Syndecan-1 Levels Research Articles

Mild-to-Moderate COVID-19 Convalescents May Present Pro-Longed Endothelium Injury.

The SARS-CoV-2 pandemic posed a great threat to public health, healthcare systems and the economy worldwide. It became clear that, in addition to COVID-19 and acute disease, the condition that develops after recovery may also negatively impact survivors' health and quality of life. The damage inflicted by the viral infection on endothelial cells was identified quite early on as a possible mechanism underlying the so-called post-COVID syndrome. It became an urgent matter to establish whether convalescents present chronic endothelial impairment, which could result in an increased risk of cardiovascular and thrombotic complications. In this study, we measured the levels of CRP, ICAM-1, VCAM-1, E-selectin and syndecan-1 as markers of inflammation and endothelial injury in generally healthy convalescents selected from blood donors and compared these to a healthy control group. We found higher concentrations of E-selectin and a lower level of syndecan-1 in convalescents in comparison to those of the control group. Based on our results, it can be concluded that, at least 6 months after infection, there is only slight evidence of endothelial dysfunction in COVID-19 convalescents who do not suffer from other comorbidities related to endothelial impairment.

Circulating syndecan-1 and glypican-4 predict 12-month survival in metastatic colorectal cancer patients.

Cell surface syndecans and glypicans play important roles in the development and prognosis of colorectal cancer (CRC). Their soluble forms from proteoglycan shedding can be detected in blood and have been proposed as new prognostic biomarkers in several cancer entities. However, studies on circulating syndecan-1 (SDC1) and glypican-4 (GPC4) in CRC are limited. We, therefore, evaluated the impact of plasma SDC1 and GPC4 on the prognosis of metastatic (m)CRC patients. The present study included 93 patients with mCRC. The endpoints were progression-free survival (PFS) and overall survival (OS) at12 months. SDC1 and GPC4 levels were measured in plasma using enzyme-linked immunosorbent assays. Plasma levels of SDC1 and GPC4 were significantly correlated. Significant correlations of these two markers were also found with carcinoembryonic antigen (CEA). Kaplan-Meier curve analyses indicated that PFS and OS probabilities significantly decreased with increasing levels of SDC1 and GPC4, respectively. Multivariable Cox regression analyses showed that both markers were significantly associated with PFS and OS independently from clinicopathological characteristics including CEA. Respective adjusted hazard ratios (HR) together with corresponding 95% confidence intervals for onestandard deviation change of SDC1 were 1.32 [1.02-1.84] for PFS and 1.48 [1.01-2.15] for OS. Adjusted HRs [95% confidence intervals] of GPC4 were 1.42 [1.07-1.89] for PFS and 2.40 [1.51-3.81] for OS. Results from area under the receiver operating characteristic curve analyses suggest that GPC4 and SDC1 add additional prognostic values to CEA for OS. In conclusion, we showed significant associations of circulating SDC1 and GPC4 with poor survival of mCRC patients.

Changes in novel cardiac extracellular matrix biomarkers in STEMI: associations with adverse outcomes

