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Background: Increasing evidence suggests an association between schizophrenia and atherosclerosis. We conducted a systematic review and meta-analysis of cell adhesion molecules, critically involved in early atherosclerosis, in schizophrenia., Methods: We searched electronic databases from inception to 11 November 2023 for case-control studies assessing vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, and Down syndrome cell, DSCAM, adhesion molecules, selectins (E-, L-, and P-selectin), integrins, and cadherins in patients with schizophrenia and healthy controls. Risk of bias and certainty of evidence were assessed using the JBI checklist and GRADE, respectively., Results: In 19 eligible studies, there were non-significant between-group differences in the concentrations of cell adhesion molecules, barring higher P-selectin in patients with schizophrenia (standard mean difference, SMD = 2.05, 95 % CI 0.72 to 3.38, p = 0.003; I 2  = 97.2 %, p<0.001; very low certainty of evidence). Limited or no information was available regarding PECAM-1, DSCAM, ESAM, integrins, and cadherins. In meta-regression and subgroup analysis, there were significant associations between the SMD of ICAM-1 and matrix used (plasma or serum) and pharmacological treatment of schizophrenia, and between the SMD of VCAM-1 and pharmacological treatment, but not with other study and patient characteristics., Conclusions: The results of our systematic review and meta-analysis do not support a significant role of immunoglobulin-like adhesion molecules, selectins, integrins, or cadherins in mediating the associations between schizophrenia, atherosclerosis, and cardiovascular disease. Further studies are warranted to investigate these associations in patients with different cardiovascular risk and the effects of antipsychotic treatments on cell adhesion molecules and surrogate markers of atherosclerosis (PROSPERO registration number: CRD42023463916)., Competing Interests: Declaration of competing interest The authors report no financial interests or potential conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The phytochemical investigation of the EtOAc extract from the aerial parts of Isodon eriocalyx afforded seventeen diterpenoids, including eight undescribed compounds. Eriocalyxins H-L have unique structural characteristics featuring a 5-epi-ent-kaurane diterpenoid scaffold with eriocalyxins H-K also possess an unusual 6,11-epoxyspiro-lactone ring while eriocalyxin L, a 1,7:3,20-diepoxy-ent kaurene, features an 1,7-oxygen linkage. The structures of these compounds were elucidated by spectroscopic data interpretation, and the absolute configurations of eriocalyxins H, I, L, and M were confirmed by single-crystal X-ray diffraction. The isolates were screened for their inhibitory activities against VCAM-1 and ICAM-1 at 5 μM. While eriocalyxin O, coetsoidin A and laxiflorin P were found to significantly inhibit both VCAM-1 and ICAM-1, 8 (17),13-ent-labdadien-15 → 16-lactone-19-oic acid displayed evidently inhibitory effect against ICAM-1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Vascular cell adhesion molecule-1 (VCAM-1) plays a regulatory role in inflammatory diseases. However, the exact role of VCAM-1 in diabetic retinopathy (DR) remains unclear, and there is a lack of meta-analyses., Methods: The role of VCAM-1 in DR was screened by database searching. A random effects model was used, and the estimated mean difference was evaluated., Results: Twenty articles were included. The level of VCAM-1 increased significantly in the DR group compared with the control group (SMD: 0.67, 95 % CI: 0.34-1.01, P < 0.0001). VCAM-1 levels correlated with sample size and DR type, method and severity based on subgroup analysis., Conclusion: A high level of VCAM-1 is present in DR patients and is related to the severity of DR. Therefore, VCAM-1 is a potential detection biomarker for DR., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Yellow fever (YF) may cause lesions in different organs. There are no studies regarding the in situ immune response in the human lung and investigating immunopathological aspects in fatal cases can help to better understand the evolution of the infection. Lung tissue samples were collected from 10 fatal cases of human yellow fever and three flavivirus-negative controls who died of other causes and whose lung parenchymal architecture was preserved. In YFV-positive fatal cases, the main histopathological changes included the massive presence of diffuse alveolar inflammatory infiltrate, in addition to congestion and severe hemorrhage. The immunohistochemical analysis of tissues in the lung parenchyma showed significantly higher expression of E-selectin, P-selectin, ICAM-1, VCAM-1 in addition to cytokines such as IL-4, IL-10, IL-13, TNF- α, IFN-γ and TGF-β compared to the negative control. The increase in immunoglobulins ICAM-1 and VCAM-1 results in strengthening of tissue transmigration signaling. E-selectin and P-selectin actively participate in this process of cell migration and formation of the inflammatory infiltrate. IFN-γ and TNF-α participate in the process of cell injury and viral clearance. The cytokines IL-4 and TGF-β, acting in synergism, participate in the process of tissue regeneration and breakdown. The anti-inflammatory cytokines IL-4, IL-10 and IL-13 also act in the reduction of inflammation and tissue repair. Our study indicates that the activation of the endothelium aggravates the inflammatory response by inducing the expression of adhesion molecules and cytokines that contribute to the rolling, recruitment, migration and eliciting of the inflammatory process in the lung parenchyma, contributing to the fatal outcome of the disease., Competing Interests: The authors declare no conflict of interest.

Endothelial inflammation is a crucial event in the initiation of atherosclerosis. Here, we identify Ataxin-10 protein as a novel negative modulator of endothelial activation by suppressing IRF-1 transcription activity. The protein level of Ataxin-10 is relatively higher in human vascular endothelial cells, which can be significantly suppressed by TNF- α in both HUVECs and HLMECs. Overexpression of Ataxin-10 markedly inhibited the mRNA expressions of VCAM-1 and several cytokines including MCP-1, CXCL-1, CCL-5, and TNF- α ; thus, it can also suppress monocyte adhesion to endothelial cells. Accordingly, Ataxin-10 silencing promoted endothelial inflammation. However, Ataxin-10 did not affect the MAPK/NF- κ B signaling pathway stimulated by TNF- α in HUVECs. Using the yeast two-hybrid assay, we found that Ataxin-10 can directly bind to interferon regulatory factor-1 (IRF-1). Upon TNF- α stimulation, Ataxin-10 promoted the cytoplasmic localization of IRF-1, which inhibited the transcription of VCAM-1. Moreover, knockdown of IRF-1 can eliminate the effect of Ataxin-10 on the expression of VCAM-1 in HUVECs induced by TNF- α . Taken together, these results indicate that Ataxin-10 inhibits endothelial cell activation and may serve as a promising therapeutic target for some vascular inflammatory-related diseases such as atherosclerosis., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Yong Li et al.)

Objective: This study examined the impact of submaximal walking training (WT) on local and systemic nitric oxide (NO) bioavailability, inflammation, and oxidative stress in patients with intermittent claudication (IC)., Methods: The study employed a randomised, controlled, parallel group design and was performed in a single centre. Thirty-two men with IC were randomly allocated to two groups: WT (n = 16, two sessions/week, 15 cycles of two minutes walking at an intensity corresponding to the heart rate obtained at the pain threshold interspersed by two minutes of upright rest) and control (CO, n = 16, two sessions/week, 30 minutes of stretching). NO bioavailability (blood NO and muscle nitric oxide synthase [eNOS]), redox homeostasis (catalase [CAT], superoxide dismutase [SOD], lipid peroxidation [LPO] measured in blood and muscle), and inflammation (interleukin-6 [IL-6], C-reactive protein [CRP], tumour necrosis factor α [TNF-α], intercellular adhesion molecules [ICAM], vascular adhesion molecules [VCAM] measured in blood and muscle) were assessed at baseline and after 12 weeks., Results: WT statistically significantly increased blood NO, muscle eNOS, blood SOD and CAT, and muscle SOD and abolished the increase in circulating and muscle LPO observed in the CO group. WT decreased blood CRP, ICAM, and VCAM and muscle IL-6 and CRP and eliminated the increase in blood TNF-α and muscle TNF-α, ICAM and VCAM observed in the CO group., Conclusion: WT at an intensity of pain threshold improved NO bioavailability and decreased systemic and local oxidative stress and inflammation in patients with IC. The proposed WT protocol provides physiological adaptations that may contribute to cardiovascular health in these patients., (Copyright © 2021 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

