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Background There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Introduction Endothelial dysfunction occurs at the very beginning of hypertension. The primary goal of our study was to determine plasmatic levels of multiple endothelial substances in otherwise healthy patients with primary hypertension and compare them to healthy individuals. Secondary goals were to determine the change in NOx levels after initiation of treatment and to compare the NOx levels in patients with established resistant hypertension. Materials and methods 87 consecutive patients were enrolled. In the exploratory cohort of 22 healthy and 28 hypertensive individuals, plasmatic levels of big endotelin-1, asymmetric dimethylarginin, osteopontin, oxidized LDL, 3-nitro-L-tyrosine, growth/differentiation factor 15, intercellular adhesion molecule, vascular cell adhesion molecule, tumor necrosis factor-α, vascular endothelial growth factor, interleukins -1β, -6 and nitric oxide levels (NO, expressed as NOx) were determined. The remaining 27 individuals were used as a validation cohort. Ten patients with established resistant hypertension were enrolled from our Hypertension Clinic. Results There was a statistically significant difference in NOx levels between healthy controls and hypertensive patients/resistant hypertensive patients: 45.164 µmol/L ± 48.627 vs 17.763 µmol/L ± 10.333 (P=0.00004)/14.36 µmol/L ± 7.194 (P=0.00007). Conclusion We identified a decrease in total NOx plasmatic levels in otherwise healthy patients with primary hypertension that was more profound in patients with resistant hypertension. Plasmatic levels of other determined endothelial substances did not differ among the groups. However, due to the significant variability of plasmatic NOx levels even in healthy controls and many factors that affect it, we cannot recommend it to be used to assess endothelial function routinely.

Agricultural workplaces consist of multiple airborne contaminants and inhalation exposures induce respiratory effects in workers. Endotoxin (LPS) and glyphosate are two common airborne contaminants in agricultural environments. We have previously shown that exposure to a combination of LPS and glyphosate synergistically modulates immune reactions as compared to individual exposures. The immunopathogenesis of acute and chronic exposure to complex agricultural exposures including LPS and glyphosate is not known; therefore, we further investigated the lung cellular inflammatory differences in mice exposed to either a combination, or individual, LPS, and glyphosate for 1 day, 5 days, and 10 days. Exposure to a combination of LPS and glyphosate resulted in greater cellular inflammatory effects in lungs as compared to individual exposures to LPS or glyphosate. Repeated exposures to the combination of LPS and glyphosate resulted in robust infiltration of inflammatory cells in the perivascular, peribronchiolar, and alveolar regions, and increases of alveolar septal thicknesses and perivascular spaces in the lungs with intense intercellular adhesion molecule (ICAM) - 1 staining in the perivascular region, but minimal staining in the pulmonary artery endothelium.

Proinflammatory mediators such as interleukin (IL)-1β cause retinal pigment epithelium (RPE) inflammation, which is related to visual deterioration, including age-related macular degeneration and diabetic retinopathy. Oleuropein is a polyphenol compound that shows potent anti-inflammatory, antioxidant, and anti-cancer activities, but its effects on IL-1β-induced inflammation have not been examined in the adult RPE cell line ARPE-19. Here, we assessed the ability of oleuropein to attenuate this inflammation in ARPE-19 cells. IL-1β induced secretion of the inflammatory cytokines IL-6, monocyte chemoattractant protein-1 (MCP)-1, and soluble intercellular adhesion molecule (sICAM)-1. As measured by enzyme-linked immunosorbent assay, oleuropein significantly inhibited levels of all three proteins and led to decreased monocyte adhesiveness to ARPE-19 cells. To clarify the underlying anti-inflammatory mechanisms, we used western blots to evaluate the effect of oleuropein on inactivation of the nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. The results showed that oleuropein significantly decreased levels of the inflammatory mediator cyclooxygenase-2 and increased anti-inflammatory protein HO-1 expression. We next examined if the anti-inflammatory activity of oleuropein arises via inactivated NF-κB. We found that suppressing phosphorylation of the JNK1/2 and p38 MAPK signaling pathways inhibited IL-6, MCP-1, and sICAM-1 secretion, implicating these pathways and NF-κB suppression in the effects of oleuropein. These results indicate that oleuropein shows potential for the prevention and treatment of inflammatory diseases of the retina.

In vivo genome editing meets numerous challenges including efficiency and safety. Here we describe an efficient in vivo genome editing method of delivering CRISPR-Cas9 into vascular endothelial cells with adeno-associated viruses (AAVs). In this system, expression of SpCas9 is driven by a specific endothelial promoter of intercellular adhesion molecule 2 (pICAM2) to restrict this foreign enzyme in vascular endothelial cells, which can be efficiently infected by AAV1. We exemplify this approach by editing VEGFR2 in retinal vascular endothelial cells in a mouse model of oxygen-induced retinopathy, and expect that this simplified protocol can be expanded to other researches on editing endothelial genome in vivo.