Abstract Background Ischemia-reperfusion (IR)-injury contributes to adverse outcomes following myocardial infarction undergoing reperfusion. Exaggerated remodelling of the extracellular matrix (ECM) is likely to be involved in IR-injury, potentially releasing ECM components to the systemic circulation. To improve prognostication and future therapeutic options in patients with myocardial infarction, more knowledge is warranted about ECM components associated with IR-injury. Purpose To investigate whether ECM components quantified in serum samples associate with myocardial injury and function, and clinical outcomes in patients with ST-elevation myocardial infarction (STEMI). Methods We selected biomarkers previously suggested to be involved in ECM changes in the heart, i.e. growth differentiation factor 15 (GDF-15), periostin, osteopontin, syndecan-1, syndecan-4, and bone morphogenetic protein 7. The concentrations of the biomarkers were measured in serum samples from patients with STEMI (n=239) enrolled in the POSTEMI trial, at day 1 and month 4 after hospital admission. Infarct size, microvascular obstruction (MVO), left ventricular remodelling, and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging. Major adverse cardiovascular events (MACE) and all-cause mortality were recorded after 12 months and with a median of 70 months, respectively. Results Serum levels of GDF-15, osteopontin, syndecan-1 and syndecan-4 declined, whereas periostin increased, from day 1 to month 4. Higher levels of syndecan-1 were associated with the presence of MVO (n=116) (day 1 OR 1.39 (1.06–1.82); month 4 OR 1.53 (1.08–2.17)), while higher GDF-15 and syndecan-1 were associated with the development of large infarct size (>75th percentile, n=57) and reduced cardiac function defined as LVEF <50% (n=64) at month 4. Higher levels of GDF-15 at month 4 and periostin at both time points were associated with increased risk of both MACE (n=16) (GDF-15: HR 1.42 (1.04–1.94); periostin day 1: HR 1.88 (1.09–3.25); periostin month 4: HR 1.64 (1.03–2.62)) and all-cause mortality (n=20) (GDF-15: HR 1.59 (1.28–1.97); periostin day 1: HR 1.85 (1.16–2.95); periostin month 4: HR 2.02 (1.35–3.02)) (Figure 1). On the contrary, elevated levels of syndecan-4 at month 4 were associated with lower risk of adverse outcomes, including all-cause mortality (HR 0.48 (0.28–0.84)) (Figure 1) and less IR-injury as assessed by a higher myocardial salvage index. Conclusion Elevated serum levels of GDF-15, periostin, and syndecan-1 were associated with a higher risk of adverse outcomes or detrimental remodelling in patients with STEMI. Increased levels of syndecan-4 measured 4 months after STEMI were associated with a reduced risk of all-cause mortality. Our results suggest the potential use of these biomarkers as prognostic tools and may suggest a role for these ECM components in IR injury. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): South-Eastern Norway Regional Health AuthorityNorwegian Health Association

Correlation of Syndecan-1 Level and Fluid Overload in Children with Sepsis

Background: Fluid resuscitation is one of the basic principles for managing sepsis, but excessive fluid causes the shedding of the endothelial glycocalyx (syndecan-1) and can cause capillary leakage and tissue edema. This study aimed to determine the correlation between the syndecan-1 level and fluid overload in children with sepsis. Materials and Methods: This was an analytic, cross-sectional study conducted in a pediatric intensive care unit. A total of 49 children aged 0–18 participated in this study. Factors investigated were age, gender, nutritional status, the site of infection, organ dysfunction, the severity of sepsis, outcome, blood culture, procalcitonin level, and Pediatric Logistic Organ Dysfunction-2 score. The syndecan-1 level was measured by examining the subject’s blood serum. Statistical analysis was done using the Spearman correlation test. Results: Forty-nine sepsis children aged 0–18 were enrolled, with a median age of 12 months. The respiration system was the most common site of infection, and dysfunction of the respiration system was the most common found in the subjects. The median of fluid overload was 8.3%, and the median of procalcitonin and syndecan levels was 17 ng/mL (interquartile range [IQR] = 1.97–64.03 ng/mL) and 372 ng/mL (IQR = 223.5–1389 ng/mL), respectively. The Spearman’s correlation test found a moderate correlation between syndecan-1 and fluid overload (r = 0.469, P = 0.001). Conclusion: The plasma concentrations of syndecan-1, a marker of endothelial glycocalyx shedding, were moderately correlated with the fluid overload in patients with sepsis, indicating the link between the fluid overload and the shedding of the glycocalyx.

Alterations of the Extracellular Matrix in Colorectal Carcinoma.

Background: The process of proliferation and invasion of tumor cells depends on changes in the extracellular matrix (ECM) through the activation of enzymes and alterations in the profile of ECM components. Our aims were to investigate the mRNA and protein expression profiles of the ECM components, heparanase-1 (HPSE), heparanase-2 (HPSE2), matrix metalloproteinase-9 (MMP-9), and syndecan-1 (SDC1) in neoplastic and nonneoplastic tissues of 24 patients with colorectal carcinoma (CRC) and to test for associations between the expression patterns of these genes with the presence or absence of lymph node metastases. Materials and Methods: This was a cross-sectional study in which 24 adult patients with CRC were admitted for resectional surgery. We analyzed the mRNA and protein expression patterns of the HPSE, HPSE2, MMP-9, and SDC1 genes by quantitative reverse transcription PCR and immunohistochemistry, respectively. Additionally, we investigated whether variations exist in the expression of the ECM components between the affected tissue and nontumoral tissue collected from the same patient. Tissue samples were collected during the surgical resection. Results and Conclusions: The data showed higher mRNA and protein expression levels of HPSE2 (p = 0.0058), MMP-9 (p = 0.0268), and SDC1 (p = 0.0002) in tumor samples when compared to the adjacent non-neoplastic tissues. There was, however, only an increase in the HPSE protein levels in the tumoral tissues. Increased expression of HPSE2 was observed in patients with lymph node metastasis (p = 0.031). This elevation in HPSE2 mRNA expression in patients with lymph node metastases potentially indicates that it may participate in driving colorectal carcinoma progression.