Background: Emergent large vessel occlusion (ELVO) strokes are devastating ischemic vascular events for which novel treatment options are needed. Using vascular cell adhesion molecule 1 (VCAM1) as a prototype, the objective of this study was to identify proteomic biomarkers and network signaling functions that are potential therapeutic targets for adjuvant treatment for mechanical thrombectomy., Methods: The blood and clot thrombectomy and collaboration (BACTRAC) study is a continually enrolling tissue bank and registry from stroke patients undergoing mechanical thrombectomy. Plasma proteins from intracranial (distal to clot) and systemic arterial blood (carotid) were analyzed by Olink Proteomics for N=42 subjects. Statistical analysis of plasma proteomics used independent sample t tests, correlations, linear regression, and robust regression models to determine network signaling and predictors of clinical outcomes. Data and network analyses were performed using IBM SPSS Statistics, SAS v 9.4, and STRING V11., Results: Increased systemic (p<0.001) and intracranial (p=0.013) levels of VCAM1 were associated with the presence of hypertension. Intracranial VCAM1 was positively correlated to both infarct volume (p=0.032; r=0.34) and edema volume (p=0.026; r=0.35). The %∆ in NIHSS from admittance to discharge was found to be significantly correlated to both systemic (p=0.013; r = -0.409) and intracranial (p=0.011; r = -0.421) VCAM1 levels indicating elevated levels of systemic and intracranial VCAM1 are associated with reduced improvement of stroke severity based on NIHSS from admittance to discharge. STRING-generated analyses identified biologic functional descriptions as well as function-associated proteins from the predictive models of infarct and edema volume., Conclusions: The current study provides novel data on systemic and intracranial VCAM1 in relation to stroke comorbidities, stroke severity, functional outcomes, and the role VCAM1 plays in complex protein-protein signaling pathways. These data will allow future studies to develop predictive biomarkers and proteomic targets for drug development to improve our ability to treat a devastating pathology.

Exosomes contain proteins, lipids, RNA, and DNA that mediate intercellular signaling. Exosomes can contribute to the pathological processes of various diseases, although their roles in ocular diseases are unclear. We aimed to isolate exosomes from tear fluids (TF) of patients with Thyroid eye disease (TED) and analyze the exosomal proteins. TFs were collected from eight patients with TED and eight control subjects. The number of TF exosomes were measured using nanoparticle-tracking analysis. The expression of specific proteins in the purified exosome pellets were analyzed using a Proteome Profiler Array Kit. Cultured normal orbital fibroblasts were incubated with TF exosomes from patients with TED and control subjects, and changes in inflammatory cytokine levels were compared. TF exosomes from TED patients showed more exosomes than the control subjects. The expression levels of exosomal proteins vitamin D-binding (VDB) protein, C-reactive protein (CRP), chitinase 3-like 1 (CHI3L1), matrix metalloproteinase-9 (MMP-9), and vascular adhesion molecule-1 (VCAM-1) were significantly increased in patients with TED, compared to those of controls. Orbital fibroblasts exposed to TF exosomes from patients with TED showed significantly higher levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) production than those treated with control TF exosomes. Specific proteins showed higher expression in exosomes from TED patients, implying that they may play keys roles in TED pathogenesis.

Older adults are at high risk of developing cardiovascular disease (CVD). Pre-clinical studies indicate that resveratrol (RSV), a polyphenol commonly found in grapes and red wine, may help prevent development of CVD. Based on our previous reports where the 300 mg and 1000 mg doses appeared safe and improved psychomotor function in a dose-dependent manner, our hypothesis was that RSV would reduce biomarkers of CVD risk in overweight, but otherwise healthy older adults and that 1000 mg would lower CVD biomarkers >300 mg. This analysis was performed on samples from older participants (65 years and older) who were randomized to a 90 day RSV treatment with 300 mg (n = 10), 1000 mg (n = 9) or placebo (n = 10). We measured levels of CVD risk biomarkers i.e. oxidized low-density lipoprotein (oxLDL), soluble E-selectin-1 (sE-selectin), soluble Intercellular Adhesion Molecule-1 (sICAM-1), Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), total plasminogen activator inhibitor (tPAI-1). Statistical significance was set at p < 0.05. Both sVCAM-1 and tPAI increased significantly more in the 1000 mg vs. 300 mg and placebo groups. Other biomarkers (300 mg vs. 1000 mg vs. placebo: oxLDL, sEselectin-1 and sICAM-1) followed the same trend toward higher levels in the 1000 mg group compared to the 300 mg and placebo groups, without reaching statistical significance. This pilot project suggests that a higher dose of RSV may increase the levels of CVD risk biomarkers in overweight older adults. Given no change in the CVD risk biomarkers in response to a lower dose, future studies should test the effects of different doses of RSV to evaluate potential detrimental effects of higher doses on CVD biomarkers and measures of cardiovascular function in older adults at risk for CVD., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Emerging evidence shows that phytochemicals, the secondary plant metabolites present in a large variety of foods, have the potential ability in reducing the risk of cardiovascular diseases. However, the dosages of phytochemicals in the cellular and animal studies are too high to reach in humans by relevant foods or dietary supplement intake. The aims of this study were to investigate whether and how combined curcumin and luteolin synergistically inhibit tumor necrosis factor-alpha (TNF-α)-induced monocytes adhesion endothelium, a crucial step of the development of endothelial dysfunction, both in human vascular cells and mouse aortic endothelium. Our results show that combined curcumin (1 μM) and luteolin (0.5 μM) synergistically (combination index is 0.60) inhibited TNF-α-induced monocytes adhesion to human EA.hy926 endothelial cells while the individual chemicals did not have such effect at the selected concentrations. We also found that TNF-α-enhanced protein expressions of vascular cell adhesion molecule 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) and nuclear factor (NF)-κB translocation were synergistically reduced by the combined curcumin and luteolin in EA.hy 926 cells while the individual chemical did not have this inhibitory effect. Consistently, 2 weeks dietary intake of combined curcumin (500 mg/kg) and luteolin (500 mg/kg) in C57BL/6 mice synergistically prevented TNF-α-stimulated adhesion of mouse monocytes to aortic endothelium ex vivo as well as the TNF-α-increased aortic protein expression of MCP-1 and VCAM-1. Therefore, combined curcumin and luteolin at physiological concentrations synergistically inhibits TNF-α-induced monocytes adhesion to endothelial cells and expressions of MCP-1 and VCAM-1 via suppressing NF-κB translocation into the nucleus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Bacground and Purpose: Tumor chemotherapy and radiotherapy induces hematopoietic cell damage, resulting in thrombocytopenia. Conventional platelet transfusion strategies or drug therapies are used to treat thrombocytopenia. However, these therapies may result in a several side effects, including heightened susceptibility to infectious diseases and the formation of anti-TPO-antibodies. Therefore, a more secure strategy should be explored to overcome and compensate for the shortcomings of conventional strategies., Experimental Approach: Effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were determined by analysing mRNA expression, promoter activity, protein expression. The molecular mechanisms of the effects of rhTyrRS(Y341A) on the expression of VCAM-1 on the surface of HUVECs were investigated by determining the activation of VEGF-R II/NF-κB pathway., Key Results: Our results provide evidence that rhTyrRS (Y341A) activates NF-κB to upregulate VCAM-1 in a VEGF-R II/NF-κB pathway-dependent, resulting in megakaryocyte adhering to PVECs to induce platelet production., Conclusions: This study suggested that rhTyrRS (Y341A), a novel human tyrosyl-tRNA synthetase mutation, increased the platelet count under normal conditions. Further more, we confirmed that an NF-κB-mediated mechanism is involved in rhTyrRS (Y341A)-induced thrombopoiesis, which involves its interaction with VEGF-R II., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells. Endothelial markers, ICAM-1 and VCAM-1, are implicated in atherosclerosis and associated with cardiovascular risk. Chronic kidney disease (CKD) patients have endothelial dysfunction and high levels of endothelial derived MPs. Vitamin D treatment has been reported to ameliorate endothelial function in CKD patients. We aimed to examine cell specific MP profiles and concentrations of MPs expressing the atherosclerotic markers ICAM-1 and VCAM-1 after treatment with paricalcitol in patients with CKD stage 3-4., Methods: Sub-study of the previously reported SOLID trial where 36 patients were randomly assigned to placebo, 1 or 2 μg paricalcitol, for 12 weeks. MPs were measured by flow cytometry after labelling with antibodies against endothelial (CD62E), platelet (CD62P, CD41, CD154) leukocyte (CD45) and vascular (CD54, CD106) markers., Results: Patients had a mean age of 65 years with a mean eGFR of 40 mL/min/1.73m 2 . Concentrations of ICAM-1 positive MPs were significantly reduced by treatment (repeated measures ANOVA p = 0.04). Repeated measures MANOVA of concentrations of endothelial, platelet and leukocyte MPs showed sustained levels in the 2 μg treatment group (p = 0.85) but a decline in the 1 μg (p = 0.04) and placebo groups (p = 0.005)., Conclusions: Treatment with paricalcitol reduces concentrations of ICAM-1 positive MPs. This is accompanied by sustained concentrations of all cell specific MPs in the 2 μg group, and decreasing concentrations in the other groups, possibly due to a more healthy and reactive endothelium with paricalcitol treatment.

