Heparin-Binding Protein Stratifies Mortality Risk Among Ugandan Children Hospitalized With Respiratory Distress.

Background: Current prognostic tools do not reliably and objectively identify children with pneumonia at risk of a severe or life-threatening episode. Heparin-binding protein (HBP) is a host immune protein that is released in response to infection. We hypothesized that measuring HBP concentrations at hospital admission could help risk-stratify children with pneumonia and identify those at higher risk of an adverse prognosis. Methods: We evaluated the prognostic accuracy of HBP for predicting in-hospital mortality among children with respiratory distress, and whether HBP could improve the accuracy of validated composite clinical severity scores. Results: Of 778 Ugandan children under 5 years of age and presenting with clinically defined pneumonia, 60 (7.7%) died during hospital admission. HBP concentrations at presentation were significantly higher in children with fatal outcomes (median, 76 ng/mL [interquartile range {IQR}, 41-150]) compared to children who survived (median, 31 ng/mL [IQR, 18-57]) (P < .001). Children with HBP >41 ng/mL on admission had an elevated risk of death (hazard ratio, 5.3 [95% confidence interval {CI}, 2.9-9.5]; P < .0001). In receiver operating characteristic (ROC) curve analysis, HBP concentrations distinguished between fatal and nonfatal outcomes (area under the ROC curve, 0.75 [95% CI, .66-.84]) and significantly improved the prediction provided by the Respiratory Index of Severity in Children, a composite clinical severity score (P = .0026). Conclusions: Measuring HBP at presentation could help identify children at risk of severe and fatal pneumonia. Adding HBP to clinical scores could improve the recognition and triage of children with pneumonia at risk of death.

The performance of a combination of heparin-binding protein with other biomarkers for sepsis diagnosis: an observational cohort study.

BACKGROUND: HBP, a novel biomarker released from neutrophils, may induce inflammatory responses and exacerbate vascular permeability, representing the pathophysiological characteristics of sepsis and septic shock. However, it remains uncertain whether the combination of HBP with other biomarkers yields enhanced diagnostic capacity for sepsis. We hypothesized that measurements included IL-6·IL-8·HBP, IL-6·IL-8·HBP/ALB and HBP/ALB which based on HBP will improve its diagnostic efficacy and even better than the traditional infection biomarkers. METHODS: Between July 2021 and June 2022, we carried out a comprehensive, multi-center, observational cohort study spanning six leading tertiary hospitals located in Heilongjiang Province, China. Patients were stratified into three categories based on the severity of infection: non-sepsis, sepsis, and septic shock. We collected clinical and laboratory data, along with infection and inflammation biomarkers, for analysis. RESULTS: A total of 195 patients were enrolled. Among the three groups, patients with septic shock (n = 75, 38.5%) had significantly higher baseline levels of HBP, WBC, Lac, CRP, PCT, IL-6, IL-8, and IL-10 compared to non-sepsis patients (n = 43, 22.0%) and sepsis patients (n = 77, 39.5%), with statistically significant differences (p < 0.05) observed for all parameters. When compared to SOFA score and traditional markers of CRP, PCT, IL-6 and IL-8, the combined indexes of IL-6·IL-8·HBP and IL-6·IL-8·HBP/ALB demonstrated significantly improved diagnostic performance for sepsis and septic shock (AUC 0.911 and 0.902 respectively, p < 0.001). CONCLUSIONS: The combined measurements of IL-6·IL-8·HBP and IL-6·IL-8·HBP/ALB can augment the diagnostic capacity of HBP for sepsis, and offer reliable early supplementary indicators to traditional biomarkers for assessing disease severity in patients with infection.

Heparin-binding protein as a predictor of mortality in patients with diabetes mellitus and community-acquired pneumonia in intensive care unit : a propensity score matched study.

