Soluble Vascular Cellular Adhesion Molecule-1 Research Articles

Acute kidney injury is associated with soluble vascular cell adhesion molecule 1 levels and short-term mortality in patients with ischemic stroke

BackgroundThe mechanisms that modulate the onset of acute kidney inlury (AKI) after ischemic stroke (IS) and valuable biomarkers to predict the occurrence and prognosis of AKI among patients with IS are missing. ObjectiveTo evaluate the frequency of AKI and the prognostic validity of clinical and laboratory biomarkers in predicting AKI and short-term mortality after the IS. MethodsNinety-five patients with IS were enrolled. Baseline IS severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and disability was determined after three-month follow-up using the modified Rankin Scale. Patients with IS were also categorized as survivors and non-survivors after the follow-up. Baseline data and laboratory biomarkers were obtained up to 24 h of the admission. ResultsFifteen (15.7 %) patients with IS presented AKI. The proportion of patients with vitamin D deficiency and the mortality were higher among those with AKI than those without AKI (p=0.011 and p-0.009, respectively). Patients with AKI showed higher disability and higher increased soluble vascular cellular adhesion molecule-1 (sVCAM-1) than those without AKI (p=0.029 and p=0.023, respectively). Logistic regression analysis showed that only sVCAM-1 was associated with the occurrence of AKI after IS [odds ratio (OR): 2.715, 95 % confidence intereval (CI): 1.12–6.67, p=0.027]. When both AKI and NIHSS were evaluated as explanatory variables, this panel showed an OR of 5.782 (95 % CI: 1.09–30.43, p<0.001) and correctly classified 83.6 % of cases. ConclusionIn conclusion, sVCAM-1 levels showed a potential useful for prediction of AKI after IS.

Angiopoietin-2 is associated with sickle cell complications, including stroke risk, and decreases with hydroxyurea therapy

AbstractHydroxyurea reduces morbidity and mortality in children with sickle cell anemia (SCA). The endothelium is central to SCA-related complications including stroke. However, hydroxyurea’s impact on the endothelium is not well described. To address this gap, we measured plasma levels of endothelial activation markers (angiopoietin-2, P-selectin, soluble endothelial selectin [sE-selectin], soluble intercellular cellular adhesion molecule 1, and soluble vascular endothelial cellular adhesion molecule) by enzyme-linked immunosorbent assay after initiation of hydroxyurea therapy. Samples were collected from Ugandan children with SCA enrolled in a clinical trial evaluating hydroxyurea vs placebo (NOHARM trial). Samples were collected at enrollment; and then after 2, 4, and 12 months of follow-up. Longitudinal changes in biomarker levels were evaluated using linear mixed effects models. Transcranial Doppler (TCD) velocities were measured at 10 to 12 months follow-up to assess cerebral blood flow and primary stroke risk. Mediation analysis was used to explore causal pathways of hydroxyurea-mediated effects on TCD velocities. In total, 798 plasma samples were tested from 205 children (mean enrollment age, 2.2 years). At enrollment, higher levels of angiopoietin-2 were associated with a previous medical history of dactylitis, vaso-occlusive crises, acute chest syndrome, and transfusion (P < .05 for all). Hydroxyurea therapy at a fixed dose of 20 mg/kg per day decreased plasma angiopoietin-2, P-selectin, and sE-selectin levels over the study period (P < .05 for all). Angiopoietin-2 and sE-selectin were associated with higher TCD velocities. Mediation analysis suggests that hydroxyurea decreases TCD velocities through an increase in fetal and total hemoglobin. Increased fetal and total hemoglobin, and decreased white blood cell count may decrease TCD velocity, in part, through an angiopoiten-2–mediated pathway. This trial was registered at www.ClinicalTrials.gov as #NCT01976416.

Baseline severity and soluble vascular cell adhesion molecule 1 (sVCAM-1) as biomarker predictors of short-term mortality in acute ischemic stroke.

The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5-14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795-0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.