This study investigated the capacity of an anthocyanin-rich fraction (ACN-RF) from blueberry, single anthocyanins (cyanidin, delphinidin and malvidin-3-glucoside; Cy, Dp and Mv-3-glc) and related metabolites (protocatechuic, gallic and syringic acid; PrA, GA and SA) to resolve an inflammation-driven adhesion of monocytes (THP-1) on endothelial cell (HUVECs) and secretion of cell adhesion molecules E-selectin and vascular cell adhesion molecule 1 (VCAM-1). The adhesion of THP-1 to HUVECs was induced by tumour necrosis factor α (TNF-α, 100 ng mL -1 ). Subsequently, ACN-RF, single ACNs and metabolites (from 0.01 to 10 μg mL -1 ) were incubated for 24 h. The adhesion was measured in a fluorescence spectrophotometer. E-selectin and VCAM-1 were quantified by ELISA. No toxicological effects were observed for the compounds and the doses tested. ACN-RF and Mv-3-glc reducedTHP-1 adhesion at all the concentrations with the maximum effect at 10 μg/ml (-60.2% for ACNs and-33.9% for Mv-3-glc). Cy-3-glc decreased the adhesion by about 41.8% at 10 μg mL -1 , while PrA and GA reduced the adhesion of THP-1 to HUVECs both at 1 and at 10 μg mL -1 (-29.5% and -44.3% for PrA, respectively, and -18.0%and -59.3% for GA, respectively). At the same concentrations a significant reduction of E-selectin, but notVCAM-1 levels, was documented. No effect was observed following Dp-3-glc and SA supplementation. Overall, ACNs and metabolites seem to resolve, in a dose-dependent manner, the inflammation-driven adhesion of THP-1 to HUVECs by decreasing E-selectin concentrations. Interestingly, Mv-3-glc was active at physiologically relevant concentrations., (Copyright © 2019. Published by Elsevier B.V.)

Chronic inflammation and proliferation play important roles in atherosclerosis progression. This study aimed to identify the mechanisms responsible for the anti-inflammatory and antiproliferative effects of melatonin on tumor necrosis factor-α (TNF-α)- and platelet-derived growth factor-BB (PDGF-BB)-treated rat aortic smooth muscle cells (RASMCs). Melatonin reduced TNF-α-induced RASMC inflammation by decreasing vascular cell adhesion molecule-1 (VCAM-1) expression and nuclear factor-kappa B (NF-κB) P65 activity by inhibiting P38 mitogen-activated protein kinase phosphorylation ( P < 0.05). Additionally, melatonin inhibited PDGF-BB-induced RASMC proliferation by reducing mammalian target of rapamycin (mTOR) phosphorylation ( P < 0.05) but not migration in vitro. Melatonin also reduced TNF-α- and PDGF-BB-induced reactive oxygen species (ROS) production ( P < 0.05). Furthermore, melatonin treatment (prevention and treatment groups) significantly repressed high cholesterol diet-stimulated atherosclerotic lesions in vivo (19.59 ± 4.11%, 20.28 ± 5.63%, 32.26 ± 12.06%, respectively, P < 0.05). Taken together, the present study demonstrated that melatonin attenuated TNF-α-induced RASMC inflammation and PDGF-BB-induced RASMC proliferation in cells and reduced atherosclerotic lesions in mice. These results showed that melatonin has anti-inflammatory and antiproliferative properties and may be a novel therapeutic target in atherosclerosis.

Inflammatory cytokine, adipokine and adhesion molecules are known to play a key role in pathogenesis of diabetic kidney disease (DKD). In this study, our aim was to investigate the role of fetuin-A in relation with pro-inflammatory cytokines (IL-6, IL-18), adipokines (adiponectin, leptin), chemokine (MCP-1), and adhesion molecules (ICAM-1, VCAM-1) in control and DKD subjects. We recruited a total of 224 type 2 diabetic (T2D) subjects. The control subjects were T2D with a normal albumin excrete (albumin-to-creatinine ratio-ACR ≤ 30 mg/g creatinine) and estimated glomerular filtration rate (eGFR) ≥ 60 (ml/min/1.73 m 2 ), while cases were T2D subjects with albumin excrete (ACR ≥ 30 mg/g creatinine) and eGFR ≤ 60 (ml/min/1.73 m 2 ). FBS, HbA1c, lipid profile (TC, LDL, HDL, triglyceride), ALT, AST, GGT, serum creatinine, BMI, blood pressure was evaluated in all the study subjects. Randox evidence biochip analyzer was used for measuring inflammatory cytokines, adipokines, and adhesion molecules by chemiluminescent assay. Serum fetuin-A and IL-18 were measured by ELISA kits. Serum fetuin-A levels were significantly decreased in DKD cases compare to control group [456.8 (299.2-649.0) µg/ml versus 670.6 (573.0-726.1) µg/ml; p < 0.001)]. Serum fetuin-A levels correlates significantly with IL-6, IL-18, TNF-α, PAI-1, leptin, resistin and ACR (p < 0.001). This study concludes that serum fetuin-A and pro-inflammatory markers (IL-18, IL-6, IL-1α and TNF-α) might play an important role in the pathophysiology and inflammatory process of DKD.

Background: Microvascular free flap reconstruction has become a standard technique in head and neck reconstructive surgery. Pre-operative radiotherapy is associated with a higher incidence of free flap malperfusion and the need for operative revision. Irradiated vessels present characteristic histomorphological and structural changes. Alterations in endothelial cells of irradiated arteries remain incompletely investigated especially with regard to long-term changes in endothelial dysfunction supporting an intraluminal pro-thrombotic and pro-inflammatory milieu., Methods: Endothelial expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E‑ and P‑selectin, endothelial NO-synthase (eNOS), thrombomodulin and plasminogen activator inhibitor-1 (PAI-1) in irradiated and non-irradiated arteries was analysed using immunohistochemistry and Remmele scale grading. The average radiation dose was 58.7 ± 7.0 Gy; the time interval between end of radiation and tissue sampling was 106.0 ± 86.8 months., Results: Endothelial expression of ICAM-1, VCAM-1, E‑ and P‑selectin as well as PAI-1 was significantly increased in previously irradiated arteries compared with non-irradiated controls, whereas thrombomodulin and eNOS expression did not show any differences. However, when comparing non-irradiated free flap arteries with irradiated arteries from the head and neck area in respective individuals, eNOS expression was significantly lower in irradiated vessels whereas ICAM-1, VCAM-1, E‑/p-Selectin and PAI-1 showed significantly higher expression levels., Conclusion: There is ongoing endothelial dysfunction in terms of increased expression of pro-thrombotic and pro-inflammatory markers in irradiated arteries even years after radiotherapy. Treating this endothelial dysfunction might reduce the complication rates associated with microvascular free flap reconstructions in irradiated patients.

Background: Molecular imaging of carotid plaque vulnerability to atheroembolic events is likely to lead to improvements in selection of patients for carotid endarterectomy (CEA). The aims of this study were to assess the relative value of endothelial inflammatory markers for this application and to develop molecular ultrasound contrast agents for their imaging., Methods: Human CEA specimens were obtained prospectively from asymptomatic (30) and symptomatic (30) patients. Plaques were assessed by semiquantitative immunohistochemistry for vascular cell adhesion molecule 1 (VCAM-1), lectin-like oxidized low-density lipoprotein receptor 1, P-selectin, and von Willebrand factor. Established small peptide ligands to each of these targets were then synthesized and covalently conjugated to the surface of lipid-shelled microbubble ultrasound contrast agents, which were then evaluated in a flow chamber for binding kinetics to activated human aortic endothelial cells under variable shear conditions., Results: Expression of VCAM-1 on the endothelium of CEA specimens from symptomatic patients was 2.4-fold greater than that from asymptomatic patients (P < .01). Expression was not significantly different between groups for P-selectin (P = .43), von Willebrand factor (P = .59), or lectin-like oxidized low-density lipoprotein receptor 1 (P = .99). Although most plaques from asymptomatic patients displayed low VCAM-1 expression, approximately one in five expressed high VCAM-1 similar to plaques from symptomatic patients. In vitro flow chamber experiments demonstrated that VCAM-1-targeted microbubbles bind cells that express VCAM-1, even under high-shear conditions that approximate those found in human carotid arteries, whereas binding efficiency was lower for the other agents., Conclusions: VCAM-1 displays significantly higher expression on high-risk (symptomatic) vs low-risk (asymptomatic) carotid plaques. Ultrasound contrast agents bearing ligands for VCAM-1 can sustain high-shear attachment and may be useful for identifying patients in whom more aggressive treatment is warranted., (Copyright © 2018 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Oxidised low-density lipoprotein (ox-LDL) is a pro-atherogenic molecule, which induces inflammatory response and contributes to the pathogenesis of vascular dysfunction to atherosclerosis. The aim of the present study was to explore the anti-inflammatory effect of a novel bioavailable formulation of curcumin as 'curcumagalactomannosides' (CGM) against ox-LDL-induced inflammatory responses in human peripheral blood mononuclear cells (hPBMCs). Curcumagalactomannosides was made from natural curcumin using the soluble dietary fibre (galactomannans) derived from fenugreek seeds (Trigonella foenumgracum) and the hPBMCs were isolated from healthy human volunteers. The cells were cultured in collagen-coated plates at 37 °C and grouped as Group I (Control), Group II (ox-LDL treated) and Group III (ox-LDL + CGM treated). Further analysis of inflammatory markers, reactive oxygen species and mRNA expression levels indicated significantly increased expressions of iNOS, TNF-α, IL-6 and VCAM-1 in ox-LDL-treated group along with the nuclear translocation of NF-κB. Other inflammatory markers such as LOX, PGE2, total COX and lipid peroxidation level were also found to be significantly (p < 0.05) increased upon ox-LDL treatment. The treatment with CGM on the other hand was found to down-regulate and reverse the ox-LDL-induced alterations indicating its potential anti-inflammatory effect on hPBMCs via. NF-κB signalling pathway.