Background: The purpose of this study was to investigate the effect of four weeks of endurance training (EXE) on inflammatory markers predicting atherosclerosis by gender. Materials and Methods: Forty male and female Wistar rats were divided into 4 groups including male myocardial infarction (MI), male MI + EXE, female MI, and female MI+EXE. After the induction of MI with two intraperitoneal injections of isoproterenol (150 mg/kg), the training groups performed an (EXE) program for 4 weeks on a treadmill (speed 18 m/min, 30 minutes, 5 sessions per week). The animals were sacrificed 24 hours after the last training session. Finally, data were analyzed using a two-way analysis of variance and Fishers’ least significant difference post hoc test. Results: Despite the clinical difference in the training groups, the intercellular adhesion molecule (ICAM, 3.74±0.61 ng/mL) was more significant in the female MI + EXE group (P=0.009). Conclusion: In general, despite observing clinical changes, there were no significant vascular cell adhesion molecules and osteoprotegerin (OPG) after EXE in cardiovascular inflammatory factors in male and female rats following MI. Nevertheless, gender had a significant independent effect on the ICAM index. The results showed that ICAM values were higher in female rats in comparison with male rats.

Objective To assess biomarkers between symptomatic and asymptomatic patients, and to construct a classification and regression tree (CART) algorithm for their discrimination. Patients and Methods 136 patients were enrolled. They were symptomatic (high risk) (N = 82, stenosis degree ≥ 50%, proven to be responsible for ischemic stroke the last six months) and asymptomatic (low risk) (N = 54, stenosis degree ≤ 50%). Levels of fibrinogen, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), soluble intercellular adhesion molecule (SiCAM), soluble vascular cell adhesion molecule (SvCAM), adiponectin and insulin were measured on a Luminex 3D platform and their differences were evaluated; subsequently, a CART model was created and evaluated. Results All measured biomarkers, except adiponectin, had significantly higher levels in symptomatic patients. The constructed CART prognostic model had 97.6% discrimination accuracy on symptomatic patients and 79.6% on asymptomatic, while the overall accuracy was 90.4%. Moreover, the population was split into training and test sets for CART validation. Conclusion Significant differences were found in the biomarkers between symptomatic and asymptomatic patients. The CART model proved to be a simple decision-making algorithm linked with risk probabilities and provided evidence to identify and, therefore, treat patients being at high risk for cardiovascular disease.

BACKGROUND Endothelial dysfunction might contribute to the development of leptospiral pulmonary hemorrhage syndrome (LPHS). HYPOTHESIS Serum concentrations of markers of endothelial activation and dysfunction are higher in dogs with leptospirosis and correlate with the occurrence of LPHS and a higher case fatality rate. ANIMALS Clinically healthy dogs (n = 31; 10/31 dogs confirmed healthy based on no detected abnormalities on blood work), dogs with leptospirosis with LPHS (n = 17) and without LPHS (n = 15), dogs with acute kidney injury not due to leptospirosis (AKI-nL, n = 34). METHODS Observational study. Serum concentrations of soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), and angiopoietin-2 (Ang-2) at admission were compared between groups. Correlations with outcome and the accuracy to predict LPHS were examined. RESULTS Soluble intercellular adhesion molecule (sICAM-1), VEGF, and Ang-2 concentrations were higher in dogs with AKI-nL (sICAM-1 34.7 ng/mL, interquartile range [IQR] = 24.4-75.5; VEGF 43.1 pg/mL, IQR = 12.3-79.2; Ang-2 8.5 ng/mL, IQR = 6.2-12.3), leptospirosis without LPHS (sICAM-1 45.1 ng/mL, IQR = 30.6-59.0; VEGF 32.4 pg/mL, IQR = 12.5-62.6; Ang-2 9.6 ng/mL, IQR = 6.9-19.3), and LPHS (sICAM-1 69.7 ng/mL, IQR = 42.1-89.1; VEGF 51.8 pg/mL, IQR = 26.3-96.7; Ang-2 8.0 ng/mL, IQR = 5.6-12.2) compared to controls (P

Increased circulating intercellular adhesion molecule 3 (ICAM3) is associated with a risk of acute ischemic stroke. This study aims to investigate the association of serum levels of ICAM3 with the severity and short-term outcomes of ischemic stroke. This study recruited 152 stroke patients with supratentorial cerebral infarcts and 133 healthy controls. Patients were followed up for 2 weeks since admission for observation of functional outcomes. Serum ICAM3 concentrations at baseline were determined by Elisa. Serum ICAM3 concentrations were higher in stroke patients than in healthy controls. Serum concentrations of ICAM3 were not associated with stroke severity at baseline, as reflected by NIH Stroke Scale (NIHSS) and infarction volume. However, serum ICAM3 levels were positively associated with mRS scores at 2 weeks since admission. Furthermore, regression analyses found that increased serum ICAM3 levels were associated with worse short-term functional outcomes of stroke. These findings imply that circulating ICAM3 might be a potential short-term prognostic biomarker for acute ischemic stroke.

