectively. This study showed that serum HMGB1 at 16–20+6 weeks of gestation were effective in predicting preeclampsia. The addition of UAPI did not improve the prediction performance.

Chlorogenic acid alleviated liver fibrosis in methionine and choline deficient diet-induced nonalcoholic steatohepatitis in mice and its mechanism

Nonalcoholic steatohepatitis, one of the most common chronic liver diseases, is a progressive form of nonalcoholic fatty liver disease accompanied by the development of liver fibrosis. Chlorogenic acid (CGA) is a natural polyphenolic compound. This study aims to observe the CGA-provided alleviation on liver fibrosis in methionine and choline deficient (MCD) diet-induced nonalcoholic steatohepatitis in mice and to elucidate its engaged mechanism. CGA attenuated hepatocellular injury, decreased the elevated hepatic lipids accumulation and attenuated liver fibrosis by reducing hepatic collagen deposition in mice fed with MCD diet. CGA abrogated the activation of hepatic stellate cells (HSCs) and promoted mitochondrial biogenesis both in vivo and in vitro. Moreover, the CGA-provided inhibition on HSCs activation in vitro was obviously disappeared after the application of peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PGC1α) siRNA. CGA reduced the enhanced hepatic extracellular matrix (ECM) expression and the elevated serum high-mobility group box 1 (HMGB1) content in mice fed with MCD diet. CGA decreased the HMGB1-induced ECM production in both human liver sinusoidal endothelial cells and human umbilical vein endothelial cells. CGA also weakly promoted mitochondrial biogenesis in both liver sinusoidal endothelial cells and human umbilical vein endothelial cells incubated with HMGB1. Hence, CGA ameliorated hepatic fibrosis in mice fed with MCD diet through inhibiting HSCs activation via promoting mitochondrial biogenesis and reducing the HMGB1-initiated ECM production in hepatic vascular endothelial cells.

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

Assessment of Serum High Mobility Group Box - 1 Level as Predictor of Diabetic Peripheral Neuropathy

Background: High mobility group B1 is linked to central ischemia damage, and after an ischemic insult, it is discharged to the extracellular space, so that it stimulates neuroinflammation, such as neuropathy, which considered as a serious complication of diabetes that is challenging to heal. Objective: is to investigate the changes of sera levels of High Mobility.Group Box-1 Protein. (HMGB-1) as well as its connection with the incidence of developing neuropathic complications among diabetic patients. Material &amp; Methods: A 30 patients with diabetic peripheral neuropathy was included with another 30 patients with Diabetes Mellitus type 2 without complications and a 30 healthy subject as control group both sex-aged matched with the patients groups. This study included the measurement of serum high.mobility group box-1. (HMGB-1) by ELISA technique in addition to HbA1c by turbidimetric immunoassay technology, Fasting blood sugar and finally Lipid.profile (Total cholesterol,. LDL, VLDL,. HDL and. Triglycerides) were measured by spectrophotometer. Results: Analyzing the current data of samples (n=90) showed that the comparison between serum level of HMGB-1 was significant. The mean of HMGB_1 for NPDM (689.08± 104.63) was significantly higher than both for Non-NPDM (354.97±137.56), p&lt;0.001 and for control (312.91±100.66), (p&lt;0.001). Also serum levels of (Total Cholesterol, TG, LDL, VLDL) of NPDM patients were significantly higher (p&lt;0.001) than both Non-NPDM and control groups. We conclude that serum level of HMGB-1 can be used as predictor marker of neuropathy complication of type 2 diabetes.