Syndecan-1 as a severity biomarker for patients with trauma.

Tissue injury and hemorrhage induced by trauma lead to degradation of the endothelial glycocalyx, causing syndecan-1 (SDC-1) to be shed into the blood. In this study, we investigated whether serum SDC-1 is useful for evaluating trauma severity in patients. A single-center, retrospective, observational study was conducted at Gifu University Hospital. Patients transported to the emergency room for trauma and subsequently admitted to the intensive care unit from January 2019 to December 2021 were enrolled. A linear regression model was constructed to evaluate the association of serum SDC-1 with injury severity score (ISS) and probability of survival (Ps). A total of 76 trauma patients (54 men and 22 women) were analyzed. ISS was significantly associated with serum SDC-1 level in trauma patients. Among the six body regions defined in the AIS used to calculate the ISS score, “chest” and “abdominal or pelvic contents” were significantly associated with serum SDC-1 level, and “extremities or pelvic girdle” also tended to show an association with serum SDC-1 level. Moreover, increasing serum SDC-1 level was significantly correlated with decreasing Ps. Serum SDC-1 may be a useful biomarker for monitoring the severity of trauma in patients. Further large-scale studies are warranted to verify these results.

Association of endothelial glycocalyx shedding and coronary microcirculation assessed by an angiography-derived index of microcirculatory resistance in patients with suspected coronary artery disease.

BackgroundThe endothelial glycocalyx (EG) is essential for maintaining microvascular homeostasis. However, the relationship between the EG and coronary microcirculation remains to be elucidated. One of the main components of EG is syndecan-1, and its shedding has been claimed to represent the state of the EG. In this study, we aimed to analyze the association between syndecan-1 and the coronary microcirculation.MethodsWe enrolled suspected coronary artery disease (CAD) patients who consecutively underwent coronary angiography (CAG) and angiography-based analysis of physiological indices in the left anterior descending artery (LAD). Serum syndecan-1 was measured by enzyme-linked immunosorbent assay (ELISA). The coronary microcirculation was evaluated by the presence of coronary microvascular dysfunction (CMD) and an impaired microvascular vasodilatory capacity (IMVC), which were quantified by an angiography-derived index of microcirculatory resistance (IMRangio) in the maximum hyperemic state (H-IMRangio) induced by adenosine triphosphate and the ratio (RRRangio) of IMRangio in the non-hyperemic phase to H-IMRangio, respectively.ResultsA total of 528 patients were enrolled in this study. There was no difference in epicardial coronary complexity between patients with high syndecan-1 (HSG) and low syndecan-1 (LSG) levels grouped by the median concentration of syndecan-1 (SYNTAX: 7[3, 10] vs. 9[4, 12], P = 0.15). However, H-IMRangio and RRRangio were different between the LSG and HSG groups (H-IMRangio: 23.64 ± 6.28 vs. 27.67 ± 5.59, P < 0.01; RRRangio: 1.74[1.46, 2.08] vs. 1.55[1.34, 1.72], P < 0.01). Patients with CMD (H-IMRangio > 25) and patients with IMVC (RRRangio below the median value) both had higher syndecan-1 levels (CMD: 86.44 ± 54.15 vs. 55.2 ± 43.72, P < 0.01; IMVC: 83.86 ± 55.41 vs. 59.68 ± 45.06, P < 0.01). After adjustment for confounding factors, HSG remained associated with the presence of CMD and IMVC (CMD: odds ratio [OR]: 2.769, P < 0.01; IMVC: OR: 1.908, P < 0.01).ConclusionHigh levels of syndecan-1 are independently associated with the presence of CMD and IMVC among patients with suspected CAD.

The Protective Effects on Ischemia-Reperfusion Injury Mechanisms of the Thoracic Aorta in Daurian Ground Squirrels (Spermophilus dauricus) over the Torpor-Arousal Cycle of Hibernation.