Background: Electronic cigarettes (e-cigarettes) generally have a more favorable toxicant profile than conventional cigarettes; however, limited information exists for women of reproductive age (WRA). Our aim was to compare biomarkers of toxicant exposure, inflammation, and oxidative stress among WRA who self-report exclusive e-cigarette use, exclusive cigarette smoking, or never tobacco use (controls). Methods: Multivariable linear regression models were used to compare the geometric means of urinary biomarkers of toxicant exposure and their metabolites, serum markers of inflammation [highly sensitive C-reactive protein, soluble intercellular adhesion molecule (sICAM), interleukin 6, fibrinogen], and a measurement of oxidative stress [prostaglandin F2a-8-isoprostane (F2PG2a)] among WRA from the Population Assessment of Tobacco and Health survey. Results: E-cigarette users had higher levels of lead, tobacco-specific nitrosamines, nicotine metabolites, and some volatile organic compounds (VOCs) than controls. Except for cadmium and lead, e-cigarette users had lower levels of the analyzed urinary toxicant biomarkers compared with cigarette smokers. Cigarette smokers had higher levels of all the biomarkers of toxicant exposure than controls. There were no significant differences in the levels of markers of inflammation and oxidative stress between e-cigarette users and controls. E-cigarette users and controls had lower levels of sICAM and F2PG2a than cigarette smokers. Conclusion: WRA who use e-cigarettes had lower levels of some of the evaluated urinary biomarkers of toxicant exposure and serum biomarkers of inflammation and oxidative stress than those who smoke cigarettes, but higher lead, nicotine metabolites, and some VOCs than controls, which can increase health risks.

Aims: To assess the anti-atherosclerotic effects of Myricetin (pharmaceutical) in human THP-1 macrophages following IFN-γ or MCP-1 stimulation. Study Design: The protective effects of myricetin against atherosclerosis was evaluated using the humanTHP-1 macrophages and studying the following parameters namely, cell viability, cell proliferation, cell migration, inflammation related gene expression and cholesterol efflux in vitro. Place and Duration of Study: THP-1 cell line: Department of biochemistry (faculty of science), Cell Culture Unit, Experimental Biochemistry Unit (King Fahad Medical Research Centre), King Abdul Aziz University, between September 2019 and September 2020. Methodology: The THP-1 cell lines were differentiated into macrophages by incubation with PMA (160 nM) for 24 hours. The viability percentage was determined using Pierce LDH cytotoxicity assay kit, the percentage change in macrophages proliferation was evaluated by crystal violet dye, the RNA was extracted then the cDNA was synthesized and the quantitative real time polymerase chain reaction (qRT-PCR) was done for inflammation-related genes, ICAM-1 and MCP-1. The percentage of monocyte migration and cholesterol efflux were also calculated. Results: Cytotoxicity assays demonstrated no significant toxicity with myricetin at 25μM and 50 μM concentrations on THP-1 macrophages. The quantitative real-time RT-PCR (qRT-PCR) demonstrated a significant increase in interferon gamma (IFN-γ) mediated expression of both intercellular adhesion molecule (ICAM-1) and monocyte chemo-attractant protein-1 (MCP-1) by 2.1 and 7.1 fold respectively, compared to the control. Treatment with myricetin (25 μM and 50 μM) significantly inhibited the IFN-γ induced overexpression of ICAM-1 by 42.86% & 71.34% and MCP-1 by 53.52% & 87.32% respectively. Myricetin (25 μM) significantly reduced the migration of monocytes by 33.66% compared to MCP-1. The cholesterol efflux from THP-1 macrophages treated with myricetin was significantly increased by 47% and 57% in the absence and presence of IFN-γ, respectively compared to the control. Conclusion: Myricetin has anti-inflammatory effects and supports cholesterol efflux, which can help in prevention of atherosclerosis. Furthermore, myricetin did not exhibit any cytotoxic effects and therefore is a safe phytochemical which can complement conventional therapeutics.