The dynamic of Soluble Vascular Cellular Adhesion Molecule -1 (sVCAM-1) level in Overnutritious children with Dengue Infection

Introduction: Dengue infection is still posed a significant medical challenge for pediatric population in developing countries. However, increased prevalence of overweight and obesity among children in those countries increased the possibility of the coexistence of these conditions. However, their interaction is still under investigated. Therefore, this study was aimed to study the dynamic of sVCAM-1 level as the known predictor of the severity of dengue infection with over nutritional status in children with dengue infection.Method: An analytic observational nested case-control study was conducted in Paediatric Division Sanglah General Hospital, Bali. The children with DHF between 6 months old to 12 years old were included as the case group while control groups consisted of pediatric patients with just Dengue Fever (DF) with the same age range. The diagnosis of dengue was established using 1997 WHO criteria while nutritional status was assessed using WHO curve. The sVCAM-1 was evaluated using ELISA technique.Results: The level of sVCAM-1 was significantly higher in patients with DHF than patients with DF only. The level was also fluctuated more in DHF patients. Likewise, the sVCAM-1 level was also significantly higher in DHF patients with overnutrition compared to normal DHF patients with a more fluctuated pattern over the course of 3 days (starting from day 4 to day 7). Finally, no significant finding was observed in sVCAM-1 level in DSS patients albeit the difference in concentration pattern.Conclusion: Overnutrition is seems to be associated with higher concentration of sVCAM-1 and higher fluctuation of its concentration in children with DHF.

Effect of Rosuvastatin Therapy on Biomarkers of Inflammation and Immune Activation in People With Human Immunodeficiency Virus at Intermediate Cardiovascular Risk.

Statins may help prevent cardiovascular disease (CVD) in people with human immunodeficiency virus (PWH) with chronic inflammation owing to their pleotropic lipid-lowering and anti-inflammatory properties. The impact of 48 weeks of rosuvastatin therapy on inflammation and immune activation in a double-blind, placebo-controlled trial in PWH at moderate cardiovascular disease risk was assessed. Rosuvastatin did not alter plasma levels of interleukin 6, soluble tumor necrosis factor receptor type 2, CXCL10, soluble CD14, or soluble vascular cellular adhesion molecule 1 (P ≥ .1 for all). Proportions of CD16+ monocyte subsets were increased in PWH receiving rosuvastatin. The potential benefits of statin use in PWH with normal lipid levels requires further clinical outcome research.

Fecal Calprotectin Is Elevated in HIV and Related to Systemic Inflammation.

Fecal calprotectin (FC), a biomarker of gastrointestinal (GI) inflammation, is used in the diagnosis and management of inflammatory bowel disease. HIV infection severely damages gut-associated lymphoid and epithelial tissues leading to GI inflammation that drives systemic inflammation and increases subsequent risk of comorbidities. For the first time, we compared FC concentrations by HIV and antiretroviral therapy (ART) status and determined the relationship to systemic inflammation. People with and without HIV were enrolled and underwent a comprehensive clinical and laboratory assessment. Stool samples were collected, and FC was measured by enzyme-linked immunosorbent assay ELISA. Plasma biomarkers of inflammation were also measured. One hundred one participants with HIV (83 ART-treated and 18 ART-naive) and 89 uninfected controls were enrolled. There were no significant differences between ART-naive and ART-treated participants, but both HIV groups had significantly higher FC concentrations than controls when FC was considered as a continuous variable or by cut-offs used in inflammatory bowel disease. The highest median and largest proportion of participants with FC >100 µg/g were seen in ART-naive, followed by ART-treated and then controls. Among HIV participants, FC concentrations were positively associated with high-sensitivity C-reactive protein, soluble tumor necrosis factor receptor II, and soluble vascular cellular adhesion molecule and inversely associated with CD4 counts. FC concentrations are elevated in HIV regardless of ART status. ART and immune reconstitution seem to reduce FC but not to concentrations seen in uninfected controls. Our results suggest a role for FC as a noninvasive surrogate measurement of GI inflammation and associated systemic inflammation in HIV.