Hibernators are a natural model of vascular ischemia–reperfusion injury; however, the protective mechanisms involved in dealing with such an injury over the torpor–arousal cycle are unclear. The present study aimed to clarify the changes in the thoracic aorta and serum in summer-active (SA), late-torpor (LT) and interbout-arousal (IBA) Daurian ground squirrels (Spermophilus dauricus). The results show that total antioxidant capacity (TAC) was unchanged, but malondialdehyde (MDA), hydrogen peroxide (H2O2), interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα) were significantly increased for the LT group, whereas the levels of superoxide dismutase (SOD) and interleukin-10 (IL-10) were significantly reduced in the LT group as compared with the SA group. Moreover, the levels of MDA and IL-1β were significantly reduced, whereas SOD and IL-10 were significantly increased in the IBA group as compared with the SA group. In addition, the lumen area of the thoracic aorta and the expression of the smooth muscle cells (SMCs) contractile marker protein 22α (SM22α) were significantly reduced, whereas the protein expression of the synthetic marker proteins osteopontin (OPN), vimentin (VIM) and proliferating cell nuclear antigen (PCNA) were significantly increased in the LT group as compared with the SA group. Furthermore, the smooth muscle layer of the thoracic aorta was significantly thickened, and PCNA protein expression was significantly reduced in the IBA group as compared with the SA group. The contractile marker proteins SM22α and synthetic marker protein VIM underwent significant localization changes in both LT and IBA groups, with localization of the contractile marker protein α-smooth muscle actin (αSMA) changing only in the IBA group as compared with the SA group. In tunica intima, the serum levels of heparin sulfate (HS) and syndecan-1 (Sy-1) in the LT group were significantly reduced, but the serum level of HS in the IBA group increased significantly as compared with the SA group. Protein expression and localization of endothelial nitric oxide synthase (eNOS) was unchanged in the three groups. In summary, the decrease in reactive oxygen species (ROS) and pro-inflammatory factors and increase in SOD and anti-inflammatory factors during the IBA period induced controlled phenotypic switching of thoracic aortic SMCs and restoration of endothelial permeability to resist ischemic and hypoxic injury during torpor of Daurian ground squirrels.

Correlation between the Degree of Glycocalyx Damage and the Incidence of Acute Kidney Injury in Sepsis Patients in the Intensive Care Unit: A Review of Syndecan-1 and sICAM-1

Abstracts&#x0D; Objective: This study aims to know the correlation between the degree of glycocalyx damage and the incidence of Acute Renal Injury (AKI) in sepsis patients in the intensive care unit. In this study, a review of Syndecan-1 and sICAM-1 marker represented the severity of glycocalyx damage. Furthermore, the researchers wanted to see whether this marker in the serum of septic patients could predict the occurrence of AKI in the future of septic patients in the ICU.&#x0D; Design: This study is a prospective cohort nested-case control study, a case-control study conducted in a cohort population.&#x0D; Setting: This research has been carried out in the ICU, both RSPTN UNHAS and Dr. Wahidin Sudirohusodo Makassar. Syndecan-1 and sICAM-1 examination was carried out in the Hasanuddin University Hospital laboratory.&#x0D; Patients and participants: The sample was taken from septic patients treated in the ICU of RSPTN UNHAS and Dr. Wahidin Sudirohusodo Makassar admitted in January 2021. The sample selection was carried out consecutively, namely the selection of respondents based on the arrival of patients treated in the ICU until fulfilled.&#x0D; Measurement and Results: Data analysis in this study used the Mann-Whitney and Unpaired T-test. There was a significant difference in serum syndecan-1 levels between the two groups on day 0 and day 3 of ICU admission and changes from day 0 to day three. However, there was no significant relationship between sICAM-1 level in the two groups on day 0 and day 3 of ICU admission likewise its changes. Changes in syndecan-1 levels between the two groups were significantly different through the unpaired T-test.&#x0D; Conclusions: In this study, syndecan-1 levels can be used to predict the occurrence of AKI in the future for septic patients, while sICAM-1 is not statistically significant in predicting the occurrence of AKI among septic patients. Syndecan-1 is vital in the glycocalyx damage and helps predict clinical outcomes in patients with AKI.&#x0D;

Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice.