Background: The efficacy of allergen-specific immunotherapy (AIT) is mainly depended on the tolerogenic immune responses elicited. Properly conjugated nano-vaccine has the advantages of both specific targeting and continuous and on-demand release of allergen. Objectives: The aim of this study is to investigate the effects of a dendritic cells (DCs)-targeting nano-vaccine for AIT. Methods: The nano-vaccine was produced by coupling polylactic-co-glycolic acid (PLGA)-encapsulated ovalbumin (OVA) with mannan. Allergen capture, human monocytes-derived DCs (hMoDCs) activation, and T cells responses were assessed by flow cytometry, confocal microscopy, quantitative real-time PCR, ELISA, and Cytometric Bead Array. Balb/c mice were immunized with the nano-vaccines, and the immune responses were analyzed. Results: OVA-PLGA nanoparticle (NP) displayed favorable safety profile. OVA-mannan-PLGA NP was captured more efficiently by hMoDCs than OVA-PLGA NP, which was mediated mainly through DC-specific intercellular adhesion molecule 3-grabbing nonintegrin. A tolerogenic phenotype of hMoDCs was induced by OVA-mannan-PLGA NP, but not OVA-PLGA NP, and increased number of regulatory T (Treg) cells was generated subsequently in in vitro coculture. Immunization of Balb/c mice with OVA-mannan-PLGA NP resulted in lower serum level of OVA-specific immunoglobulins and less production of pro-inflammatory cytokines in splenocytes culture than the mice immunized with OVA-PLAG NP, PLGA NP, or OVA, while the number of splenic Treg cells was higher in OVA-mannan-PLGA group than in other groups. Moreover, preimmunization with OVA-mannan-PLGA NP significantly inhibited the Th2 immune response induced by OVA sensitization. Conclusions: The biocompatible PLGA-encapsulated OVA coupling with mannan has augmented ability for tolerance induction and could be developed as a novel vaccine for AIT.

The present study aimed to compare decidual protein levels and gene expression levels of chemokines between patients with early pregnancy loss and those with voluntary abortion. A total of 15 patients between 6 and 10 gestational weeks, who presented with negative fetal heartbeat to the obstetrics and gynecology outpatient clinics of Gaziosmanpasa Hospital (Yeni Yuzyil University, Istanbul, Turkey) and who had no additional systemic disease and 13 patients between 6 and 10 gestational weeks, who presented with positive fetal heartbeat for voluntary abortion were included in the present study. CX3CL1, CCL17, CXCR4, chemokine ligand 12 (CXCL12) and intercellular adhesion molecule (ICAM)5 protein expression levels were determined by ELISA and gene expression levels by reverse transcription-quantitative PCR in fresh materials recovered after therapeutic curettage. CX3CL1, CCL17, CXCR4, CXCL12 protein levels were significantly higher and ICAM protein level was significantly lower in pregrant women with missed abortion compared with those with voluntary abortion. While the amount of increase in mean CX3CL1, CCL17, CXCR4 and CXCL12 gene expression levels in the tissues of pregnant women with missed abortion was statistically higher than the pregnant women who underwent voluntary abortion, the amount of increase in ICAM5 gene expression was found to be lower (P

Sepsis is a serious clinical condition characterized by systemic inflammation. The long noncoding RNA (lncRNA) highly upregulated in liver cancer (HULC) was validated to partake in the development of sepsis. The present study aimed to investigate the potential mechanism of HULC in lipopolysaccharide (LPS)-induced sepsis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis was employed to examine the expression of HULC, microRNA (miR)-128-3p, Rac family small GTPase 1 (RAC1) and pro-inflammatory factors [IL-6, TNF-α, intercellular adhesion molecule (ICAM1) and vascular cell adhesion molecule (VCAM1)] in the serum of patients with sepsis or LPS-induced human dermal microvascular endothelial cells (HMEC-1). Flow cytometry and western blot assays were performed to detect cell apoptosis. The targeted relationship among HULC, miR-128-3p and RAC1 was confirmed by a dual-luciferase reporter assay, RNA binding protein immunoprecipitation (RIP) assay and RNA pull-down assay. HULC and RAC1 were found to be upregulated, and miR-128-3p was downregulated in the serum of patients with sepsis and LPS-stimulated HMEC-1 cells. LPS promoted apoptosis and inflammation, which were decreased by silencing of HULC. HULC targeted miR-128-3p and negatively regulated its expression. HULC knockdown protected HMEC-1 cells from LPS-induced injury by upregulating miR-128-3p. RAC1 was a target of miR-128-3p, and gain of RAC1 also relieved the silencing of HULC-mediated suppressive effects on apoptosis and inflammation in LPS-stimulated HMEC-1 cells. In conclusion, HULC knockdown partially reversed LPS-induced sepsis via the regulation of miR-128-3p/RAC1 axis.

Pathophysiological events that modulate the progression of structural changes in osteoarthritis (OA) include monocyte adhesion and infiltration, and synovial inflammation. In particular, the adhesion protein intercellular adhesion molecule type 1 (ICAM-1) promotes monocyte recruitment into the synovial tissue. Visfatin is an adipocyte hormone that promotes the release of inflammatory cytokines during OA progression. We report that visfatin enhances ICAM-1 expression in human OA synovial fibroblasts (OASFs) and facilitates the adhesion of monocytes with OASFs. AMPK and p38 inhibitors, as well as their respective siRNAs, attenuated the effects of visfatin upon ICAM-1 synthesis and monocyte adhesion. We also describe how miR-320a negatively regulates visfatin-induced promotion of ICAM-1 expression and monocyte adhesion. We detail how visfatin affects ICAM-1 expression and monocyte adhesion with OASFs by inhibiting miR-320a synthesis via the AMPK and p38 signaling pathways.