Endothelial Dysfunction Marker Variation in Young Adults with Chronic Apical Periodontitis before and after Endodontic Treatment

IntroductionCardiovascular diseases are the leading cause of mortality worldwide. Apical periodontitis (AP) has been associated with an increased risk of cardiovascular diseases. A correlation has been shown between chronic AP and endothelial dysfunction (ED), but there is no evidence to indicate ED improves after endodontic treatment in patients with periapical lesions. The aim of this study was to investigate vascular and molecular markers of early ED before and after root canal treatment in young adults with chronic AP. MethodsTwenty control subjects and 21 patients with AP were assessed at baseline. The AP patients were also evaluated 2 and 12 months post-treatment. Endothelial flow reserve was assessed via an endothelial function test, and enzyme-linked immunosorbent assays were used to evaluate plasma levels of proinflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor alpha; vasoconstrictor ED marker endothelin (ET)-1; circulating endothelial adhesion markers intercellular adhesion molecule 1 (ICAM-1)/CD54 and soluble vascular cellular adhesion molecule (sVCAM)-1/CD106; soluble CD14; and the endothelial leukocyte adhesion molecule (E-selectin). ResultsAP was associated with increased serum levels of ET-1, ICAM-1, E-selectin, IL-1, and sCD14, suggesting early vascular ED, with no macroscopic evidence of a reduction in endothelial flow reserve. Root canal treatment ameliorated inflammation and early ED, lowering plasma levels of IL-1, sCD14, ET-1, ICAM-1/CD54, and E-selectin to those of control subjects. ConclusionsOur findings suggest that AP may drive early vascular ED and that the endodontic therapy of AP ameliorates early ED.

Elevated Systemic Inflammatory Burden and Cardiovascular Risk in Young Adults with Endodontic Apical Lesions

IntroductionThe aim of this study was to assess whether apical lesions are associated with inflammatory serum markers of cardiovascular risk, especially high-sensitivity C-reactive protein (hsCRP), in young adults. MethodsIn this cross-sectional study, otherwise healthy individuals with apical lesions of endodontic origin (ALEOs) and a clinical diagnosis of asymptomatic apical periodontitis and controls aged between 18 and 40 years were included. Patients’ sociodemographic characteristics, medical history, and classic cardiovascular risk factors were recorded, and the pathobiological determinants of atherosclerosis in youth score was calculated. Oral clinical and radiographic examinations were performed. Blood samples were collected to determine the lipid profile, glycated hemoglobin, hsCRP, immunoglobulin G, interleukin (IL)-6, IL-10, IL-12p70, matrix metalloproteinase 8, soluble vascular cellular adhesion molecule-1, soluble intercellular adhesion molecule-1, and soluble E-selectin. Bivariate and multivariate analyses adjusting for oral and classic cardiovascular risk factors were performed. ResultshsCRP levels were significantly higher in ALEO patients versus controls (median = 2.54 vs 0.78), whereas the pathobiological determinants of atherosclerosis in youth score was comparable among the groups. Also, the levels of IL-6, matrix metalloproteinase 8, and soluble E-selectin were significantly higher in ALEO patients. hsCRP, IL-6, and IL-12 correlated with soluble adhesion molecules. Bivariate analysis based on hsCRP serum concentrations ≥1 mg/L showed an odds ratio (OR) = 6.8, and the risk increased 3.3 times for an additional ALEO. In multivariate analysis, ALEO was significantly associated with hsCRP levels ≥1 mg/L (OR = 5.1–12.8) independently of the adjustment model. ALEO also associated with CRP levels >3 mg/L, which was significant after the adjustment for covariates (OR = 4.0). ConclusionsALEO is associated with the systemic inflammatory burden and cardiovascular risk determined by hsCRP, supporting a mechanistic link for cardiovascular diseases in young adults.

