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An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular–immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood–brain barrier as a possible target to treat age-related neurodegeneration.The detrimental effects of aged blood on cognition and nervous system function in mice can be combatted by targeting brain endothelial cell dysfunction via inhibition of aberrant VCAM1 signaling at the blood–brain barrier.

Delirium is the most common postoperative complication of the central nervous system (CNS) that can trigger long-term cognitive impairment. Its underlying mechanism is not fully understood, but the dysfunction of the blood-brain barrier (BBB) has been implicated. The serum levels of the axonal damage biomarker, phosphorylated neurofilament heavy subunit (pNF-H) increase in moderate to severe delirium patients, indicating that postoperative delirium can induce irreversible CNS damage. Here, we investigated the relationship among postoperative delirium, CNS damage and BBB dysfunction, using pNF-H as reference. Blood samples were collected from 117 patients within 3 postoperative days. These patients were clinically diagnosed with postoperative delirium using the Confusion Assessment Method for the Intensive Care Unit. We measured intercellular adhesion molecule-1, platelet and endothelial cell adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and P-selectin as biomarkers for BBB disruption, pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6), and pNF-H. We conducted logistic regression analysis including all participants to identify independent biomarkers contributing to serum pNF-H detection. Next, by multiple regression analysis with a stepwise method we sought to determine which biomarkers influence serum pNF-H levels, in pNF-H positive patients. Of the 117 subjects, 41 were clinically diagnosed with postoperative delirium, and 30 were positive for serum pNF-H. Sensitivity and specificity of serum pNF-H detection in the patients with postoperative delirium were 56% and 90%, respectively. P-selectin was the only independent variable to associate with pNF-H detection (P < 0.0001) in all 117 patients. In pNF-H positive patients, only PECAM-1 was associated with serum pNF-H levels (P = 0.02). Serum pNF-H could be an objective delirium biomarker, superior to conventional tools in clinical settings. In reference to pNF-H, P-selectin may be involved in the development of delirium-related CNS damage and PECAM-1 may contribute to the progression of delirium- related CNS damage.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case–control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A “vascular endothelial index” (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

PurposeThe aim of the current meta-analysis was to investigate the effect of increasing dietary ALA intake on the blood concentration of inflammatory markers including tumor necrosis factor (TNF), interleukin 6 (IL-6), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in adults.MethodsAfter a systemic search on PubMed, Embase, and Cochrane library and bibliographies of relevant articles, 25 randomized controlled trials that met the inclusion criteria were identified.ResultsNo significant effect of dietary ALA supplementation was observed on TNF (SMD: −0.03, 95% CI −0.36 to 0.29), IL-6 (SMD: −0.17, 95% CI −0.46 to 0.12), CRP (SMD: −0.06, 95% CI −0.24 to 0.12), sICAM-1 (SMD: −0.06, 95% CI −0.26 to 0.13), and sVCAM-1 (SMD: −0.24, 95% CI −0.56 to 0.09). Subgroup analysis revealed that increasing dietary ALA tends to elevate CRP concentration in healthy subjects. However, the null effect of ALA supplementation on other inflammatory markers was not changed in various subgroups, indicating that the results are stable. Meta-regression results revealed a negative relationship between the effect size on CRP and its baseline concentration. No significant publication bias was observed for all inflammatory markers as suggested by funnel plot and Begg’s test.ConclusionOur meta-analysis did not find any beneficial effect of ALA supplementation on reducing inflammatory markers including TNF, IL-6, CRP, sICAM-1, and sVCAM-1. However, in healthy subjects, ALA supplementation might increase CRP concentration.