Hostile conflict in marriage can increase risks for disease and mortality. Physiological synchrony between partners-e.g., the linkage between their autonomic fluctuations-appears to capture engagement, or an inability to disengage from an exchange, and thus may amplify the health risks of noxious interactions such as marital conflict. Prior work has not examined the unique health correlates of this physiological signature. To test associations between couples' heart rate variability (HRV) synchrony during conflict and inflammation, 43 married couples engaged in a marital problem discussion while wearing heart monitors and provided four blood samples; they repeated this protocol at a second visit. When couples' moment-to-moment HRV changes tracked more closely together during conflict, they had higher levels of three inflammatory markers (i.e., IL-6, stimulated TNF-α, and sVCAM-1) across the day. Stronger HRV synchrony during conflict also predicted greater negative affect reactivity. Synchrony varied within couples, and was related to situational factors rather than global relationship traits. These data highlight partners' HRV linkage during conflict as a novel social-biological pathway to inflammation-related disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To investigate whether exogenous agmatine inhibits lipopolysaccharide (LPS)-induced activation and dysfunction of human umbilical vein endothelial cells (HUVECs) by modulating nuclear factor-κB (NF-κB) and MAPK signal pathways and the production of reactive oxygen species (ROS)., Methods: Cultured HUVECs were treated with agmatine at the optimized concentration of 1.0 mmolγL, LPS (10 µgγmL), and LPS + agmatine, with or without pretreatment with the inhibitors of NF-κB (PDTC), p38 (SB203580), and ERK (PD98059) for 1 h. The levels of soluble vascular cell adhesion molecule 1 (VCAM-1), soluble intercellular adhesion molecule 1 (sICAM-1), soluble E-selectin and monocyte chemoattractant protein 1 (MCP-1) in the supernatant were determined using ELISA, and their mRNA expressions, along with heme oxygenase-1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO-1), were assessed using real-time PCR. ROS production in the cells was determined using 2, 7-dichlorofluoresce in diacetate (DCFH-DA) as the fluorescence probe. The protein expressions of VCAM-1, ICAM-1, p65, phospho-p65 (p-p65), IκBα, p-IκBα, ERK, p-ERK, p38, p-p38, JNK, and p-JNK were detected using Western blotting., Results: LPS stimulation for 6 and 24 h significantly increased the levels of sVCAM-1, sICAM-1, sE-selectin and MCP-1 in the supernatant, intracellular ROS production, and the mRNA expressions of these molecules (P<0.05). Intervention with 1 mmolγL agmatine, similar with pretreatment with p38, ERK and NF-κB inhibitors, obviously inhibited such effects of LPS in HUVECs (P<0.05). Agmatine significantly up-regulated the mRNA expression of HO-1 (P<0.05), inhibited LPS-induced phosphorylation of p38, ERK, nuclear p65 and cytoplasmic IκBα, and up-regulated the protein expression of cytoplasmic IκBα., Conclusion: Agmatine inhibits LPS-induced activation and dysfunction of HUVECs by modulating NF-κB and MAPK signal pathways to down-regulate the expressions of adhesion molecules and chemokines and by up-regulating the expression of HO-1 to reduce ROS production.

Vascular cell adhesion molecule 1 (VCAM-1) is overexpressed in varieties of cancers. This study aimed to evaluate the application of a single chain variable fragment (scFv) of anti-VCAM-1 antibody labeled with 99m Tc as a possible imaging agent in several tumors. VCAM-1 scFv was labeled with 99m Tc using succinimidyl 6-hydrazinium nicotinate hydrochloride, and 99m Tc-HYNIC-VCAM-1 scFv was successfully synthesized with a high radiolabeling yield. VCAM-1 expression was evaluated in six cell lines by immunofluorescence staining. In vitro binding assays showed different binding affinities of 99m Tc-HYNIC-VCAM-1 scFv in different tumor cell lines, with high uptake in B16F10 melanoma and HT1080 fibrosarcoma cells, which was consistent with immunofluorescence staining results. In vivo SPECT planar imaging demonstrated that B16F10 and HT1080 tumors could be clearly visualized. Less intense uptake was observed in human SKOV3.ip ovarian tumor, and weak uptake was observed in human A375m melanoma, MDA-MB-231 breast cancer, and 786-O renal tumors. These findings were confirmed by biodistribution and immunofluorescence studies. High uptake by B16F10 tumors was inhibited by excess unlabeled VCAM-1 scFv . 99m Tc-HYNIC-VCAM-1 scFv , which selectively binds to VCAM-1, can provide a qualitative and semiquantitative method for noninvasive evaluation of VCAM-1 expression by tumors.

The presence of neopterin in gingival crevicular fluid (GCF) is a marker for local and acute immune activation, and the presence of vascular cell adhesion molecule (VCAM-1) in GCF is accepted as a marker for chronic vascular inflammation., Objectives: This study aimed to evaluate effects of periodontal treatment on GCF levels of neopterin and VCAM-1 in patients with chronic periodontitis (CP) with acute myocardial infarction (AMI) compared with systemically healthy CP patients., Material and Methods: Sixty subjects (20 CP patients with AMI, 20 healthy CP patients, and 20 healthy controls) were included. GCF samples were analyzed at baseline and after 3 and 6 months, and the probing pocket depth (PD), clinical attachment level (CAL), bleeding on probing, gingival (GI) and plaque (PI) indices were recorded. We determined neopterin and VCAM-1 levels (concentration and total amount) using enzyme-linked immunosorbent assay (ELISA). No significant differences were seen between the AMI+CP and CP groups for PI, GI, GCF levels of neopterin and VCAM-1 at baseline., Results: The number of teeth with 5 mm≤CAL<7 mm and CAL≥7 mm were significantly increased in the AMI+CP group at baseline. There were no significant differences between the AMI+CP and CP for PI, CAL, GCF volumes, and the AMI+CP group had the highest clinical improvement in the number of teeth with 5 mm≤CAL<7 mm at the sixth month. There were significant positive correlations between clinical periodontal inflammation and the presence of neopterin and VCAM-1 in GCF prior to and following periodontal treatment, and between the GCF volume and clinical parameters., Conclusions: Data suggest that the total amount and concentration of neopterin and VCAM-1 in GCF seemed to be closely associated with periodontal disease severity in CP patients with AMI. Moreover, the results of our study demonstrate that the past periodontal status is potentially correlated between groups, with similar periodontal disease severity.

Mesenchymal stem/stromal cells (MSCs) derived from placental tissue show great therapeutic potential and have been used in medical treatment, but the similarity and differences between the MSCs derived from various parts of the placenta remain unclear. In this study, we compared MSCs derived from different perinatal tissues, including the umbilical cord (UC), amniotic membrane (AM), chorionic plate (CP) and decidua parietalis (DP). Using human leukocyte antigen (HLA) typing and karyotype analysis, we found that the first three cell types were derived from the foetus, while the MSCs from the decidua parietalis were derived from the maternal portion of the placental tissue. Our results indicate that both foetal and maternal MSCs share a similar phenotype and multi-lineage differentiation potential, but foetal MSCs show a significantly higher expansion capacity than do maternal MSCs. Furthermore, MSCs from all sources showed significant differences in the levels of several paracrine factors.