One of the main pathogenetic mechanisms combining chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) is a persistence systemic inflammation leading to the formation of endothelial dysfunction (ED), which serves as an independent predictor of the adverse prognosis of most cardiovascular diseases (CVD), while the treatment of patients with COPD in combination with AH requires the inclusion of drugs that have a beneficial effect on these pathological conditions. Prolonged-release indapamide has a number of pleiotropic effects, but most studies to study its effect on the state of endothelium and the intensity of systemic inflammation were conducted in patients with AH without associated bronchial obstructive diseases. The works carried out in conditions of comorbidity with COPD and according to the data of which the influence of diuretic drugs on the markers of systemic inflammation and ET in patients would be evaluated, were not found out, in this connection the present research was initiated and carried out. The aim of the study was to evaluate the dynamics of markers of systemic inflammation and ET in the inclusion of diuretics in the complex therapy of patients with COPD in combination with BA. Materials. Patients (n = 65: 50 men and 15 women) with stage I – IV COPD suffering from arterial hypertension (AH) I – III with initially elevated levels of systemic inflammation markers and ET, in whom the antihypertensive therapy performed was not effective enough, were included in the study. Results. The results of the research on estimation of dynamics of markers of system inflammation – highly sensitive C-reactive protein (hsСRP), an intercellular adhesion molecule of type 1 (sICAM-1) and ET – endothelin-1, sP-selectin at the inclusion of diuretics in the therapy of patients with COPD with AH are presented. When analyzing the dynamics of the studied markers, a decrease in their level was noted, but statistically significant changes were obtained only in patients against the background of prolonged-release indapamide treatment. Additional pleiotropic effects of indapamide, consisting in reduction of activity of markers of systemic inflammation and ET, are also shown. Its high efficiency in achieving and maintaining the target AH levels compared to hydrochlorothiazide has been demonstrated. Conclusion. The expediency of the inclusion of prolonged-release indapamide in the complex therapy of patients with COPD in combination with AH on the first line of antihypertensive therapy has been demonstrated due to its additional pleiotropic properties, which consist in the influence on the general pathogenetic links of the formation and progression of AH in COPD and its high antihypertensive efficiency in comparison with hydrochlorothiazide.

Periodontitis is increasingly associated with increased risk of cardiovascular and other systemic diseases. The Gram-negative anaerobe, Porphyromonas gingivalis, is a key periodontal pathogen, and several lines of evidence link the presence of this bacterium in the circulation with vascular disease. The outer membrane vesicles (OMVs) produced by P. gingivalis have been shown to play a role in periodontitis, although, to date, little is known about their interaction with the vasculature; therefore, this study assessed the effects of P. gingivalis OMVs on the endothelium. OMVs were isolated from wild-type strain W83 and the gingipain-deficient strain ΔK/R-ab. Immunoblotting along with cryo-EM showed gingipain expression in W83 but not ΔK/R-ab-derived OMVs, where gingipains were localized to the cell wall surface. Confluent endothelial cell monolayers infected with either W83 or W83-derived OMV displayed significantly increased dextran permeability over those infected with ΔK/R-ab or its OMV. Moreover, W83-derived OMVs induced significantly more vascular disease in a zebrafish larvae systemic infection model over 72 h compared to those injected with gingipain-deficient OMVs or controls. In line with these data, human microvascular endothelial cells (HMEC-1) displayed an OMV-associated, gingipain-dependent decrease in cell surface levels of the intercellular adhesion molecule PECAM-1 (CD31) when examined by flow cytometry. These data show, for the first time, that OMVs from P. gingivalis mediate increased vascular permeability, leading to a diseased phenotype both in vitro and in vivo. Moreover, these data strongly implicate gingipains present on the OMV surface in mediating these vascular events, most likely via a mechanism that involves proteolytic cleavage of endothelial cell-cell adhesins such as PECAM-1. These data provide important evidence for the role of bacterial-derived OMVs in mediating systemic disease.