BACKGROUND: Patients with diabetes mellitus (DM) are vulnerable to community-acquired pneumonia (CAP), which have a high mortality rate. We aimed to investigate the value of heparin-binding protein (HBP) as a prognostic marker of mortality in patients with DM and CAP. METHODS: This retrospective study included CAP patients who were tested for HBP at intensive care unit (ICU) admission from January 2019 to April 2020. Patients were allocated to the DM or non-DM group and paired with propensity score matching. Baseline characteristics and clinical outcomes up to 90 days were evaluated. The primary outcome was the 10-day mortality. Receiver operating characteristic (ROC) curves, Kaplan-Meier analysis, and Cox regression were used for statistical analysis. RESULTS: Among 152 enrolled patients, 60 pairs were successfully matched. There was no significant difference in 10-day mortality, while more patients in the DM group died within 28 d (P=0.024) and 90 d (P=0.008). In the DM group, HBP levels at ICU admission were higher in 10-day non-survivors than in 10-day survivors (median 182.21 [IQR: 55.43-300] ng/ml vs. median 66.40 [IQR: 34.13-107.85] ng/mL, P=0.019), and HBP levels could predict the 10-day mortality with an area under the ROC curve of 0.747. The cut-off value, sensitivity, and specificity were 160.6 ng/mL, 66.7%, and 90.2%, respectively. Multivariate Cox regression analysis indicated that HBP was an independent prognostic factor for 10-day (HR 7.196, 95%CI: 1.596-32.455, P=0.01), 28-day (HR 4.381, 95%CI: 1.449-13.245, P=0.009), and 90-day mortality (HR 4.581, 95%CI: 1.637-12.819, P=0.004) in patients with DM. CONCLUSION: Plasma HBP at ICU admission was associated with the 10-day, 28-day, and 90-day mortality, and might be a prognostic factor in patients with DM and CAP.

Relationship between low molecular weight heparin calcium therapy and prognosis in severe acute kidney injury in sepsis: Mendelian randomized analysis and retrospective study.

Background: Sepsis-associated acute kidney injury (SA-AKI) poses an independent risk for mortality due to the absence of highly sensitive biomarkers and a specific treatment plan. Objective: Investigate the association between low molecular weight heparin (LMWH) calcium therapy and prognosis in critically ill SA-AKI patients, and assess the causal relationship through Mendelian randomization (MR) analysis. Methods: A single-center, retrospective, cross-sectional study included 90 SA-AKI patients and 30 septic patients without acute kidney injury (AKI) from the intensive care unit (ICU) of the First Hospital of Lanzhou University. SA-AKI patients were categorized into control or LMWH groups based on LMWH calcium usage. Primary outcome was renal function recovery, with secondary outcomes including 28-day mortality, ICU stay length, number of renal replacement therapy (RRT) recipients, and 90-day survival. MR and related sensitivity analyses explored causal effects. Results: The combination of heparin-binding protein (HBP), heparanase (HPA), and neutrophil gelatinase-associated lipocalin (NGAL) demonstrated high diagnostic value for SA-AKI. MR analysis suggested a potential causal link between gene-predicted HBP and AKI (OR: 1.369, 95%CI: 1.040-1.801, p = 0.024). In the retrospective study, LMWH-treated patients exhibited improved renal function, reduced levels of HPA, HBP, Syndecan-1, and inflammation, along with enhanced immune function compared to controls. However, LMWH did not impact 28-day mortality, 90-day survival, or ICU stay length. Conclusion: LMWH could enhance renal function in SA-AKI patients. MR analysis supports this causal link, underscoring the need for further validation in randomized controlled trials.

Potential treatment of squamous cell carcinoma by targeting heparin-binding protein 17/fibroblast growth factor-binding protein 1 with vitamin D3 or eldecalcitol.

Heparin-binding protein 17 (HBp17), first purified in 1991 from the conditioned medium of the human A431 squamous cell carcinoma (SCC) cell line, was later renamed fibroblast growth factor-binding protein 1 (FGFBP-1). HBp17/FGFBP-1 is specifically expressed and secreted by epithelial cells, and it reversibly binds to fibroblast growth factor (FGF)-1 and FGF-2, as well as FGFs-7, -10, and -22, indicating a crucial involvement in the transportation and function of these FGFs. Our laboratory has investigated and reported several studies to elucidate the function of HBp17/FGFBP-1 in SCC cells and its potential as a molecular therapeutic target. HBp17/FGFBP-1 transgene exoression in A431-4 cells, a clonal subline of A431 that lacks tumorigenicity and does not express HBp17/FGFBP-1, demonstrated a significantly enhanced proliferation in vitro compared with A431-4 cells, and it acquired tumorigenicity in the subcutis of nude mice. Knockout (KO) of the HBp17/FGFBP-1 by genome editing significantly suppressed tumor growth, cell motility, and tumorigenicity compared with control cells. A comprehensive analysis of expressed molecules in both cell types revealed that molecules that promote epithelial cell differentiation were highly expressed in HBp17/FGFBP-1 KO cells. Additionally, we reported that 1α,25(OH)2D3 or eldecalcitol (ED-71), which is an analog of 1α,25(OH)2D3, suppresses HBp17/FGFBP-1 expression and tumor growth in vitro and in vivo by inhibiting the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway. Here, we discuss the prospects of molecular targeted therapy targeting HBp17/FGFBP-1 with 1α,25(OH)2D3 or ED71 in SCC and oral SCC.