Biomarkers of inflammation and endothelial dysfunction as predictors of pulse pressure and incident hypertension in type 1 diabetes: a 20\xa0year life-course study in an inception cohort

Aims/hypothesisVascular inflammation and endothelial dysfunction are thought to contribute to arterial stiffening and hypertension. This study aims to test this hypothesis with longitudinal data in the context of type 1 diabetes.MethodsWe investigated, in an inception cohort of 277 individuals with type 1 diabetes, the course, tracking and temporal inter-relationships of BP, specifically pulse pressure (a marker of arterial stiffening) and hypertension, and the following biomarkers of systemic and vascular inflammation/endothelial dysfunction: C-reactive protein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular cellular adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin). These biomarkers and other risk factors were measured at baseline and repeatedly up to 20 years after the onset of type 1 diabetes. Data were analysed with generalised estimating equations including adjustments for age, sex, smoking status, BMI, HbA1c, serum creatinine, total cholesterol, urinary AER, insulin treatment dose and mean arterial pressure.ResultsIncreases were noted in all biomarkers except sE-selectin, which decreased over time. Levels differed from baseline at 2–4 years and preceded the increase in pulse pressure, which occurred at 8–10 years after the onset of type 1 diabetes. Higher levels of sICAM-1 and sVCAM-1, but not CRP or sE-selectin, at baseline and throughout the 20 year follow-up, were significantly associated with higher (changes in) pulse pressure at subsequent time points. Higher levels of sVCAM-1 at baseline and during follow-up were also significantly associated with the prevalence (OR 3.60 [95% CI 1.36, 9.53] and OR 2.28 [1.03, 5.25], respectively) and incidence (OR 2.89 [1.08, 7.75] and OR 3.06 [1.01, 9.26], respectively) of hypertension. We also investigated the longitudinal associations between BP or hypertension as determinants of subsequent (changes in) levels of CRP, sICAM-1, sVCAM-1 and sE-selectin, but did not find evidence to support a reverse causality hypothesis.Conclusions/interpretationThese findings support the involvement of vascular endothelial dysfunction and inflammation in the development of premature arterial stiffening and hypertension in type 1 diabetes.

Biomarkers of Cardiovascular Disease and Mortality Risk in Patients with Advanced CKD.

The high risk of cardiovascular disease (CVD) and premature death in patients with CKD associates with a plethora of elevated circulating biomarkers that may reflect distinct signaling pathways or simply, are epiphenomena of CKD. We compared the predictive strength of 12 biomarkers analyzed concomitantly in patients with stage 5 CKD. From 1994 to 2014, 543 patients with stage 5 CKD (median age =56 years old; 63% men; 199 patients had CVD) took part in our study on malnutrition, inflammation, and CVD in incident dialysis patients. Circulating levels of albumin, ferritin, high-sensitivity C-reactive protein (hsCRP), IGF-1, IL-6, orosomucoid, troponin T (TnT), TNF, soluble intracellular adhesion molecule, soluble vascular cellular adhesion molecule 1 (sVCAM-1), and platelet and white blood cell (WBC) counts were analyzed as predictors of the presence of clinically overt CVD at baseline, protein-energy wasting (PEW), and subsequent all-cause mortality. During follow-up for a median of 28 months, there were 149 deaths, 81 of which were caused by CVD. Most biomarkers were elevated compared with reference values and--except for albumin, ferritin, and IGF-1-higher in patients with CVD. In receiver operating characteristic analysis, age, IL-6, TnT, hsCRP, and IGF-1 were classifiers of baseline CVD and predictors of all-cause mortality. In addition to age, diabetes mellitus, smoking (for CVD), and PEW, only IL-6, relative risk (RR) 1.10 and 95% confidence interval ([95% CI], 1.02 to 1.19), sVCAM-1 RR 1.09 (95% CI, 1.01 to 1.17), and serum albumin RR 0.89 (95% CI, 0.83 to 0.95) associated with baseline CVD, and only WBC, hazard ratio (HR) 1.94 (95% CI, 1.34 to 2.82), IL-6 HR 1.79 (95% CI, 1.20 to 2.67), and TNF HR 0.65 (95% CI, 0.44 to 0.97) predicted all-cause mortality. In addition to age and comorbidities, only IL-6, sVCAM-1, and albumin could-independently of other biomarkers-classify clinical CVD, and only IL-6, WBC, and TNF could-independently of other biomarkers-predict all-cause mortality risk. These data underscore the robustness of IL-6 as a classifier of clinically overt CVD and predictor of all-cause mortality in patients with stage 5 CKD.