Endothelial dysfunction plays a central role in the pathogenesis of sepsis-mediated multiple organ failure. Several clinical and experimental studies have suggested that the glycocalyx is an early target of endothelial injury during an infection. Colivelin, a synthetic derivative of the mitochondrial peptide humanin, has displayed cytoprotective effects in oxidative conditions. In the current study, we aimed to determine the potential therapeutic effects of colivelin in endothelial dysfunction and outcomes of sepsis in vivo. Male C57BL/6 mice were subjected to a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP) and were treated with vehicle or colivelin (100-200 µg/kg) intraperitoneally at 1 h after CLP. We observed that vehicle-treated mice had early elevation of plasma levels of the adhesion molecules ICAM-1 and P-selectin, the angiogenetic factor endoglin and the glycocalyx syndecan-1 at 6 h after CLP when compared to control mice, while levels of angiopoietin-2, a mediator of microvascular disintegration, and the proprotein convertase subtilisin/kexin type 9, an enzyme implicated in clearance of endotoxins, raised at 18 h after CLP. The early elevation of these endothelial and glycocalyx damage biomarkers coincided with lung histological injury and neutrophil inflammation in lung, liver, and kidneys. At transmission electron microscopy analysis, thoracic aortas of septic mice showed increased glycocalyx breakdown and shedding, and damaged mitochondria in endothelial and smooth muscle cells. Treatment with colivelin ameliorated lung architecture, reduced organ neutrophil infiltration, and attenuated plasma levels of syndecan-1, tumor necrosis factor-α, macrophage inflammatory protein-1α and interleukin-10. These therapeutic effects of colivelin were associated with amelioration of glycocalyx density and mitochondrial structure in the aorta. At molecular analysis, colivelin treatment was associated with inhibition of the signal transducer and activator of transcription 3 and activation of the AMP-activated protein kinase in the aorta and lung. In long-term outcomes studies up to 7 days, co-treatment of colivelin with antimicrobial agents significantly reduced the disease severity score when compared to treatment with antibiotics alone. In conclusion, our data support that damage of the glycocalyx is an early pathogenetic event during sepsis and that colivelin may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.

The Protective Effect of Sulodexide on Acute Lung Injury Induced by a Murine Model of Obstructive Jaundice.

Introduction The effect of sulodexide (SLX) on obstructive jaundice- (OJ-) induced acute lung injury (ALI) in rats was examined in this study. Methods In this study, 48 rats were randomly assigned to one of six groups: sham, OJ, OJ+saline, OJ+SLX (0.5 mg/ml/d), OJ+SLX (1 mg/ml/d), and OJ+SLX (2 mg/ml/d). The pathological lung injury was assessed by histological analysis and lung injury grading. ELISA kits were used to evaluate the expression of IL-6, IL-1, TNF-α, and syndecan-1 (SDC-1) in bronchoalveolar lavage fluids (BALFs). Commercial assay kits were performed to evaluate malondialdehyde (MDA) production and catalase (CAT) activity in lung tissues. The apoptosis was assessed by TUNEL assay. The lung microvascular permeability was investigated using Evans blue leakage, lung wet/dry weight (W/D) ratio, and lung permeability index (LPI). SDC-1, claudin-5, ZO-1, and VE cadherin expression levels in lung tissues were measured using Western blot. Results The OJ-induced ALI rats showed severe lung injury. The value of IL-6, IL-1β, TNF-α, and SDC-1 in BALFs was remarkedly increased in the OJ group. MDA content, apoptotic area, apoptotic molecules, and SDC-1 level were all higher in the OJ group's lung tissues than in the sham group. CAT activity, Evans blue leakage, W/D ratio, LPI, and expression of claudin-5, ZO-1, and VE cadherin were all lower in the OJ group compared to the sham group. The degenerative alterations in lung tissue improved after 7 days of treatment with 2 mg/ml SLX. The BALFs had lower amounts of IL-6, IL-1, TNF-α, and SDC-1. The SLX therapy reduced MDA levels while restoring CAT activity. In lung tissues, SLX reduced apoptotic area and SDC-1 expression. SLX reduced lung microvascular permeability by raising the expression of Claudin-5, ZO-1, and VE-cadherin in lung tissue when compared to the OJ group. Conclusion The results suggested that SLX attenuates OJ-induced ALI in rats by protecting the pulmonary microvascular endothelial barrier.