Heparin-Binding Protein Promotes Acute Lung Injury in Sepsis Mice by Blocking the Aryl Hydrocarbon Receptor Signaling Pathway.

Purpose: This study aimed to explore the therapeutic effect and potential mechanism of heparin-binding protein (HBP) reduction on sepsis-related acute lung injury. Methods: We utilized a murine model of sepsis-induced by intraperitoneal injection of lipopolysaccharides (LPS) in C57BL/6J mice divided into four groups: Control, LPS, Anti-HBP, and ceftriaxone (CEF). Following sepsis induction, Anti-HBP or CEF treatments were administered, and survival rates were monitored for 48 h. We then used reverse-transcription quantitative PCR to analyze the expression levels of HBP in lung tissues, immunohistochemistry for protein localization, and Western blotting for protein quantification. Pulmonary inflammation was assessed using enzyme-linked immunosorbent assays of proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, and interferon-γ). The activation state of the aryl hydrocarbon receptor (AhR) signaling pathway was determined via Western blotting, evaluating both cytoplasmic and nuclear localization of AhR and the expression of cytochrome P450 1A1 protein by its target gene. Results: Anti-HBP specifically reduced HBP levels. The survival rate of mice in the Anti-HBP and CEF groups was much higher than that in the LPS group. The severity of lung injury and pulmonary inflammatory response in the Anti-HBP and CEF groups was significantly lower than that in the LPS group. AhR signaling pathway activation was observed in the Anti-HBP and CEF groups. Additionally, there was no significant difference in the above indices between the Anti-HBP and CEF groups. Conclusion: HBP downregulation in lung tissues significantly improved LPS-induced lung injury and the pulmonary inflammatory response, thereby prolonging the survival of sepsis mice, suggesting activation of the AhR signaling pathway. Moreover, the effect of lowering the HBP level was equivalent to that of the classical antibiotic CEF. Trial Registration: Not applicable.

Screening and Application of DNA Aptamers for Heparin-Binding Protein.

Rapid detection of heparin-binding protein (HBP) is essential for timely intervention in sepsis cases. Current detection techniques are usually antibody-based immunological methods, which have certain problems, such as complexity and slow detection, and fall short in meeting the urgency of clinical needs. The application of an aptamer can address these concerns well. In this study, HBP-specific DNA aptamers were screened first. Among which, Apt-01, Apt-02, and Apt-13 had a high affinity for HBP, exhibiting impressive KD values of 3.42, 1.44, and 1.04 nmol/L, respectively. Then, the aptamer of HBP and its partially complementary primer probe were combined to form double-stranded DNA (dsDNA) and synthesize a circular DNA template. The template is complementary to the primer probe, but due to the presence of dsDNA, ExoIII cleaves C2-13 as an RCA primer probe, rendering the template unable to recognize the primer probe and preventing the RCA reaction from proceeding. When the target is present, it competes with the adapter for recognition and releases C2-13, exposing its 3' end. After initiating the RCA at room temperature and reacting with SYBR GreenII at 37 °C for 20 min, fluorescence changes can be observed and quantitatively analyzed at a 530 nm wavelength, achieving quantitative biological analysis. Apt-01 was used to develop a fluorescent biosensor for HBP detection, which exhibited a good linear range (0.01 nmol/L to 10 nmol/L) and detection limit (0.0056 nmol/L). This advancement holds the potential to lay a solid groundwork for pioneering sensitive and specific methods for HBP detection and to significantly enhance the diagnostic processes for sepsis.