Background & objectives Sickle cell disease (SCD) is a monogenic disorder characterised by aberrant haemoglobin production, leading to haemolytic anaemia and vaso-occlusive crises. Genetic variations and altered expression of cell adhesion molecules (CAMs) are implicated in disease pathogenesis. This cross-sectional study investigated the association between single nucleotide polymorphisms (SNPs) in the SELP, SELE, ICAM-1, and VCAM-1 genes and their protein levels in individuals with SCD. Methods A total of 140 individuals with SCD were recruited. Plasma levels of P-selectin, E-selectin, ICAM-1 and VCAM-1 were measured by ELISA method alongside a control group (n=10). The selected SNPs of SELP, SELE, ICAM-1, and VCAM-1 genes were identified through Sanger sequencing method. Results The expression of adhesion molecules were found to be significantly higher in SCD group as compared to control. Furthermore, the results showed significant associations between SNPs, SELE: c.109+138A>C (P<0.0001), SELE: c.422-25T>C (P<0.0001), and SELE: c.529+15T>C (P=<0.0001) with vaso-occlusive crises even after Bonferroni correction (corrected P=0.0025). Interpretation & conclusions Significant correlation observed between SELP, SELE, and VCAM-1 levels suggests complex interactions of these markers that may influence disease progression and identify potential therapeutic targets for managing SCD complications. Further studies are warranted to validate these findings in larger cohorts and explore the functional implications of the observed genetic and molecular associations in SCD.

INTRODUCTION This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline. METHODS Data from 9414 individuals from eight Dutch cohorts were included (Ø  age‐range: 57–93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), soluble E‐selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random‐effects meta‐analyses. RESULTS A higher endothelial dysfunction composite score was cross‐sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled β‐range: −0.04, −0.02). We found no association with change in cognition over time. DISCUSSION This comprehensive two‐step, individual participant data (IPD) meta‐analysis showed a small, consistent cross‐sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association. Highlights Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two‐step, individual participant data (IPD) meta‐analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic.

Pulmonary arterial hypertension (PAH) is a life-threatening disease that can be induced by dasatinib, a dual Src and BCR-ABL tyrosine kinase inhibitor that is used to treat chronic myelogenous leukemia (CML). Today, key questions remain regarding the mechanisms involved in the long-term development of dasatinib-induced PAH. Here, we demonstrated that chronic dasatinib therapy causes pulmonary endothelial damage in humans and rodents. We found that dasatinib treatment attenuated hypoxic pulmonary vasoconstriction responses and increased susceptibility to experimental pulmonary hypertension (PH) in rats, but these effects were absent in rats treated with imatinib, another BCR-ABL tyrosine kinase inhibitor. Furthermore, dasatinib treatment induced pulmonary endothelial cell apoptosis in a dose-dependent manner, while imatinib did not. Dasatinib treatment mediated endothelial cell dysfunction via increased production of ROS that was independent of Src family kinases. Consistent with these findings, we observed elevations in markers of endothelial dysfunction and vascular damage in the serum of CML patients who were treated with dasatinib, compared with CML patients treated with imatinib. Taken together, our findings indicate that dasatinib causes pulmonary vascular damage, induction of ER stress, and mitochondrial ROS production, which leads to increased susceptibility to PH development.

Herein, we aimed to identify blood biomarkers that compensate for the poor specificity of D-dimer in the diagnosis of deep vein thrombosis (DVT). S100A8 was identified by conducting protein microarray analysis of blood samples from patients with and without DVT. We used ELISA to detect S100A8, VCAM-1, and ICAM-1 expression levels in human blood and evaluated their correlations. Additionally, we employed human recombinant protein S100A8 to induce human umbilical vein endothelial cells and examined the role of the TLR4/MAPK/VCAM-1 and ICAM-1 signaling axes in the pathogenic mechanism of S100A8. Simultaneously, we constructed a rat model of thrombosis induced by inferior vena cava stenosis and detected levels of S100A8, VCAM-1, and ICAM-1 in the blood of DVT rats using ELISA. The associations of thrombus tissue, neutrophils, and CD68-positive cells with S100A8 and p38MAPK, TLR4, and VCAM-1 expression levels in vein walls were explored. The results revealed that blood S100A8 was significantly upregulated during the acute phase of DVT and activated p38MAPK expression by combining with TLR4 to enhance the expression and secretion of VCAM-1 and ICAM-1, thereby affecting the occurrence and development of DVT. Therefore, S100A8 could be a potential biomarker for early diagnosis and screening of DVT.

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF. Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested. High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort. Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

OBJECTIVE: Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals. RESEARCH DESIGN AND METHODS: Thirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m², A1C 5.1 ± 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 ± 3 years, BMI 24 ± 2 kg/m², A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg⁻¹ · min⁻¹) euglycemic or hypoglycemic (2.9 ± 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study. RESULTS: Insulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes. CONCLUSIONS: In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.