INTESTINAL DAMAGE AND IMMUNE RESPONSE AFTER EXPERIMENTAL BLUNT ABDOMINAL TRAUMA

Abdominal trauma (AT) is of major global importance, particularly because the civil, terroristic, and military traumatic potential of blast injuries has increased. The consequences of blunt abdominal injuries are highly variable and frequently underestimated or even overlooked. However, the underlying path mechanisms and subsequent innate immune response remain poorly understood. Therefore, we investigated the spatiotemporal local and systemic effects of a standardized blast-induced blunt AT on the intestine and innate immune response. In an established AT model, 66 male C57Bl6 mice were anesthetized and exposed to either a single blast wave centered on the epigastrium or control treatment (sham). At 2, 6, or 24 hours after trauma induction, animals were sacrificed. In 16 of 44 (36%) AT animals, one or more macroscopically visible injuries of the intestine were observed. Epithelial damage was detected by histological analysis of jejunum and ileum tissue samples, quantified by the Chiu score and by increased plasma concentrations of the intestinal fatty acid-binding protein, an enterocyte damage marker. Moreover, in the early posttraumatic period, elevated syndecan-1, claudin-5, and mucin-2 plasma levels also indicated alterations in the gut-blood barrier. Increased levels of pro-inflammatory cytokines such as TNF and macrophage inflammatory protein 2 in tissue homogenates and plasma indicate a systemic immune activation after blunt AT. In conclusion, we detected early morphological intestinal damage associated with high, early detectable intestinal fatty acid-binding protein plasma levels, and a considerable time- and dose-dependent impairment of the gut-blood barrier in a newly established mouse model of blunt AT. It appears to be a sufficient model for further studies of the intestinal immunopathophysiological consequences of AT and the evaluation of novel therapeutic approaches.

Elevated NETs and Calprotectin Levels after ChAdOx1 nCoV-19 Vaccination Correlate with the Severity of Side Effects.

ChAdOx1 nCoV-19 vaccination has been associated with the rare side effect; vaccine-induced immune thrombotic thrombocytopenia (VITT). The mechanism of thrombosis in VITT is associated with high levels of neutrophil extracellular traps (NETs). The present study examines whether key markers for NETosis, such as H3-NETs and calprotectin, as well as syndecan-1 for endotheliopathy, can be used as prognostic factors to predict the severity of complications associated with ChAdOx1 vaccination. Five patients with VITT, 10 with prolonged symptoms and cutaneous hemorrhages but without VITT, and 15 with only brief and mild symptoms after the vaccination were examined. Levels of H3-NETs and calprotectin in the vaccinated individuals were markedly increased in VITT patients compared to vaccinees with milder vaccination-associated symptoms, and a strong correlation (r ≥ 0.745, p < 0.001) was found with severity of vaccination side effects. Syndecan-1 levels were also positively correlated (r = 0.590, p < 0.001) in vaccinees to side effects after ChAdOx1 nCoV-19 vaccination. We hypothesize that the inflammatory markers NETs and calprotectin may be used as confirmatory tests in diagnosing VITT.

Plasma syndecan-1 concentration as a biomarker for endothelial glycocalyx degradation in septic adult horses.

Limited information is available regarding endothelial glycocalyx degradation during sepsis in horses. Plasma syndecan-1 concentrations are increased in consequence of sepsis in other species and have been useful for prognostication. To determine whether plasma syndecan-1 levels are increased in adult horses affected with sepsis. Retrospective cohort study. Adult horses were assigned to one of three groups based on results of physical and laboratory examinations, clinical diagnosis, and results of previously described SIRS classification: Group 1 horses included healthy, nonseptic horses; Group 2 included horses in which clinical illness was identified but that were not considered to be septic; Group 3 included horses with a clinical diagnosis of sepsis. Plasma syndecan-1 concentration was determined in blood obtained at admission into the hospital for each horse, using an equine specific ELISA. Data were analysed using ANOVA and linear regression (p ≤ 0.05). One hundred and ninety-one horses were included and divided into three groups. Scores for SIRS were highest for Group 3 horses and lowest in Groups 1 and 2. Plasma syndecan-1 concentrations in Group 3 horses (50.73 ± 84.24 μg/ml; n=42) were greater than those for Group 1 (15.69 ± 11.28 μg/ml; n=66) and Group 2 (16.88 ± 15.30 μg/ml; n=83). There was no difference regarding syndecan concentrations between Groups 1 and 2. Retrospective study design, solitary time point of measurement for each patient, and lack of a widely accepted consensus regarding definitive diagnosis of sepsis in adult horses. Circulating plasma levels of syndecan-1, a biochemical marker of endothelial glycocalyx damage, are increased in septic adult horses.