Diagnostic, monitoring, and prognostic value of combined detection of cerebrospinal fluid heparin-binding protein, interleukin-6, interleukin-10, and procalcitonin for post-neurosurgical intracranial infection.

OBJECTIVE: Intracranial infection is a common complication after neurosurgery and can increase the length of hospital stay, affect patient prognosis, and increase mortality. We aimed to investigate the value of the combined detection of cerebrospinal fluid (CSF) heparin-binding protein (HBP), interleukin-6 (IL-6), interleukin-10 (IL-10), and procalcitonin (PCT) for post-neurosurgical intracranial infection. METHODS: This study assessed the diagnostic values of CSF HBP, IL-6, IL-10, PCT levels, and combined assays for post-neurosurgical intracranial infection with the area under the receiver operating characteristic (ROC) curve by retrospectively analysing biomarkers of post-neurosurgical patients. RESULTS: The CSF HBP, IL-6, IL-10, and PCT levels were significantly higher in the infected group than the uninfected group and the control group (P < 0.001). The indicators in the groups with severe intracranial infections were significantly higher than those in the groups with mild intracranial infections (P < 0.001), and the groups with poor prognoses had significantly higher indexes than the groups with good prognoses. According to the ROC curve display, the AUC values of CSF HBP, IL-6, IL-10, and PCT were 0.977 (95 % CI 0.952-1.000), 0.973 (95 % CI 0.949-0.998), 0.884 (95 % CI 0.823-0.946), and 0.819 (95 % CI 0.733-0.904), respectively. The AUC of the combined test was 0.996 (95 % CI 0.989-1.000), which was higher than those of the four indicators alone. CONCLUSION: The combined detection can be an important indicator for the diagnosis and disease monitoring of post-neurosurgical intracranial infection.

The effect of heparins on plasma concentration of heparin-binding protein: a pilot study.

Background: Neutrophil-derived heparin-binding protein (HBP) plays a role in the pathophysiology of impaired endothelial dysfunction during inflammation. HBP has been suggested as a predictor of organ dysfunction and disease progression in sepsis. We investigated the effects of heparins on plasma concentrations of HBP in patients undergoing surgery. Methods: We studied three groups of patients receiving heparins during or after surgery. The vascular surgery group received 3000-7500 U, whereas the cardiac surgery group received 27 500-40 000 U. After major general surgery, the third group received 5000 U of low-molecular-weight heparin (LMWH) subcutaneously. Serial plasma HBP concentrations were measured after these treatments with two different methods: Axis-Shield ELISA and Joinstar FIC-Q100. In addition, plasma myeloperoxidase and syndecan-1 were measured in the cardiac surgery group. Results: During vascular surgery, heparin induced a six-fold increase in HBP within 2 min, from 3.6 (2.4-5.4) to 21.4 (9.0-35.4) ng ml-1 (P<0.001). During cardiac surgery, the higher dose of heparin elevated HBP concentrations from 5.3 (2.7-6.1) to 48.7 (38.4-70.1) ng ml-1 (P<0.0001) within 3 min. Patients receiving LMWH showed an increase from a baseline of 5.7 (3.7-12.1) ng ml-1 to a peak HBP concentration of 14.8 (9.5-18.1) ng ml-1 (P<0.0001) after 3 h. Plasma concentrations of myeloperoxidase, but not syndecan-1, also responded with a rapid increase after heparin. There was a strong correlation between the two methods for HBP analysis (r=0.94). Conclusions: Plasma concentrations of HBP increased rapidly and dose-dependently after heparin administration. Subcutaneous administration of LMWH increases plasma HBP, but to a lesser degree. Clinical trial registration: ClinicalTrials.gov identifier: NCT04146493.

The diagnostic utility of heparin-binding protein among patients with bacterial infections: a systematic review and meta-analysis.