Common Phenolic Metabolites of Flavonoids, but Not Their Unmetabolized Precursors, Reduce the Secretion of Vascular Cellular Adhesion Molecules by Human Endothelial Cells

Background: Flavonoids have been implicated in the prevention of cardiovascular disease; however, their mechanisms of action have yet to be elucidated, possibly because most previous in vitro studies have used supraphysiological concentrations of unmetabolized flavonoids, overlooking their more bioavailable phenolic metabolites.Objective: We aimed to explore the effects of phenolic metabolites and their precursor flavonoids at physiologically achievable concentrations, in isolation and combination, on soluble vascular cellular adhesion molecule-1 (sVCAM-1).Method: Fourteen phenolic acid metabolites and 6 flavonoids were screened at 1 μM for their relative effects on sVCAM-1 secretion by human umbilical vein endothelial cells stimulated with tumor necrosis factor alpha (TNF-α). The active metabolites were further studied for their response at different concentrations (0.01 μM–100 μM), structure-activity relationships, and effect on vascular cellular adhesion molecule (VCAM)-1 mRNA expression. In addition, the additive activity of the metabolites and flavonoids was investigated by screening 25 unique mixtures at cumulative equimolar concentrations of 1 μM.Results: Of the 20 compounds screened at 1 μM, inhibition of sVCAM-1 secretion was elicited by 4 phenolic metabolites, of which protocatechuic acid (PCA) was the most active (−17.2%, P = 0.05). Investigations into their responses at different concentrations showed that PCA significantly reduced sVCAM-1 15.2–36.5% between 1 and 100 μM, protocatechuic acid-3-sulfate and isovanillic acid reduced sVCAM-1 levels 12.2–54.7% between 10 and 100 μM, and protocatechuic acid-4-sulfate and isovanillic acid-3-glucuronide reduced sVCAM-1 secretion 27.6% and 42.8%, respectively, only at 100 μM. PCA demonstrated the strongest protein response and was therefore explored for its effect on VCAM-1 mRNA, where 78.4% inhibition was observed only after treatment with 100 μM PCA. Mixtures of the metabolites showed no activity toward sVCAM-1, suggesting no additive activity at 1 μM.Conclusions: The present findings suggest that metabolism of flavonoids increases their vascular efficacy, resulting in a diversity of structures of varying bioactivity in human endothelial cells.

Association of homocysteine and inflammatory-related molecules in sickle cell anemia

Objective: Investigate the role of homocysteine (Hcy), Th17-related cytokines, and adhesion molecules in the inflammatory state seen in the sickle cell anemia (SCA).Methods: We studied the Hcy, interleukin (IL)-17, and transforming growth factor β (TGF-β) cytokine levels of 62 SCA patients, as well as the expression levels of inflammatory and endothelial activation markers.Results: We found significant associations between Hcy levels and increased expression of IL-17 and TGF-β among SCA patients, and a positive significant correlation between Hcy and soluble vascular cellular adhesion molecules (sVCAM). SCA individuals had raised IL-17 levels when compared with controls.Discussion: These results suggest a possible role of Hyc in the induction of TGF-β and IL-17. Other authors proposed that Hcy may contribute to the initiation and progression of vascular disease by monocyte activation, resulting in the secretion of cytokines that amplify the inflammatory response. The role of Hcy in cytokine production and oxidative stress in the endothelium may explain the increase of sVCAM expression and, the vascular activation currently described among the SCA individuals with the highest Hcy serum levels. The chronic inflammation was observed in hyperhomocysteinemic mice, with an increased expression of VCAM-1 and plasma levels of tumor necrosis factor-alpha, showing an association of this inflammatory molecule and vascular changes.Conclusion: Our findings suggest that the increased levels of IL-17,Hcy and sVCAM contributes contributes to the vascular inflammation and activation presented by SCA patients, which probably have an important role in vaso-occlusion. On the basis of the presented data, IL-17 and Hcy might be considered as important components in the pathogenesis of SCA.