The objective of this study was to develop and validate the method based on micro-liquid chromatography-tandem mass spectrometry (microLC/MS-MRM) for simultaneous determination of adiponectin (ADN), von Willebrand factor (vWF), soluble form of vascular cell adhesion molecule 1 (sVCAM-1), soluble form of intercellular adhesion molecule 1 (sICAM-1) and syndecan-1 (SDC-1) in mouse plasma. The calibration range was established from 2.5pmol/mL to 5000pmol/mL for ADN; 5pmol/mL to 5000pmol/mL for vWF; 0.375pmol/mL to 250pmol/mL for sVCAM-1 and sICAM-1; and 0.25pmol/mL to 250pmol/mL for SDC-1. The method was applied to measure the plasma concentration of selected proteins in mice fed high-fat diet (HFD), and revealed the pro-thrombotic status by increased concentration of vWF (1.31±0.17 nmol/mL (Control) vs 1.98±0.09 nmol/mL (HFD), p <0.05) and the dysregulation of adipose tissue metabolism by decreased concentration of ADN (0.62±0.08 nmol/mL (Control) vs 0.37±0.06 nmol/mL (HFD), p <0.05). In conclusion, the microLC/MS-MRM-based method allows for reliable measurements of selected protein biomarkers of endothelial dysfunction in mouse plasma., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Anthocyanins, the naturally occurring pigments responsible for most red to blue colours of flowers, fruits and vegetables, have also attracted interest because of their potential health effects. With the aim of contributing to major insights into their structure-activity relationship (SAR), we have evaluated the radical scavenging and biological activities of selected purified anthocyanin samples (PASs) from various anthocyanin-rich plant materials: two fruits (mahaleb cherry and blackcurrant) and two vegetables (black carrot and "Sun Black" tomato), differing in anthocyanin content (ranging from 4.9 to 38.5 mg/g DW) and molecular structure of the predominant anthocyanins. PASs from the abovementioned plant materials have been evaluated for their antioxidant capacity using Trolox Equivalent Antioxidant Capacity (TEAC) and Oxygen Radical Absorbance Capacity (ORAC) assays. In human endothelial cells, we analysed the anti-inflammatory activity of different PASs by measuring their effects on the expression of endothelial adhesion molecules VCAM-1 and ICAM-1. We demonstrated that all the different PASs showed biological activity. They exhibited antioxidant capacity of different magnitude, higher for samples containing non-acylated anthocyanins (typical for fruits) compared to samples containing more complex anthocyanins acylated with cinnamic acid derivatives (typical for vegetables), even though this order was slightly reversed when ORAC assay values were expressed on a molar basis. Concordantly, PASs containing non-acylated anthocyanins reduced the expression of endothelial inflammatory antigens more than samples with aromatic acylated anthocyanins, suggesting the potential beneficial effect of structurally diverse anthocyanins in cardiovascular protection., Competing Interests: The authors declare no conflict of interest.

This chapter describes the methodologies which may be used in evaluating in vitro endothelial cell dysfunction in preeclampsia.

The present study aimed to identify whether FK506 suppresses hypoxia‑induced inflammation and protects tight junction function via the calcineurin‑nuclear factor of activated T‑cells 1 (CaN‑NFATc1) signaling pathway in mouse retinal microvascular endothelial cells (mRMECs). The mRMECs were treated with FK506 at different concentrations following the induction of hypoxia. Trans‑epithelial electrical resistance (TEER) and cell permeability were examined to measure the integrity of the tight junctions. The concentrations of inflammatory cytokines were measured using reverse transcription‑quantitative polymerase chain reaction analysis and enzyme‑linked immunosorbent assays. The protein expression levels of zonula occludens‑1 (ZO‑1) and nuclear factor of activated T‑cell 1 (NFATc1) were identified using immunofluorescent microscopy and western blot analysis. The TEER value was decreased following hypoxia, but increased following treatment with FK506 (1 and 10 µM) for 24 and 48 h. The protein expression of ZO‑1 was also increased following FK506 treatment for 24 h at 1 and 10 µM. By contrast, following treatment with FK506 (1 and 10 µM) for 24 and 48 h, the elevated cell permeability in the hypoxia group was significantly downregulated. Similarly, the concentrations of inflammatory cytokines, including cyclooxygenase‑2, inducible nitric oxide synthase, monocyte chemoattractant protein‑1, interleukin‑6, intercellular adhesion molecule‑1 and vascular cell adhesion molecule‑1, were downregulated following treatment with FK506 for 24 h at 1 and 10 µM. Following treatment with FK506, the level of total NFATc1 was downregulated and the level of phosphorylated NFATc1 was upregulated. Taken together, FK506 suppressed injury to the tight junctions and downregulated the expression of inflammatory cytokines in hypoxia‑induced mRMECs via the CaN‑NFATc1 signaling pathway. This suggests a potentially effective therapy for hypoxia‑induced retinal microangiopathy.

Brassinin, a phytoalexin firstly identified as a constituent of Chinese cabbage, has been demonstrated to exhibit antiproliferative effects on various cancer cell lines, by reducing reactive oxygen species (ROS) production via regulation of the antioxidant pathway. The present study aimed to explore the protective effects of brassinin in TNF‑α‑induced vascular inflammation in human umbilical vein endothelial cells (HUVECs). Pretreatment with brassinin significantly inhibited adhesion of U937 cells to TNF‑α‑induced HUVECs in a dose‑dependent manner. Brassinin treatment decreased the expression levels of cell adhesion molecules, including intracellular adhesion molecule‑1 (ICAM‑1), vascular cell adhesion molecule‑1 (VCAM‑1), and endothelial‑selectin (E‑selectin) following stimulation with TNF‑α in HUVECs. In addition, pretreatment with brassinin decreased the protein expression levels of nuclear factor (NF)‑κB p65 in the nucleus, suggesting that brassinin inhibited NF‑κB p65 nuclear translocation. Brassinin treatment also markedly decreased the mRNA expression levels of interleukin‑8 in a dose‑dependent manner. Finally, brassinin pretreatment significantly decreased TNF‑α‑induced intracellular reactive oxygen species (ROS) production in HUVECs compared with control. The present results therefore suggest that brassinin may serve as a potential therapeutic agent for atherosclerosis.

Scope: The physiological relevance of contemporary cell culture studies is often perplexing, given the use of unmetabolized phytochemicals at supraphysiological concentrations. We investigated the activity of physiologically relevant anthocyanin metabolite signatures, derived from a previous pharmacokinetics study of 500 mg 13 C 5 -cyanidin-3-glucoside in eight healthy participants, on soluble vascular adhesion molecule-1 (VCAM-1) and interleukin-6 (IL-6) in human endothelial cells., Methods and Results: Signatures of peak metabolites (previously identified at 1, 6, and 24 h post-bolus) were reproduced using pure standards and effects were investigated across concentrations ten-fold lower and higher than observed mean (<5 μM) serum levels. Tumor necrosis factor-α (TNF-α)-stimulated VCAM-1 was reduced in response to all treatments, with maximal effects observed for the 6 and 24 h profiles. Profiles tested at ten-fold below mean serum concentrations (0.19-0.44 μM) remained active. IL-6 was reduced in response to 1, 6, and 24 h profiles, with maximal effects observed for 6 h and 24 h profiles at concentrations above 2 μM. Protein responses were reflected by reductions in VCAM-1 and IL-6 mRNA, however there was no effect on phosphorylated NFκB-p65 expression., Conclusion: Signatures of anthocyanin metabolites following dietary consumption reduce VCAM-1 and IL-6 production, providing evidence of physiologically relevant biological activity., (© 2017 The Authors. Molecular Nutrition & Food Research published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)