BACKGROUND: Bacterial infections are considered a leading cause of hospitalization and death globally. There is still a need for a rapid and feasible biomarker for bacterial infections. Heparin-binding protein (HBP) was shown to be related to bacterial infections. The objective of the study is to investigate the diagnostic accuracy of HBP in bacterial infections. METHODS: Articles were screened in PubMed, SCOPUS, Web of Science, and Cochrane to recognize eligible studies. We included studies investigating the diagnostic accuracy of HBP and reported the necessary data to construct 2 × 2 tables. A univariate analysis was conducted to determine the pooled sensitivity and specificity, and a bivariate diagnostic random-effects model was used to calculate the optimal cut-off point. RESULTS: The analysis comprised sixteen studies in total. Plasma HBP showed a sensitivity of 0.90 (95% CI: [0.79, 0.96]) and a specificity of 0.87 (95% CI: [0.66, 0.96]) in diagnosing bacterial infections using blood samples. Pooling data from seven studies revealed that HBP in cerebrospinal fluid (CSF) has sensitivity and specificity of 96% (95% CI: [0.85, 0.99]), and 95% (95% CI: [0.89, 0.97]), respectively, for the diagnosis of bacterial meningitis. In urinary tract infections (UTI), urine-HBP was revealed to have a high diagnostic value in discriminating bacterial from non-bacterial UTI infection at a cut-off value of 32.868 ng/ml with sensitivity and specificity of 87%. CONCLUSION: HBP has shown a high diagnostic accuracy of bacterial infections, including UTI and meningitis. Further studies are needed to determine its prognostic value and whether it could guide antibiotic therapy.

Heparin Binding Protein in Early Differential Diagnosis of Bacterial Meningitis.

Heparin-binding protein is a serine protease that is mobilized rapidly from emigrating polymorphonuclear leukocytes that acts as a chemoattractant activator of monocyte and macrophages. We investigated the potential role and efficacy of serum and cerebrospinal fluid heparin binding protein in differentiating bacterial meningitis from tuberculosis and viral meningitis. A case diagnosed with acute bacterial meningitis (n:37), viral meningitis (n:30) and tuberculous meningitis (n:30) was included in this study. The diagnosis was based on history, clinical criteria, cerebrospinal fluid examination, latex agglutination and culture, and response to therapy. Heparin-binding protein was measured using enzyme-linked immunosorbent technique in both cerebrospinal fluid and serum. Cerebrospinal fluid heparin-binding protein levels were 7.81 ± 0.23 ng/mL in bacterial meningitis, 6.11 ± 0.3 ng/mL in tuberculosis meningitis and 5.75 ± 0.1 ng/mL in viral meningitis. The mean serum level was 14.98 ± 1.1 ng/mL in bacterial meningitis, 6.89 ± 0.4 ng/mL in tuberculosis meningitis, and 6.02 ± 0.4 ng/mL in viral meningitis. Both heparin-binding protein levels were significantly higher in patients with bacterial meningitis. We found that serum and cerebrospinal fluid heparin binding protein is a useful marker for differentiating bacterial meningitis from non-bacterial meningitis.

Diagnostic value of plasma heparin-binding protein and the heparin-binding protein-to-albumin ratio in patients with community-acquired Pneumonia: a retrospective study.

BACKGROUND: Patients presenting to the emergency department with community-acquired pneumonia (CAP) are characterized by advanced age, comorbidities, critical illness and less-than-typical symptoms, posing a diagnostic challenge. Plasma heparin-binding protein (HBP) and the heparin-binding protein-to-albumin ratio (HBP/Alb) have not been adequately studied in the early diagnosis of CAP. This study assessed the diagnostic value of plasma HBP, HBP/Alb, and conventional inflammatory markers in emergency department patients with CAP. METHODS: We enrolled 103 patients with CAP, retrospectively analyzed the patients' clinical data, and divided the CAP patients into antibiotic (n = 79) and non-antibiotic (n = 24) groups based on whether antibiotics were administered prior to blood sampling and laboratory tests. The control group was comprised of 52 non-infected patients admitted during the same period. Within 24 h of admission, plasma HBP, serum procalcitonin (PCT), white blood cell count (WBC), neutrophil-to-lymphocyte ratio (NLR) and HBP/Alb levels were collected separately and compared. The receiver operating characteristic (ROC) curve was plotted to assess the diagnostic value of each indicator for CAP patients. Utilizing the Kappa test, the consistency of each indicator used to evaluate CAP and clinical diagnosis was analyzed. Spearman correlation was used to analyze the correlation between plasma HBP and clinical indicators of CAP patients. RESULTS: Plasma HBP, serum PCT, WBC, NLR and HBP/Alb were all elevated in the CAP group in comparison to the control group (P < 0.001). Plasma HBP, serum PCT, WBC, NLR and HBP/Alb levels did not differ statistically between antibiotic and non-antibiotic groups (P > 0.05). Plasma HBP and HBP/Alb had the highest diagnostic accuracy for CAP, the area under the ROC curve (AUC) were 0.931 and 0.938 (P < 0.0001), and the best cut-off values were 35.40 ng/mL and 0.87, respectively. In evaluating the consistency between CAP and clinical diagnosis, the Kappa values for HBP, PCT, WBC, NLR and HBP/Alb were 0.749, 0.465, 0.439, 0.566 and 0.773, respectively. Spearman correlation analysis showed that plasma HBP was positively correlated with serum PCT, WBC, NLR and HBP/Alb in CAP patients (P < 0.001). CONCLUSIONS: Plasma HBP and HBP/Alb have a high clinical diagnostic value for CAP and can be used as good and reliable novel inflammatory markers in the emergency department for the early diagnosis of CAP patients.