Endothelial Activation Is Associated With Cognitive Performance in Patients With Hypertension.

Hypertension is associated with the occurrence of cognitive deficits and dementia, probably because hypertension is a major risk factor for the occurrence of brain damage as a result of cerebral small vessel disease (cSVD). Endothelial activation and inflammation have been suggested to play an important role in the pathogenesis of cSVD. We investigated if compound scores of endothelial activation or inflammation, based on several blood markers, are associated with cognitive performance 3 years later in patients with essential hypertension. At baseline, levels of blood markers of endothelial activation (soluble vascular cellular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), sP-selectin, and sE-selectin) and markers of inflammation (neopterin, C-reactive protein, and sICAM-1) were measured and transformed into compound scores using z-scores. In addition, a brain magnetic resonance imaging (MRI) was performed to determine the presence of cSVD-related MRI markers. Three years later, patients underwent a neuropsychological assessment to determine cognitive performance. A total of 101 patients with hypertension were included in the present study. In multiple linear regression analyses with correction for demographics and MRI markers, the compound score of endothelial activation (B = -0.19, 95% confidence interval = -0.34 to -0.04, P = 0.014), but not of inflammation (B = -0.09, 95% confidence interval = -0.22 to 0.05, P = 0.198), was associated with worse cognitive performance. Our results show that an overall measure of endothelial activation is associated with cognitive performance in patients with essential hypertension. This indicates that a process involving endothelial activation might play a role in the pathogenesis of cognitive problems in patients with hypertension.

Markers of renal disease and function are associated with systemic inflammation in HIV infection.

Both renal disease and systemic inflammation predict non-AIDS-defining events and overall mortality in HIV-infected patients. Here, we sought to determine the relationships between renal disease and circulating inflammation markers. We performed a secondary analysis of AIDS Clinical Trials Group Study A5224s to determine if markers of renal disease [urine protein:creatinine ratio (uPCR), urine albumin:creatinine ratio (uACR), and estimated glomerular filtration rate (eGFR), using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine and cystatin C-creatinine] were associated with markers of systemic inflammation [high-sensitivity C-reactive protein, interleukin-6, tumour necrosis factor (TNF)-α, soluble TNF-α receptor I (sTNFRI), sTNFRII, and soluble vascular cellular and intercellular adhesion molecules]. We correlated these renal and inflammatory markers prior to antiretroviral initiation and after 96 weeks of therapy. We found that eGFR (estimated using CKD-EPI cystatin C-creatinine), uPCR, and uACR were significantly correlated with most assessed markers of systemic inflammation prior to antiretroviral initiation. uPCR and eGFR (using CKD-EPI cystatin C-creatinine), but not uACR, remained significantly correlated with most of the assessed inflammatory markers after 96 weeks of antiretroviral therapy (ART). Most of these correlations, although statistically significant, were < 0.50. eGFR using CKD-EPI creatinine was much less frequently associated with inflammation markers and only significantly correlated with sTNFR1 at week 0 and with sTNFRI and II at week 96. Renal disease and function were associated with systemic inflammation in HIV infection, both before and after ART. Systemic inflammation may partially explain the relationships between proteinuria, albuminuria, and reduced renal function and future adverse outcomes.

Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway

Vascular endothelial insulin resistance (IR) is a critically initial factor in cardiocerebrovascular events resulted from diabetes and is becoming a worldwide public health issue. Thiazolidinediones (TZDs) are clinical insulin-sensitizers acting through a canonical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent insulin trans-activation pathway. However, it remains elusive whether there are other mechanisms. In current study, we investigated whether TZDs improve endothelial IR induced by high glucose concentration or hyperglycemia via a non-canonical PPARγ-dependent nuclear factor-kappa B (NF-κB) trans-repression pathway. Our results showed that pre-treatment with TZDs dramatically decrease the susceptibility of endothelial cell to IR, while post-treatment notably improve the endothelial IR both in vitro and in vivo. Moreover, TZDs substantially increase the levels of endothelial nitric oxide synthase (eNOS) and inhibitory κB alpha (IκBα), whereas decrease those of the phosphorylated inhibitory κB kinase alpha/beta (phosphor-IKKα/β) and the cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cellular adhesion molecule-1 (sVCAM-1), suggesting that TZDs act indeed through a PPARγ-dependent NF-κB trans-repression pathway. These findings highlighted a non-canonical mechanism for TZDs to ameliorate endothelial IR which might provide a potential strategy to prevent and treat the diabetic vascular complications clinically.