Cardiovascular disease (CVD) is common in peritoneal dialysis (PD) patients. This study was designed to investigate the effects of isoflavones on systemic and vascular inflammation markers and oxidative stress in PD patients. In this randomized clinical trial, 40 PD patients were randomly assigned to either the isoflavone or the placebo group. The isoflavone group received 100 mg soy isoflavones daily for 8 weeks, whereas the placebo group received corresponding placebos. At baseline and the end of eighth week, serum high sensitive C-reactive protein (hs-CRP), intercellular adhesion molecule type 1 (ICAM-1), vascular cell adhesion molecule type 1 (VCAM-1), E-selectin, and malondialdehyde were measured. Serum VCAM-1 decreased significantly in the isoflavone group at the end of Week 8 compared to baseline (p = .01), whereas no significant change was observed in the placebo group. Serum ICAM-1 decreased significantly in the isoflavone (p = .01) and placebo (p = .01) group compared to baseline. However, the reduction of ICAM-1 was significantly higher in the isoflavone group than in the placebo group (p = .02). There were no significant differences between the two groups in mean changes of serum E-selectin, malondialdehyde, and hs-CRP. This study indicates that isoflavones reduce serum VCAM-1 and ICAM-1, which are two CVD risk factors, in PD patients.

Chronic sleep-restriction (SR) is shown to be correlated with neurodevelopmental disorders. However, the effects of SR during stroke recovery on neurorepair remain unclear. In this study, mice were subjected to 60 min of cerebral ischemia followed by reperfusion. The SR protocol was accomplished by depriving mice of sleep for 20 h/day for 14 days starting at 14 days post-ischemia. We found that SR increased CD169+ macrophages infiltration into the ischemic brain parenchyma and inhibited neurogenesis and functional recovery. SR decreased CD169+ macrophages infiltration into the choroid plexus (CP) and cerebrospinal fluid (CSF), accompanied by increased expression of Chemokine C-X3-C-Motif Ligand 1 (CX3CL1) and intercellular adhesion molecule (ICAM-1) via IFN-γ/IFN-γR signaling in the CP. When splenic CD169+ macrophages sorted from Kaede transgenic mice were administered into CSF of C57BL/6 mice, they homed to the ischemic brain parenchyma. Moreover, blockade of IFN-γ/IFN-γR signaling, CX3CL1 or ICAM-1 decreased CD169+ macrophages infiltration into the CP, CSF and ischemic brain parenchyma, as well as decreasing neurogenesis and functional recovery after SR. The promoting roles of infiltrated CD169+ macrophages in post-stroke neurogenesis were due to increasing regulatory T cells (Tregs) in the ischemic brain parenchyma. Furthermore, dexmedetomidine treatment during SR increased CD169+ macrophages infiltration into the CP, CSF and ischemic brain parenchyma, and promoted neurogenesis and functional recovery. Taken together, our results showed that SR during stroke recovery decreased Tregs in the ischemic brain parenchyma by decreasing CD169+ macrophages infiltration to the ischemic brain parenchyma across the CP, which inhibited neurogenesis and functional recovery.

Prior studies reported that haploinsufficiency of the transcription factor ETS-1 is renoprotective in Dahl salt-sensitive rats, but the mechanism is unclear. Here, we tested whether ETS-1 is involved in hypertension-induced renal microvascular pathology and autoregulatory impairment. Hypertension was induced in salt-sensitive rats and salt-sensitive rats that are heterozygous with one wild-type or reference allele of Ets1 (SS(Ets1+/−)) by feeding a diet containing 4% sodium chloride for one week. Increases in blood pressure did not differ. However, phosphorylated ETS-1 increased in afferent arterioles of hypertensive salt-sensitive rats, but not in hypertensive SS(Ets1+/−) rats. Afferent arterioles of hypertensive salt-sensitive rats showed increased monocyte chemotactic protein-1 expression and infiltration of CD68 positive monocytes/macrophages. Isolated kidney microvessels showed increased mRNA expression of vascular cell adhesion molecule, intercellular adhesion molecule, P-selectin, fibronectin, transforming growth factor-β, and collagen I in hypertensive salt-sensitive rats compared with hypertensive SS(Ets1+/−) rats. Using the in vitro blood-perfused juxtamedullary nephron preparation, pressure-mediated afferent arteriolar responses were significantly blunted in hypertensive salt-sensitive rats compared to hypertensive SS(Ets1+/−) rats. Over a 65-170 mm Hg pressure range tested baseline arteriolar diameters averaged 15.1 μm and remained between 107% and 89% of baseline diameter in hypertensive salt-sensitive rats vs. 114% and 73% in hypertensive SS(Ets1+/−) rats (significantly different). Thus, ETS-1 participates in renal arteriolar pathology and autoregulation and thereby is involved in hypertension-mediated kidney injury in salt-sensitive rats.