Systemic Inflammatory Status of Patients with Obstructive Sleep Apnea Syndrome and the Predictive Value of Heparin-Binding Protein.

Objective: To investigate the alteration of the systemic inflammatory status of patients with obstructive sleep apnea syndrome (OSAS) and the predictive value of heparin-binding protein (HBP) for OSAS. Methods: Patients with OSAS who were hospitalized in our hospital from 2020 January to 2022 December and diagnosed by polysomnography (PSG) (OSAS group, n = 79) were retrospectively studied and their relevant examination findings and demographic characteristics were recorded. Sex- and age-matched non-OSAS patients hospitalized at the same time were selected as the control group (control group, n = 28). Differences in peripheral blood neutrophil counts, lymphocyte counts, neutrophil-to-lymphocyte ratio (NLR), procalcitonin (PCT), and HBP were compared between the 2 groups. The predictive value of these markers for OSAS was analyzed using the receiver operating characteristic curve, and independent risk factors for OSAS were determined using logistic regression analysis. Peripheral blood was drawn from all patients in the fasting state of the morning. Results: The number of peripheral blood neutrophils, lymphocytes, and HBP was higher in the OSAS group than in the control group, and the differences were statistically significant (P all <.05), while the differences in NLR and PCT between the 2 groups were not statistically significant (P all >.05). Plasma HBP level had an area under the curve (AUC) of 0.79 (P < .0001) in determining OSAS, with a sensitivity of 80.49% and a specificity of 70.83% and the best cutoff value was >10.73 ng/ml. Combining body mass index (BMI), neutrophil, lymphocyte, and HBP improved the predictive value of OSAS with an AUC of 0.89 (P < .0001), a sensitivity of 80.49%, and a specificity of 87.50%. Logistic regression analysis showed that both BMI and HBP were independent risk factors for OSAS (PBMI < .001, PHBP < .01), while neutrophils and lymphocytes were not (P all >.05). Conclusions: This is the first study to objectively examine HBP in OSAS patients, and HBP is an independent risk factor that may serve as a diagnostic biomarker in OSAS. Patients with OSAS have an altered systemic inflammatory state and may be more prone to severe bacterial infections.

A heparin-binding protein of Plasmodium berghei is associated with merozoite invasion of erythrocytes.

BACKGROUND: Malaria caused by Plasmodium species is a prominent public health concern worldwide, and the infection of a malarial parasite is transmitted to humans through the saliva of female Anopheles mosquitoes. Plasmodium invasion is a rapid and complex process. A critical step in the blood-stage infection of malarial parasites is the adhesion of merozoites to red blood cells (RBCs), which involves interactions between parasite ligands and receptors. The present study aimed to investigate a previously uncharacterized protein, PbMAP1 (encoded by PBANKA_1425900), which facilitates Plasmodium berghei ANKA (PbANKA) merozoite attachment and invasion via the heparan sulfate receptor. METHODS: PbMAP1 protein expression was investigated at the asexual blood stage, and its specific binding activity to both heparan sulfate and RBCs was analyzed using western blotting, immunofluorescence, and flow cytometry. Furthermore, a PbMAP1-knockout parasitic strain was established using the double-crossover method to investigate its pathogenicity in mice. RESULTS: The PbMAP1 protein, primarily localized to the P. berghei membrane at the merozoite stage, is involved in binding to heparan sulfate-like receptor on RBC surface of during merozoite invasion. Furthermore, mice immunized with the PbMAP1 protein or passively immunized with sera from PbMAP1-immunized mice exhibited increased immunity against lethal challenge. The PbMAP1-knockout parasite exhibited reduced pathogenicity. CONCLUSIONS: PbMAP1 is involved in the binding of P. berghei to heparan sulfate-like receptors on RBC surface during merozoite invasion.