Endocan — the new endothelial activation marker independently associated with soluble endothelial adhesion molecules in uraemic patients with cardiovascular disease

ObjectivesEndocan is a new marker of endothelial cell activation that mediates adhesion of leukocytes into endothelium. Soluble intercellular (sICAM-1) and vascular cellular (sVCAM-1) adhesion molecules play an important role in the prevalence of cardiovascular disease (CVD) in chronic kidney disease (CKD) patients. The aim of this study is to investigate whether endocan could affect the concentrations of sICAM-1 and sVCAM-1 in CKD patients, particularly in those with CVD. Design and methodsWe evaluated plasma endocan, sICAM-1, sVCAM-1 and the markers of inflammation: high sensitivity C-reactive protein (hs CRP), interleukin-6, tumor necrosis factor-α (TNF-α) and their interrelationships in 53 CKD patients (both with and without CVD) and 29 healthy controls. ResultsEndocan, sICAM-1, sVCAM-1 and inflammatory markers were significantly higher in CKD patients than in controls, and patients with CVD had levels significantly higher (except interleukin-6 and TNF-α) than those without CVD. The presence of CVD, ferritin, TNF-α and SBP were the independent predictors of endocan levels in the whole CKD group. In this group, the weak relationship was between endocan and sICAM-1 and sVCAM-1, but age was the only independent predictor of these adhesion molecules. The strong association between endocan and sICAM-1 and sVCAM-1 was exclusively observed in subgroup with CVD, and the low % of lymphocytes followed by increased endocan was identified as the independent variables significantly associated with these soluble molecule levels. ConclusionsThis study shows that plasma endocan is significantly increased and independently associated with sICAM-1 and sVCAM-1 levels in CKD patients with cardiovascular complications.

Serum Protein S100β is a Diagnostic Biomarker for Distinguishing Posterior Circulation Stroke from Vertigo of Nonvascular Causes

Background: In patients presenting with acute vertigo or dizziness, identifying the posterior fossa stroke as the underlying cause can be a major challenge. We therefore evaluated the serum biomarkers for the differential diagnosis of nonvascular vertigo and posterior circulation stroke. Methods: Of a total of 80 patients, 31 patients had an ischemic stroke in the posterior circulation and 12 infratentorial hemorrhage. Findings in these patients were compared with those in 22 patients with vertigo of nonvascular origin and 15 matched control patients without neurological symptoms. Blood samples drawn <24 h after symptom onset were analyzed for S100 calcium-binding protein B (S100β), matrix metalloproteinase 9 (MMP-9), soluble vascular cellular adhesion molecule-1 (sVCAM-1), and glial fibrillary acidic protein (GFAP). Results/Conclusion: Serum levels of S100β were significantly higher in stroke patients than in nonvascular vertigo patients. Serum concentrations of MMP-9 tended to be higher in stroke patients, whereas no significant differences among groups were found for sVCAM-1 and GFAP. Receiver-operating characteristic analysis revealed a sensitivity of 94.4% and a specificity of 31.8% for detecting stroke in patients presenting with vertigo for S100β. S100β may serve as a biomarker for distinguishing between vertigo of vascular causes and nonvascular, acute vertigo.

Endothelial activation and repair during hantavirus infection: association with disease outcome.