Background: Varicose vein (VV) disease is a frequently occurring pathology of the lower extremities. Although the pathogenesis of varicosity development is not clearly defined, the final common pathway leading to chronic venous insufficiency is the development of venous hypertension, which is associated with severe changes in the venous wall. The aim of this study was to clarify the histological and immunohistochemical changes in great saphenous veins (GSVs) in chronic venous insufficiency., Methods: A histopathological study was conducted on 20 patients with VVs (4 males, 16 females) and 4 (1 male, 3 females) patients undergoing distal bypass surgery. Tissues were processed for histological routine straining and immunohistochemical studies of vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, protein gene product 9.5 (PGP 9.5), and collagen type IV, laminin, and fibronectin. A semiquantitative evaluation method was used., Results: Compared with the normal SV, VV sections showed the damaged endothelium areas, significant disorganization of the smooth muscle bundles, and highest density of the vasa vasorum in the tunica media and tunica adventitia, as well as sclerotic blood vessels and neoangiogenesis in almost all specimens. Immunohistochemistry study showed statistically significant difference between the VVs and the control group of several parameters, such as PGP 9.5 positive structures (P < 0.05; 1-tailed significance) and laminin positive structures in subendothelial layer of VVs (P < 0.05; 1-tailed significance). There is also the tendency in increasing of VEGF expression and decreasing of collagen IV structures. Our study did not show statistically significant difference in VEGF, ICAM-1, and VCAM-1 positive structures between varicose and normal veins; however, it could be explained by the limitations of the study., Conclusions: Varicose GSVs represent nonhomogeneous integrity of the basement membrane, smooth muscle disorganization, and active neoangiogenesis, suggesting remodulation of blood vessels. Changes in the appearance of PGP 9.5-containing innervation, laminin, and collagen IV in tunica intima confirm the remodulation of damaged blood vessels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Atherosclerosis is a complex inflammatory disease associated with elevated levels of atherogenic molecules for leukocyte recruitment. Sinigrin (2-propenylglucosinolate) is found mainly in broccoli, brussels sprouts, and black mustard seeds. Recently, sinigrin has received attention for its role in disease prevention and health promotion. In this study, we examined the effect of sinigrin on development of atherosclerosis in ApoE -/- mice and the expression of adhesion molecules in vascular smooth muscle cells (VSMCs). The serum concentrations of lactate dehydrogenase (LDH), triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL), calcium (Ca 2+ ), and pro-inflammatory cytokines were reduced by sinigrin treatment in ApoE -/- mice. In addition, oral administration of sinigrin attenuated the mRNA expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), C-C motif chemokine ligand 2 (CCL2), and CCL5 on aorta tissues and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), liver X receptor (LXR), sterol regulatory element-binding protein-2 (SREBP-2), and low density lipoprotein receptor (LDLR) on liver tissues in ApoE -/- mice. To provide a potential mechanism underlying the action of sinigrin, we evaluated the in vitro effect of sinigrin on the expression of the VCAM-1 in TNF-α-induced VSMCs. The increased expression of VCAM-1 by TNF-α stimulation was significantly suppressed by the treatment of sinigrin (1-100 μg/ml) and sinigrin inhibited the nuclear translocation of NF-κB and the phosphorylation of p38 MAPK and JNK pathways, suggesting that sinigrin decreases the TNF-α-stimulated VCAM-1 expression through the suppression of NF-κB and MAP kinases signaling pathways. Overall, sinigrin has the potential to be used in reducing the risks of atherosclerosis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aims of the present study were to determine the effects of heparin-derived oligosaccharides (HDOs) on vascular intimal hyperplasia (IH) in balloon-injured carotid artery and to elucidate the underlying mechanisms of action. An animal model was established by rubbing the endothelia within the common carotid artery (CCA) in male rabbits. The rabbits were fed a high-cholesterol diet. Arterial IH was determined by histopathological changes to the CCA. Serum lipids were detected using an automated biochemical analysis. Expressions of mRNAs for vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1), scavenger receptor class B type I (SR-BI), and ATP-binding cassette transporter A1 (ABCA-1) were analyzed using reverse transcription polymerase chain reaction assays. Expressions of VEGF, VCAM-1, MCP-1, SR-BI and ABCA-1 proteins were analyzed by Western blotting. Enzyme-linked immunosorbent assays were used to quantify expression levels of VEGF and bFGF. Our results showed that administration of HDO significantly inhibited CCA histopathology and restenosis induced by balloon injury. The treatment with HDOs significantly decreased the mRNA and protein expression levels of VEGF, bFGF, VCAM-1, MCP-1, and SR-BI in the arterial wall; however, ABCA-1 expression level was elevated. HDO treatment led to a reduction in serum lipids (total cholesterol, triglycerides, high-density and low-density lipoproteins). Our results from the rabbit model indicated that HDOs could ameliorate IH and underlying mechanism might involve VEGF, bFGF, VCAM-1, MCP-1, SR-BI, and ABCA-1., (Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.)

Staphylococcus aureus causes many infections, such as skin and soft tissue, pneumonia, osteomyelitis, and infective endocarditis (IE). IE is an endovascular infection of native and prosthetic valves and the lining of the heart; it is characterized by the formation of cauliflower-like "vegetations" composed of fibrin, platelets, other host factors, bacteria, and bacterial products. β-Toxin is an S. aureus virulence factor that contributes to the microorganism's ability to cause IE. This cytolysin has two enzymatic activities: sphingomyelinase (SMase) and biofilm ligase. Although both activities have functions in a rabbit model of IE, the mechanism(s) by which β-toxin directly affects human cells and is involved in the infectious process has not been elucidated. Here, we compared the in vitro effects of purified recombinant wild-type β-toxin, SMase-deficient β-toxin (H289N), and biofilm ligase-deficient β-toxin (H162A and/or D163A) on human aortic endothelial cells (HAECs) and platelets. β-Toxin was cytotoxic to HAECs and inhibited the production of interleukin 8 (IL-8) from these cells by both SMase and biofilm ligase activities. β-Toxin altered HAEC surface expression of CD40 and vascular cell adhesion molecule 1 (VCAM-1). HAECs treated with β-toxin displayed granular membrane morphology not seen in treatment with the SMase-deficient mutant. The altered morphology resulted in two possibly separable activities, cell rounding and redistribution of cell membranes into granules, which were not the result of endosome production from the Golgi apparatus or lysosomes. β-Toxin directly aggregated rabbit platelets via SMase activity. IMPORTANCE Each year there are up to 100,000 cases of infective endocarditis (IE) in the United States. S. aureus is the most common pathogen in patients with health care-associated IE and the leading cause of community-associated IE in the developed world. Multiple clonal group strains as defined by the Centers for Disease Control and Prevention, particularly USA200 and other clones encoding β-toxin, are highly associated with IE. Considering the strong association and established contribution of β-toxin in animal models of IE, determining how β-toxin directly affects human cell types, including endothelial cells and platelets, is important. In this study, we demonstrate that β-toxin functions to modulate endothelial cells and platelets by both toxin sphingomyelinase and biofilm ligase activities. Our data suggest that these activities modulate inflammation and increase infection severity., (Copyright © 2017 Herrera et al.)

Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Glucosamine is a possible cause of vascular endothelial injury in the initial stages of atherosclerosis, through endoplasmic reticulum (ER) stress resulting in fatty streaks in the vascular wall. Quercetin is an anti‑diabetic and cardiovascular protective agent that has previously been demonstrated to reduce ER stress in human umbilical vein endothelial cells (HUVECs). The present study aimed to investigate whether quercetin prevents glucosamine‑induced apoptosis and inflammation via ER stress pathway in HUVECs. The effect of quercetin on cell viability, apoptosis, and protein expression levels of inflammatory cytokines and ER stress markers was investigated in glucosamine‑supplemented HUVECs. Quercetin was demonstrated to protect against glucosamine‑induced apoptosis, improved cell viability, and inhibited expression of pro‑inflammatory factors and endothelin‑1. Quercetin treatment also reduced the expression levels of glucose‑regulated protein 78, phosphorylated protein kinase‑like ER kinase, phosphorylated c‑Jun N‑terminal kinase and C/EBP homologous protein. In conclusion, quercetin may have auxiliary therapeutic potential against glucosamine‑induced cell apoptosis and inflammation, which may be partially due to alleviation of ER stress.

Leprosy is a chronic infectious disease that requires better understanding since it continues to be a significant health problem in many parts of the world. Leprosy reactions are acute inflammatory episodes regarded as the central etiology of nerve damage in the disease. The activation of endothelium is a relevant phenomenon to be investigated in leprosy reactions. The present study evaluated the expression of endothelial factors in skin lesions and serum samples of leprosy patients. Immunohistochemical analysis of skin samples and serum measurements of VCAM-1, VEGF, tissue factor and thrombomodulin were performed in 77 leprosy patients and 12 controls. We observed significant increase of VCAM-1 circulating levels in non-reactional leprosy (p = 0.0009). The immunostaining of VEGF and tissue factor was higher in endothelium of non-reactional leprosy (p = 0.02 for both) than healthy controls. Patients with type 1 reaction presented increased thrombomodulin serum levels, compared with non-reactional leprosy (p = 0.02). In type 2 reaction, no significant modifications were observed for the endothelial factors investigated. The anti-inflammatory and antimicrobial activities of the endotfhelial factors may play key-roles in the pathogenesis of leprosy and should be enrolled in studies focusing on alternative targets to improve the management of leprosy and its reactions.

p-cresyl sulfate (PCS) is a protein-bound uremic toxin retained in the blood of patients with chronic kidney disease (CKD) As atherosclerosis is a primary cardiovascular complication for patients with CKD, the aim of the present study was to investigate the mechanisms underlying the aggravation of atherosclerosis by PCS. In addition, the effect of atorvastatin was assessed in reversing the effects of PCS. PCS was revealed to promote the initiation and progression of atherosclerosis. Following treatment with atorvastatin, apolipoprotein E knockout mice demonstrated a reduction in PCS‑induced atherogenesis and plaque vulnerability. In addition, atorvastatin decreased the protein expression levels of vascular cell adhesion molecule‑1 and intercellular cell adhesion molecule‑1, and the interaction between leukocytes and endothelia. The plasma lipid profiles of mice were not significantly affected by gavage of low‑dose atorvastatin. The results of the present study indicate that PCS promotes plaque growth and instability by enhancing leukocyte‑endothelium interaction, and that these effects may be attenuated by atorvastatin treatment.