A First Computational Frame for Recognizing Heparin-Binding Protein.

Heparin-binding protein (HBP) is a cationic antibacterial protein derived from multinuclear neutrophils and an important biomarker of infectious diseases. The correct identification of HBP is of great significance to the study of infectious diseases. This work provides the first HBP recognition framework based on machine learning to accurately identify HBP. By using four sequence descriptors, HBP and non-HBP samples were represented by discrete numbers. By inputting these features into a support vector machine (SVM) and random forest (RF) algorithm and comparing the prediction performances of these methods on training data and independent test data, it is found that the SVM-based classifier has the greatest potential to identify HBP. The model could produce an auROC of 0.981 ± 0.028 on training data using 10-fold cross-validation and an overall accuracy of 95.0% on independent test data. As the first model for HBP recognition, it will provide some help for infectious diseases and stimulate further research in related fields.

Tamibarotene targets heparin-binding protein for attenuating lung injury in sepsis.

BACKGROUND: Excessively active pulmonary inflammation is a hallmark of sepsis-induced lung damage. A synthetic retinoid drug called tamibarotene reduces inflammation in a variety of conditions, including acute promyelocytic leukemia (APL), renal fibrosis, and neuroinflammation. Its effect on sepsis-related lung injury, however, has not been explained. PURPOSE: The purpose of the study was to investigate how tamibarotene affected lung damage induced by cecal ligation and puncture (CLP) procedure. METHODS: A CLP sepsis mouse model was developed, and tamibarotene was pretreated to determine whether it improved lung injury and survival. The degree of lung injury was evaluated using the Hematoxylin and eosin staining and lung injury score. In order to determine pulmonary vascular permeability, measurements were taken for total protein and cell content of bronchoalveolar lavage fluid (BALF), wet/dry ratio of the lung, and Evans blue stain. The BALF inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1ß, and IL-17A were discovered by enzyme-linked immunosorbent serologic assay (ELISA). Then, the levels of heparin-binding protein (HBP), and phospho-nuclear factor kappa-B (p-NF-κB) P65, and NF-κB P65 were determined using ELISA and Western blot analysis, respectively. RESULTS: Tamibarotene considerably increases survival and lessens lung damage stimulated by sepsis. Specifically, tamibarotene significantly relieves pulmonary vascular permeability and inhibits inflammation response in sepsis. Moreover, we further confirmed that these ameliorating effects of tamibarotene on sepsis may be exerted by targeting HBP and regulating the activation of NF-κB signaling pathway. CONCLUSION: These findings demonstrated that tamibarotene lessens sepsis-induced lung injury, and the effect could be exerted by targeting HBP and thereby deregulating the NF-κB signaling pathway.

The Predictive Value of Heparin-Binding Protein and D-Dimer in Patients with Sepsis.