Aim Tumour-associated macrophages (TAMs) are prominent immune cells infiltrating in solid tumours with phenotypic and functional heterogeneity. However, the clinical significance of heterogeneous subtypes of TAMs in gastric cancer still remains obscure. Here, we aimed to explore the clinical significance of TAMs expressing dendritic cell–specific intercellular adhesion molecule 3–grabbing non-integrin (DC-SIGN) and its relevance with immune contexture in gastric cancer. Methods We selected 453 formalin-fixed and paraffin-embedded samples and 51 fresh tissue specimens of patients with gastric cancer from Zhongshan Hospital. The association of DC-SIGN+ macrophages with clinicopathological parameters, overall survival (OS) and responsiveness to fluorouracil-based adjuvant chemotherapy (ACT) was inspected. Immunohistochemistry (IHC) and flow cytometry (FCM) were applied to characterize immune cells in gastric cancer. Results We demonstrated that high intratumoral DC-SIGN+ macrophages infiltration predicted poor OS and inferior therapeutic responsiveness to fluorouracil-based ACT in patients with gastric cancer. Furthermore, higher infiltration of DC-SIGN+ macrophages indicated an increased number of Foxp3+ regulatory T cells (Tregs), CD8+ T cells and a higher ratio of Foxp3+/CD8+ within the tumour microenvironment (TME). In addition, CD8+ T cells in DC-SIGN+ macrophages high subgroup were functionally impaired, showing decreased interferon-γ (IFN-γ), granzyme B (GZMB) and perforin production yet elevated programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression. Conclusions DC-SIGN+ macrophages were associated with immunoinvasive TME and indicated poor prognosis and inferior therapeutic responsiveness to fluorouracil-based ACT. DC-SIGN+ macrophages might be an independent prognosticator and a potential immunotherapeutic target for gastric cancer.

Background: Renal disease is prevalent in gouty patients and monosodium urate (MSU) crystal deposition in the kidney can be detected in some gouty nephropathy patients. MSU crystals can induce inflammatory events, we investigated the MSU-induced expression of intercellular adhesion molecule (ICAM)-1 on human renal mesangial cells (HRMCs) and the involved signal transduction mechanisms. Methods: The HRMCs cell line was purchased from ScienCell Research Laboratories. MSU crystals were made by dissolving uric acid in sodium hydroxide (NaOH) solution. The involvement of MAPKs, apoptosis-associated speck-like protein containing a CARD domain (ASC), and Toll-like receptor (TLR) was investigated using pharmacological inhibitors, transfection with short hairpin RNA (shRNA), or monoclonal antibodies. Protein expression was evaluated by Western blotting. The functional activity of ICAM-1 was evaluated with cell–cell adhesion assay and immunofluorescence analysis. Results: MSU stimulation increased expression of ICAM-1 and adhesion between HRMCs and human monocytic THP-1 cells. The interaction between HRMCs and THP-1 was suppressed by ICAM-1 neutralizing antibodies. MSU stimulation induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK), but only p38 was responsible for MSU-induced expression of ICAM-1 and cell–cell adhesion. ASC also play a role in MSU-induced effects. Pretreatment with monoclonal antibodies against toll-like receptor (TLR)2 or TLR4 reduced MSU-induced ICAM-1 expression, cell–cell adhesion, p38 phosphorylation but the reduction of ASC activation is insignificant. Conclusion: The MSU induced ICAM-1 expression on HRMCs and cell–cell adhesion involved TLR2/4-p38-ICAM1 pathway and TLR2/4 independent ASC-p38-ICAM1 axis. These findings might partly explain the mechanisms underlying gouty nephropathy. Keywords: Cell–cell adhesion, Intercellular adhesion molecule-1 (ICAM-1), Monosodium urate crystals (MSU), p38, Renal mesangial cells, Toll-like receptor

Purpose: To determine the level of intercellular adhesion molecule-1 (ICAM-1) in vitreous fluid of patients with proliferative diabetic retinopathy (PDR) and its affecting factors including HbA1c level, duration of diabetes mellitus (DM) and insulin usage. Methods: A cross-sectional study was conducted in Cipto Mangunkusumo National General Central Hospital, Jakarta, Indonesia from June 2015 to August 2016. Thirty-three consecutive vitreous samples harvested from PDR patients underwent vitrectomy. The level of vitreous ICAM-1 was determined by enzyme-linked immunosorbent assay. Results: Based on the glycemic status, vitreous ICAM-1 level in the uncontrolled glycemic group (21.61 ng/ml) was lower than controlled glycemic group (24.20 ng/ml). Patients with DM for more than 10 years had higher level of vitreous ICAM-1 (26.30 ng/ml). Vitreous ICAM-1 level in DM patients with insulin was higher than those without insulin (27.07 ng/ml vs. 24.17 ng/ml). There was no statistically significant difference between vitreous ICAM-1 levels among all groups (p > 0.05). Conclusion: The concentration of vitreous ICAM-1 may not be influenced by glucose control and conventional insulin therapy.