Background: Traditional fermented cheese whey (TFCW), containing probiotics, has been used both as a dairy food with ethnic flavor and a medicine for cardiovascular disease, especially regulating blood lipid among Kazakh. We therefore investigated anti-atherosclerotic effects of TFCW in atherosclerotic rabbits and identified lactic acid bacteria (LAB) and yeasts in TFCW., Methods: Atherosclerotic rabbits were induced by administration of atherosclerotic diet for 12 weeks and divided randomly into three groups and treated for 4 weeks with Simvastatin (20 mg/kg) or TFCW (25 mg/kg) and (50 mg/kg). In addition, a normal control group and an atherosclerotic group were used for comparison. All drugs were intragastrical administered once daily 10 mL/kg for 4 weeks. Body weight (BW), lipid profiles, C-reactive protein (CRP), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) were tested and theromatous plaques and the number of foam cells and infiltrating fibroblast cells in the thoracic aorta endothelium was evaluated by hematoxylin and eosin stainin. LAB and yeasts were isolated and purified by conventional techniques and identified using morphological and biochemical properties as well as gene sequences analysis., Results: After 4 weeks of treatment, high and low dose TFCW decreased serum TC, TG, LDLC, CRP, VCAM-1 and ICAM-1 (P < 0.05) compared to atherosclerotic group, and increased HDL-C (P < 0.05) compared to normal controls. Histological analysis showed TFCW reduced VCAM-1 expression and formation of atheromatous plaques on the aortic endothelium of atherosclerotic rabbits., Conclusion: Seven classes of LBA from two different genera including Lactobacillus brevis, Lactobacillus kefianofaciens, Lactobacillus helveticus, Lactobacillus Casei, Lactobacillus plantarum, Lactobacillus kefiri and Lactococcus lactic as well as 2 classes of yeasts from two different genera including Saccharomyces unisporus and Issatchenkia orientalis were isolated and identified from TFCW. In summary, TFCW, containing 7 classes of LBA and 2 classes of yeasts, has significant anti-atherosclerotic potential in atherosclerotic rabbits and may modulate lipid metabolism and protect aorta in the atherosclerotic condition, which might be related to various probiotics acting through reducing the CRP, VCAM-1 and ICAM-1 levels and protecting the aortic endothelium.

Objectives/hypothesis: Clinically, inflammatory polyps are found in the middle turbinate (MT) in patients with chronic rhinosinusitis (CRS) but not in the inferior turbinate (IT). The purpose of this study was to investigate differences in protein expression between IT and MT tissue in patients with CRS., Study Design: Prospective cohort., Methods: Pathologic specimens obtained from patients with CRS undergoing functional endoscopic sinus surgery with IT reduction were evaluated by immunohistochemical analysis of inflammatory markers cysteinyl leukotriene 1 receptor (CysLT1R), toll-like receptor 2 (TLR2), and vascular cell adhesion molecule 1 (VCAM1). Protein expression was quantified with nuance multispectral analysis and results compared between MT and IT tissue., Results: The total expression of VCAM1 and CysLT1R was decreased in the IT compared to the MT. There was no difference in total TLR2 expression between the IT and MT. When comparing patients with eosinophilic CRS to noneosinophilic CRS (neCRS), there was decreased expression of VCAM1 in the IT of patients with neCRS. When comparing patients with nasal polyposis to those without polyps, there was decreased expression of VCAM1 in the IT of patients without polyps., Conclusions: There is a difference in protein receptor expression of VCAM1 and CysLT1R in MT compared to IT tissue. Although the leukotrienes are a well-known target for treatment of chronic sinusitis, this is the first study demonstrating an upregulation of VCAM1 expression in the MT and could be a potential future target for the treatment of CRS., Level of Evidence: NA Laryngoscope, 126:E179-E183, 2016., (© 2015 The American Laryngological, Rhinological and Otological Society, Inc.)

Unlabelled: Rheumatoid arthritis (RA) is a chronic inflammatory disease with autoimmune pathogenesis. It affects mainly small joints (of the hands and feet) and has many systemic manifestations. Studying biomarkers in rheumatology intensely appeared from the need to understand the mechanisms underlying some rheumatic diseases. Discovering new biomarkers with key roles in various stages of evolution, remains a subject of interest for RA. Currently, according to the EULAR 2010 criteria, the rheumatoid factor (RF) and the anti-cyclic citrullinated peptide (anti-CCP) are used for RA diagnosis. Since 2010, new biomarkers were discovered and proved useful in identifying RA in early stages. For a more rigorous management of these cases, one of the key steps in the evolution of patients with RA is to recognize and distinguish the more aggressive forms of the disease through prognostic biomarkers. "Treat to target" recommends the use of 3 composite scores to monitor the evolution of the disease: disease activity score (DAS 28), simple disease activity index (SDAI) and clinical disease activity index (CDAI), but, a new test was developed which better monitors the disease activity. The introduction of biological therapies has revolutionized the treatment of RA. Despite these advances, 20-40% of the patients are declared nonresponders to at least one of the therapies. The patient exposure to the potential side effects and high costs requires the discovery of a biomarker that could identify those who can benefit from the pretreatment of a certain therapy., Abbreviations: RA = rheumatoid arthritis, RF = rheumatoid factor, DAS 28 = disease activity score, SDAI = simple disease activity index, CDAI = clinical disease activity index, ACR = American College of Rheumatology, EULAR = European League against Rheumatism, anti-CCP = antibodies against cyclic citrullinated proteins, anti-MCV = mutated citrullinated vimentin antibodies, anti-CarP = antibodies against carbamylated proteins, MBDA = multi biomarker disease activity test, COMP = cartilage oligomeric matrix protein, ADAs = antidrug antibodies, CDA = clinical disease activity index, SDAI = simplified disease activity index, ESR = erythrocyte sedimentation rate, CRP = C reactive protein, SAA = serum amyloid A, VCAM-1 = vascular cell adhesion molecule-1, IL-6 = interleukin-6, TNF-R1 = tumor necrosis factor receptor 1, EGF = epidermal growth factor, VEGF-A = vascular endothelial growth factor A.

Introduction: Pulmonary vascular endothelial activation has been implicated in acute respiratory distress syndrome (ARDS), yet little is known about the presence and role of endothelial activation markers in the alveolar space in ARDS. We hypothesized that endothelial activation biomarkers would be differentially expressed in bronchoalveolar lavage fluid from patients with ARDS compared with healthy volunteers, and that biomarker concentrations would be associated with ARDS severity., Methods: We performed a cross-sectional analysis of data from 26 intubated patients with ARDS undergoing evaluation for clinically suspected ventilator-associated pneumonia and five healthy volunteers. Patients underwent bronchoalveolar lavage a median of five days after intubation. Healthy volunteers also underwent bronchoalveolar lavage. Endothelial activation biomarkers (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble endothelial selectin [sESEL], angiopoietin-1 [Ang-1] and angiopoietin-2 [Ang-2]) were measured in bronchoalveolar lavage fluid. Clinically suspected ventilator-associated pneumonia was confirmed with microbiologic culture data., Results: Patients with ARDS had significantly higher median sVCAM-1 concentrations in the bronchoalveolar lavage fluid compared with healthy volunteers (985 vs 119 pg/mL, p = 0.03). Additionally, there was a trend toward greater bronchoalveolar lavage fluid sVCAM-1 concentrations among patients with moderate/severe compared to mild ARDS (1395 vs 209 pg/mL, p = 0.06). We did not detect significant differences in bronchoalveolar lavage fluid levels of sESEL, Ang-1 or Ang-2 between patients with ARDS and healthy volunteers. Median bronchoalveolar lavage fluid biomarker levels did not differ between patients with and without microbiologically-confirmed ventilator-associated pneumonia., Conclusions: sVCAM-1 concentrations were significantly higher in the bronchoalveolar lavage fluid of patients with ARDS compared to healthy controls, and tended to be higher in moderate/severe ARDS compared to mild ARDS. Our findings add to the growing evidence supporting the concept that endothelial activation plays an important mechanistic role in the pathogenesis of ARDS. Further studies are necessary to characterize the role and/or clinical significance of sVCAM-1 and other endothelial activation markers present in the alveolar space in ARDS.