Objective: To explore the serial measurement of heparin-binding protein and D-dimer in the prediction of 28-day mortality and efficacy evaluation of critically-ill patients with sepsis. Methods: We recruited a total of 51 patients with sepsis in the ICU of our hospital. They were divided into a survival group or a death group according to their prognosis 28 days after treatment. The HBP and D-dimer levels in these patients were determined on the 1st (24h), 3rd, and 5th days. Besides, the sequential organ failure assessment (SOFA) score of these patients was recorded at admission. The patients in both groups were subjected to comparison regarding HBP and D-dimer levels and SOFA scores within 24h of admission. Additionally, a correlation between the levels of HBP and D-dimer and the SOFA score was statistically measured, while the predictive effectiveness of these factors for the prognosis of patients with sepsis was also determined. Moreover, the dynamic changes in HBP and D-dimer during the treatment of both groups were analyzed. Results: The HBP and D-dimer levels and the SOFA scores in the survival group were considerably lower than those in the death group, and the differences were statistically significant (P<0.05). Additionally, the levels of HBP and D-dimer in sepsis patients were positively correlated with the SOFA score (P<0.05). The area under the curve (AUC) of HBP, D-dimer, and their combination in predicting the prognosis of patients with sepsis was 0.824, 0.771, and 0.830, respectively. Besides, the sensitivity and specificity of their combination in predicting the prognosis of patients with sepsis were 68.42% and 92.31%, respectively. The HBP and D-dimer levels presented a downward trend in the survival group during treatment, while they exhibited an upward trend in the death group. Conclusion: HBP and D-dimer realize high predictive effectiveness for the prognosis of patients with sepsis, while the combined use of these two factors achieves superior effectiveness. Thus, they can be applied to the prediction of 28-day mortality and efficacy evaluation of sepsis patients.

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive. Here, we identify cell surface and soluble glycosaminoglycans, specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer glycosaminoglycan chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Furthermore, mutagenesis studies indicate that this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

TLR4-mediated release of heparin-binding protein in human airways: a co-stimulatory role for IL-26.

Background: Bacterial infection causes accumulation of neutrophils that release antimicrobial proteins including heparin-binding protein (HBP). In human airways, this neutrophil accumulation can be re-capitulated via intrabronchial exposure to lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, that also causes a local increase in the neutrophil-mobilizing cytokine IL-26. Although LPS is considered a weak stimulus for HBP release ex vivo, its effect on HBP release in human airways in vivo has not been characterized. Methods: We determined whether intrabronchial exposure to LPS causes concomitant release of HBP and IL-26 in human airways, and whether IL-26 can enhance LPS-induced release of HBP in isolated human neutrophils. Results: We found that the concentration of HBP was markedly increased in bronchoalveolar lavage (BAL) fluid 12, 24, and 48 hours after LPS exposure, and that it displayed a strong and positive correlation with that of IL-26. Moreover, the concentration of HBP in conditioned media from isolated neutrophils was enhanced only after co-stimulation with LPS and IL-26. Conclusions: Taken together, our findings indicate that TLR4 stimulation causes concomitant release of HBP and IL-26 in human airways, and that IL-26 may constitute a required co-stimulant for HBP release in neutrophils, thus enabling the concerted action of HBP and IL-26 in local host defense.

Heparin-binding protein as a marker of ventriculostomy related infection and central nervous system inflammation in neuro-intensive care.

OBJECTIVE: Diagnosis of ventriculostomy related infections (VRI) in the neuro-intensive care unit remains challenging and current biomarkers lack adequate precision. The aim of this study was to explore the potential of Heparin-binding protein (HBP) in cerebrospinal fluid (CSF) as a diagnostic biomarker of VRI. METHODS: All patients treated with an external ventricular drain (EVD) between January 2009 and March 2010 at Skåne university hospital in Lund, Sweden, were consecutively included. CSF samples obtained during routine care were analyzed for HBP. VRI was defined as a positive bacterial microbiology test result on a CSF sample with an erythrocyte-corrected leukocyte count of > 50 × 106/l. HBP levels at VRI diagnosis was compared to peak HBP levels in non-VRI controls. RESULTS: In total, 394 CSF samples from 103 patients were analyzed for HBP. Seven patients (6.8%) fulfilled VRI criteria. Levels of HBP were significantly higher in VRI subjects (31.7 ng/mL [IQR 26.9-40.7 ng/mL]) compared to non-VRI controls (7.7 ng/mL [IQR 4.1-24.5 ng/mL]) (p = 0.024). The AUC of the receiver operating characteristic (ROC) curve was 0.76 (95% confidence interval [CI], 0.62-0.90). Among non-VRI patients, HBP was highest in patients with acute bacterial meningitis. Patients with subarachnoid hemorrhage displayed higher HBP levels than those with traumatic brain injury or shunt dysfunction. CONCLUSIONS: HBP levels were higher in VRI subjects and varied between patients and different diagnoses. To validate the clinical usefulness and added value of HBP as a biomarker for VRI, the results need to be confirmed in larger studies with head-to-head comparisons to current biomarkers.