Elevated plasma syndecan-1 as glycocalyx injury marker predicts unfavorable outcomes after rt-PA intravenous thrombolysis in acute ischemic stroke.

Purpose: We aimed to examine the prognostic value of syndecan-1 as a marker of glycocalyx injury in patients with acute ischemic stroke (AIS) receiving rt-PA intravenous thrombolysis. Methods: The study included 108 patients with AIS treated with rt-PA intravenous thrombolysis and 47 healthy controls. Patients were divided into unfavorable and favorable prognosis groups based on modified Rankin Scale scores. Univariate and multivariate logistic regression analyses were used to determine risk factors affecting prognosis. Risk prediction models presented as nomograms. The predictive accuracy and clinical value of the new model were also evaluated. Results: Plasma levels of syndecan-1 were significantly higher in patients with AIS than in controls (p < 0.05). Univariate analysis indicated that higher levels of syndecan-1 were more frequent in patients with poor prognosis than in those with good prognosis (t = −4.273, p < 0.001). Syndecan-1 alone and in combination with other factors predicted patient outcomes. After adjusting for confounding factors, syndecan-1 levels remained associated with poor prognosis [odds ratio, 1.024; 95% confidence interval (CI), 1.010–1.038]. The risk model exhibited a good fit, with an area under the receiver operating characteristic curve of 0.935 (95% CI, 0.888–0.981). The categorical net reclassification index (NRI) and continuous NRI values were >0. The integrated discrimination improvement value was 0.111 (95% CI, 0.049–0.174, p < 0.001). Decision curve analysis indicated that the model incorporating syndecan-1 levels was more clinically valuable than the conventional model. Conclusion: Plasma syndecan-1 levels represent a potential marker of prognosis of AIS following intravenous thrombolysis. Adding syndecan-1 to the conventional model may improve risk stratification.

Endothelial biomarkers as predictors for haemodialysis need in severe leptospirosis patients (Weil's disease).

To investigate the prediction ability of vascular injury biomarkers for haemodialysis requirement in patients with severe leptospirosis. Prospective study with severe leptospirosis patients hospitalised in Fortaleza, Brazil. Blood samples were collected hospital admission to quantify vascular injury biomarkers: syndecan-1, ICAM-1, VCAM-1, angiopoietin-2 and FGF-23. Two groups were evaluated according to haemodialysis requirement during hospital stay. Twenty-seven patients were included, with a mean age of 39 ± 18 years. 88.9% were males. 53.8% needed haemodialysis and presented higher levels on hospital admission of syndecan-1 (572 [300-811] vs. 263 [106-421] ng/ml; p= 0.03), angiopoietin-2 (1.52 [0.72-2.72] vs. 0.63 [0.4-1.38] ng/ml; p= 0.01), and FGF-23 (291 [56-2031] vs. 10 [10-806] pg/ml; p= 0.021). Syndecan-1 showed significant correlation with creatinine (r= 0.546; p= 0.05) and total bilirubin levels (r= 0.534; p= 0.013) on hospital admission. Angiopoietin-2 showed significant correlation with creatinine levels (r= 0.513; p= 0.009) on hospital admission and with number of haemodialysis sessions (r= 0.406; p= 0.049). No significant correlation was found with FGF-23. Regarding prognostic performance, combined syndecan-1 and angiopoietin-2 levels had a better ability to predict haemodialysis need in patients with severe leptospirosis (AUC-ROC=0.744 [95% CI: 0.545-0.943] p= 0.035). Syndecan-1 and angiopoietin-2 were associated with haemodialysis need in patients with severe leptospirosis and may be useful to improve therapeutic approach and reduce mortality.

TRAUMA-DERIVED EXTRACELLULAR VESICLES ARE SUFFICIENT TO INDUCE ENDOTHELIAL DYSFUNCTION AND COAGULOPATHY.