Background. Endothelial activation and dysfunction play a central role in the pathogenesis of sepsis and viral hemorrhagic fevers. Hantaviral disease is a viral hemorrhagic fever and is characterized by capillary dysfunction, although the underlying mechanisms for hantaviral disease are not fully elucidated.Methods. The temporal course of endothelial activation and repair were analyzed during Puumala hantavirus infection and associated with disease outcome and a marker for hypoxia, insulin-like growth factor binding protein 1 (IGFBP-1). The following endothelial activation markers were studied: endothelial glycocalyx degradation (syndecan-1) and leukocyte adhesion molecules (soluble vascular cellular adhesion molecule 1, intercellular adhesion molecule 1, and endothelial selectin). Cytokines associated with vascular repair were also analyzed (vascular endothelial growth factor, erythropoietin, angiopoietin, and stromal cell-derived factor 1).Results. Most of the markers we studied were highest during the earliest phase of hantaviral disease and associated with clinical and laboratory surrogate markers for disease outcome. In particular, the marker for glycocalyx degradation, syndecan-1, was significantly associated with levels of thrombocytes, albumin, IGFBP-1, decreased blood pressure, and disease severity.Conclusions. Hantaviral disease outcome was associated with endothelial dysfunction. Consequently, the endothelium warrants further investigation when designing future medical interventions.

Associations of Inflammatory Markers With AIDS and Non-AIDS Clinical Events After Initiation of Antiretroviral Therapy

The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear. A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin-6 (IL-6), soluble receptors of tumor necrosis factor α (sTNF)-RI, sTNF-RII, TNF-α, soluble vascular cellular adhesion molecules (sVCAM-1), and soluble intercellular adhesion molecules (sICAM-1) with times to AIDS and to non-AIDS events used Cox proportional hazards models. Analysis included 244 subjects; 85% men and 48% white non-Hispanic with median age 39 years, HIV-1 RNA of 4.6 log10 copies per milliliter, and CD4 of 240 cells per microliter. Overall, 13 AIDS events (9 opportunistic infections, 3 AIDS-cancers, and 1 recurrent bacterial pneumonia) and 18 non-AIDS events (6 diabetes, 4 cancers, 3 cardiovascular, and 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, whereas adjusting for baseline CD4 count left only sTNF-RI and sICAM-1 significantly associated with increased risk. Time-updated values of IL-6, sTNFR-I and II, and sICAM-1 were also associated with an increased risk. For non-AIDS events, only higher baseline high-sensitivity C-reactive protein was significantly associated with increased risk, whereas higher IL-6 was marginally associated with higher risk. Analyses of time-updated biomarker values showed tumor necrosis factor α to be significantly associated with increased risk, even after adjustment for antiretroviral therapy, and CD4 count or HIV-1 RNA. Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events.

Plasma resistin levels are associated with homocysteine, endothelial activation, and nitrosative stress in obese youths

ObjectiveTo evaluate whether serum resistin levels are related to cardiovascular risk in obese children. Design and methodsCross-sectional study of 110 children (40 normal weight and 70 severely obese). Clinical and biochemical parameters, including lipid profile, fasting glucose and insulin, and homocysteine, were determined. The levels of adipokines (adiponectin, leptin, and resistin), markers of inflammation (high-sensitivity C-reactive protein (hs-CRP)), endothelial activation (serum concentrations of soluble intercellular and vascular cellular adhesion molecule-1 (sICAM-1, sVCAM-1)), and oxidative/nitrosative stress (malondialdehyde and urinary nitrate/nitrite) were measured. ResultsA partial correlation adjusted by gender, Tanner stage, and body mass index in obese children showed that resistin was significantly related to central obesity (p<0.002), insulin resistance (p<0.005), and homocysteine (p<0.001). No association was found with other metabolic risk factors or hs-CRP levels. Malondialdehyde (p<0.043) and sVCAM-1 (p<0.002) were positively correlated whereas urinary nitrate/nitrite was negatively correlated (p<0.007). In multiple regression analysis homocysteine, sVCAM-1, and urinary nitrate/nitrite remained independent determinants of resistin levels (R2 adjusted=0.347, p=0.000). ConclusionsResistin could be considered as a promising marker for future cardiovascular disease in obese children.