Objective: To evaluate whether levels of interleukin 6 (IL-6), interleukin 8 (IL-8), and vascular cell adhesion molecule-1 (VCAM-1) in women with premature rupture of membranes (PROM) differ from those in women without PROM., Methods: An observational study of full-term primiparous pregnant women with PROM (PROM group) and those undergoing elective cesarean delivery (control group) was performed at a center in Yangzhou, China, between January 2003 and July 2006. IL-6, IL-8, and VCAM-1 levels were measured in maternal blood, cord blood, and amniotic fluid. A pathologic examination of fetal membranes was conducted., Results: The IL-6, IL-8, and VCAM-1 levels in maternal serum, amniotic fluid, and cord blood were significantly higher in the PROM group (n=58) than in the control group (n=38; P<0.05 for all comparisons). In the PROM group, the levels increased with duration of membrane rupture (P<0.05 for all). Women with chorioamnionitis had significantly higher levels than women without chorioamnionitis (P<0.05 for all), and women with PROM whose newborns had low Apgar score (≤7) had higher levels than those whose newborns had a higher Apgar score (P<0.05 for all)., Conclusion: Combined measurements of IL-6, IL-8, and VCAM-1 might help to improve early diagnosis of PROM and chorioamnionitis, and to evaluate the prognosis of newborns., (Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

The aim of this study was to explore the intracellular mechanisms underlying the cardiovascular toxicity of air particulate matter (PM) with an aerodynamic diameter of less than 2.5 µm (PM2.5) in a human umbilical vein cell line, EA.hy926. We found that PM2.5 exposure triggered reactive oxygen species (ROS) generation, resulting in a significant decrease in cell viability. Data from Western blots showed that PM2.5 induced phosphorylation of Jun N-terminal kinase (JNK), extracellular signal regulatory kinase (ERK), p38 mitogen-activated protein kinase (MAPK) and protein kinase B (AKT), and activation of nuclear factor kappa B (NF-κB). We further observed a significant increase in expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in a time- and dose-dependent manner. Moreover, the adhesion of monocytic THP-1 cells to EA.hy926 cells was greatly enhanced in the presence of PM2.5 . However, N-acetylcysteine (NAC), a scavenger of ROS, prevented the increase of ROS generation, attenuated the phosphorylation of the above kinases, and decreased the NF-κB activation as well as the expression of ICAM-1 and VCAM-1. Furthermore, ERK inhibitor (U0126), AKT inhibitor (LY294002) and NF-κB inhibitor (BAY11-7082) significantly down-regulated PM2.5 -induced ICAM-1 and VCAM-1 expression as well as adhesion of THP-1 cells, but not JNK inhibitor (SP600125) and p38 MAPK inhibitor (SB203580), indicating that ERK/AKT/NF-κB is involved in the signaling pathway that leads to PM2.5 -induced ICAM-1 and VCAM-1 expression. These findings suggest PM2.5 -induced ROS may function as signaling molecules triggering ICAM-1 and VCAM-1 expressions through activating the ERK/AKT/NF-κB-dependent pathway, and further promoting monocyte adhesion to endothelial cells., (Copyright © 2015 John Wiley & Sons, Ltd.)

Delayed wound healing is one of the major complications in diabetes and is characterized by chronic proinflammatory response, and abnormalities in angiogenesis and collagen deposition. Sirtuin family proteins regulate numerous pathophysiological processes, including those involved in promotion of longevity, DNA repair, glycolysis and inflammation. However, the role of sirtuin 6 (SIRT6), a NAD+-dependent nuclear deacetylase, in wound healing specifically under diabetic condition remains unclear. To analyse the role of SIRT6 in cutaneous wound healing, paired 6-mm stented wound was created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and nonsense siRNA served as controls). Wound time to closure was assessed by digital planimetry, and wounds were harvested for histology, immunohistochemistry and Western blotting. SIRT6-siRNA-treated diabetic wound showed impaired healing, which was associated with reduced capillary density (CD31-staining vessels) when compared to control treatment. Interestingly, SIRT6 deficiency decreased vascular endothelial growth factor expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor-κB (NF-κB) activation resulting in increased expression of proinflammatory markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α and interleukin-1β) and increased oxidative stress. Collectively, our findings demonstrate that loss of SIRT6 in cutaneous wound aggravates proinflammatory response by increasing NF-κB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that the activation of SIRT6 signalling might be a potential therapeutic approach for promoting wound healing in diabetics., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Anaplasma phagocytophilum (Ap) is a tick-borne pathogen, which can cause granulocytic anaplasmosis in humans and animals. In vivo this obligate intracellular pathogen is primarily located in circulating mature granulocytes, but it also infects endothelial cells. In order to study the interaction between Ap-infected endothelial cells and human granulocytes under conditions similar to those found naturally in the infected host, an in vitro model that mimics physiological flow conditions in the microvasculature was established. Cell-to-cell interactions were then visualized by microscopy, which showed that granulocytes adhered strongly to Ap-infected endothelial cells at a shear stress of 0.5 dyne/cm(2). In addition, Ap-transmission assays under flow conditions showed that the bacteria transferred from infected endothelial cells to circulating granulocytes and were able to establish infection in constantly moving granulocytes. Cell surface analysis showed that Ap induced up-regulation of the cell adhesion molecules ICAM-1 and VCAM-1 on infected endothelial cells in a dose-dependent manner. Furthermore, IL-8 secretion by endothelial cells indicated that the presence of Ap induced a pro-inflammatory response. In summary, the results of this study suggest that endothelial cells of the microvasculature (1) provide an excellent site for Ap dissemination to peripheral blood granulocytes under flow conditions and therefore may play a crucial role in the development of persistent infection, and (2) are stimulated by Ap to express surface molecules and cytokines that may lead to inflammatory responses at the site of the infection.

Purpose: JAK/STAT is an evolutionarily conserved pathway and very important for second messenger system. This pathway is important in malignant transformation and accumulated evidence indicates that this pathway is involved in tumorigenesis and progression of several cancers. It was possible to assume that activation of JAK/STAT pathway is associated with increase in the expressions of ICAM/1 and VCAM-1. In this study we hypothesized that when cells were maintained as spheroids or monolayers, the structure of cancer stem cells (CSCs) could show differentiation when compared with non-CSCs., Methods: DU-145 human prostate cancer cells were cultured using the Ege University molecular embryology laboratory medium supplemented wıth 10% fetal bovine serum. Clusters of differentiation 133 (CD133)(+high)/CD44(+high) prostate CSCs were isolated from the DU145 cell line by using BD FACSAria. CD133//CD44+ CSCs were cultured until confluent with 3% noble agar. The expression of these proteins in CSCs and non-CSCs was analyzed by immunohistochemistry., Results: Different expression profiles were observed in the conventional two-dimensional (2D) and three-dimensional (3D) experimental model system when CSCs and non-CSCs were compared. Human prostate CSCs exhibited intense ICAM-1 and VCAM-1 immunoreaction when compared with non-CSCs. These findings were supported by the fact that VCAM-1 on the surface of cancer cells binds to its counterreceptor, the α4β1 integrin (also known as very-late antigen, VLA-4), on metastasis-associated macrophages, triggering VCAM-1-mediated activation of the phosphoinositide 3-kinase growth and survival pathway in cancer cells., Conclusions: The results of this study showed that changes in JAK/STAT pathway are related with adhesion molecules and could affect cancer progression.

Introduction: The aim of this study was to investigate the in situ pulmonary endothelial activation in lung lesions of granulomatosis with polyangiitis (GPA) and systemic sclerosis (SScl)., Methods: We examined the endothelial expression of ICAM-1, VCAM-1, and E-selectin using immunohistochemistry on formalin-fixed, paraffin-embedded sections of lung lesions of GPA, interstitial lung disease associated with SScl and controls., Results: A significantly enhanced expression of ICAM-1 and E-selectin was observed in GPA and SScl pulmonary endothelium compared to controls. VCAM-1 was more pronouncedly expressed in GPA compared to SScl., Conclusion: These observations are an evidence of in situ pulmonary vascular endothelial activation in lesions of GPA and SScl, adding information to the pathogenic knowledge of both diseases.