Although a number of studies have demonstrated increased release of extracellular vesicles (EVs) and changes in their origin differentials after trauma, the biologic significance of EVs is not well understood. We hypothesized that EVs released after trauma/hemorrhagic shock (HS) contribute to endotheliopathy and coagulopathy. To test this hypothesis, adoptive transfer experiments were performed to determine whether EVs derived from severely injured patients in shock were sufficient to induce endothelial dysfunction and coagulopathy. Methods: Total EVs were enriched from plasma of severely injured trauma/HS patients or minimally injured patients by ultracentrifugation and characterized for size and numbers. Under isoflurane anesthesia, noninjured naive C57BL/6J mice were administered EVs at varying concentrations and compared with mice receiving equal volume vehicle (phosphate-buffered saline (PBS)) or to mice receiving EVs from minimally injured patients. Thirty minutes after injection, mice were sacrificed, and blood was collected for thrombin generation (thrombin-antithrombin, thrombin-antithrombin complex [TAT] assay) and syndecan-1 by enzyme-linked immunoabsorbent assay (ELISA). Lungs were harvested for examination of histopathologic injury and costained with von Willebrand factor and fibrin to identify intravascular coagulation. Bronchial alveolar lavage fluid was aspirated from lungs for protein measurement as an indicator of the endothelial permeability. Data are presented as mean ± SD, P < 0.05 was considered significant, and t test was used. Results: An initial proof-of-concept experiment was performed in naive mice receiving EVs purified from severely injured trauma/HS patients (Injury Severity Score [ISS], 34 ± 7) at different concentrations (5 × 106 to 3.1 × 109/100 μL/mouse) and compared with PBS (control) mice. Neither TAT nor syndecan-1 levels were significantly different between groups at 30 minutes after EV infusion. However, lung vascular permeability and histopathologic injury were significantly higher in the EV group, and lung tissues demonstrated intravascular fibrin deposition. Based on these data, EVs from severely injured trauma/HS patients (ISS, 32 ± 6) or EVs from minimally injured patients (ISS, 8 ± 3) were administered to naive mice at higher concentrations (1 × 109 to 1 × 1010 EV/100 μL/mouse). Compared with mice receiving EVs from minimally injured patients, plasma TAT and syndecan-1 levels were significantly higher in the trauma/HS EV group. Similarly, bronchial alveolar lavage protein and lung histopathologic injury were higher in the trauma/HS EV group, and lung tissues demonstrated enhanced intravascular fibrin deposition. Conclusion: These data demonstrate that trauma/HS results in the systemic release of EVs, which are capable of inducing endotheliopathy as demonstrated by elevated syndecan-1 and increased permeability and coagulopathy as demonstrated by increased TAT and intravascular fibrin deposition. Targeting trauma-induced EVs may represent a novel therapeutic strategy.

Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4

PurposeEndotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study. ResultsThe plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients’ metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients. ConclusionsModel-driven analysis of the endothelial cells’ metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings.

Can Syndecan-1 Be Used As A Biomarker In Alzheimer’s Disease?

Background: Syndecan-1 (SDC-1) is a member of the syndecan family, which includes heparan sulfate proteoglycans. SDC-1 is important for cell-cell and cell-matrix interactions. The aim of this study is to examine the relationship between serum SDC-1 levels and mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Methods: Eighty-two patients aged 65 years and over were included in the study. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive functions of the patients. Comprehensive geriatric assessment components were administered to the patients. Serum SDC-1 levels were measured with an enzyme-linked immunosorbent assay kit. Results: When patients were grouped as control, MCI and AD, significant decreases were observed in Katz daily living activity (p&lt;0.001), Lawton instrumental daily living activity (p=0.001), Mini-nutritional assessment (p=0.001), MMSE (p=0.001) scores. SDC-1 level was 154.88±22.85 in the control group, 157.95±19.45 in the MCI group, and 159.54±14.04 ng/mL in the AD group, and no significant correlation was observed (p=0.677). When correlation analyzes were performed with SDC-1, a negative correlation was found with the Yesavage geriatric depression scale score (Spearman rho: -0.223 p=0.044). Conclusion: No correlation was found between SDC-1 level and AD, and it showed a negative correlation with depression. Clarifying the pathogenetic processes more clearly will guide the development of new treatment strategies.

Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis.

Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)—known to influence inflammation and keratinocyte hyperproliferation via α5β1 integrin in psoriasis—was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion®). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.