Objective: Xanthotoxin (XAT) is a linear furanocoumarin mainly extracted from the plants Ammi majus L. XAT has been reported the apoptosis of tumor cells, anti-convulsant, neuroprotective effect, antioxidative activity, and vasorelaxant effects. This study aimed to investigate the vascular protective effects and underlying molecular mechanisms of XAT. Methods: XAT’s activity was studied in rat thoracic aortas, isolated with aortic rings, and human umbilical vein endothelial cells (HUVECs). Results: XAT induced endothelium-dependent vasodilation in a concentration-dependent manner in the isolated rat thoracic aortas. Removal of endothelium or pretreatment of aortic rings with L-NAME, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, and wortmannin significantly inhibited XAT-induced relaxation. In addition, treatment with thapsigargin, 2-aminoethyl diphenylborinate, Gd3+, and 4-aminopyridine markedly attenuated the XAT-induced vasorelaxation. XAT increased nitric oxide production and Akt- endothelial NOS (eNOS) phosphorylation in HUVECs. Moreover, XAT attenuated the expression of TNF-α-induced cell adhesion molecules such as intercellular adhesion molecule, vascular cell adhesion molecule-1, and E-selectin. However, this effect was attenuated by the eNOS inhibitors L-NAME and asymmetric dimethylarginine. Conclusions: This study suggests that XAT induces vasorelaxation through the Akt-eNOS-cGMP pathway by activating the KV channel and inhibiting the L-type Ca2+ channel. Furthermore, XAT exerts an inhibitory effect on vascular inflammation, which is correlated with the observed vascular protective effects.

High-fat diet (HFD)-induced inflammation is associated with a variety of health risks. The systemic pentraxin serum amyloid P (SAP) inhibits inflammation. SAP activates the high-affinity IgG receptor Fcγ receptor I (FcγRI; CD64) and the lectin receptor dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209). Herein, we show that for mice on an HFD, injections of SAP and a synthetic CD209 ligand (1866) reduced HFD-increased adipose and liver tissue inflammation, adipocyte differentiation, and lipid accumulation in adipose tissue. HFD worsened glucose tolerance test results and caused increased adipocyte size; for mice on an HFD, SAP improved glucose tolerance test results and reduced adipocyte size. Mice on an HFD had elevated serum levels of IL-1β, IL-23, interferon (IFN)-β, IFN-γ, monocyte chemoattractant protein 1 [MCP-1; chemokine (C-C motif) ligand 2 (CCL2)], and tumor necrosis factor-α. SAP reduced serum levels of IL-23, IFN-β, MCP-1, and tumor necrosis factor-α, whereas 1866 reduced IFN-γ. In vitro, SAP, but not 1866, treated cells isolated from white fat tissue (stromal vesicular fraction) produced the anti-inflammatory cytokine IL-10. HFD causes steatosis, and both SAP and 1866 reduced it. Conversely, compared with control mice, SAP knockout mice fed on a normal diet had increased white adipocyte cell sizes, increased numbers of inflammatory cells in adipose and liver tissue, and steatosis; and these effects were exacerbated on an HFD. SAP and 1866 may inhibit some, but not all, of the effects of a high-fat diet.

By inducing tumor-specific immune responses, tumor vaccines have recently aroused great research interest. Herein, we design a targeted nanovaccine by equipping cell membrane vesicles (CMVs) harvested from tumor cells with functional DNA including CpG oligonucleotide, an agonist for toll-like receptor 9, as well as an aptamer targeting the dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3 grabbing nonintegrin (DC-SIGN) receptor overexpressed on DCs. Such DNA-modified CMVs could target DCs and further stimulate their maturation. Notably, our nanovaccines could trigger robust antitumor immune responses to effective delay the tumor growth. Moreover, the combination of CMV-based nanovaccines with an immune checkpoint blockade could result in improved therapeutic responses by eliminating the majority of the tumors as well as long-term immune memory to prevent tumor recurrence. Therefore, by simply assembling functional DNA on CMVs harvested from tumor cells, we propose a general platform of DC-targeted personalized cancer vaccines for effective and specific cancer immunotherapy.

Objectives The co-stimulatory CD40L–CD40 dyad exerts a critical role in atherosclerosis by modulating leukocyte accumulation into developing atherosclerotic plaques. The requirement for cell-type specific expression of both molecules, however, remains elusive. Here, we evaluate the contribution of CD40 expressed on endothelial cells (ECs) in a mouse model of atherosclerosis. Methods and Results Atherosclerotic plaques of apolipoprotein E-deficient (Apoe −/− ) mice and humans displayed increased expression of CD40 on ECs compared with controls. To interrogate the role of CD40 on ECs in atherosclerosis, we induced EC-specific (BmxCreERT2-driven) deficiency of CD40 in Apoe −/− mice. After feeding a chow diet for 25 weeks, EC-specific deletion of CD40 (iEC-CD40) ameliorated plaque lipid deposition and lesional macrophage accumulation but increased intimal smooth muscle cell and collagen content, while atherosclerotic lesion size did not change. Leukocyte adhesion to the vessel wall was impaired in iEC-CD40-deficient mice as demonstrated by intravital microscopy. In accord, expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) in the vascular endothelium declined after deletion of CD40. In vitro, antibody-mediated inhibition of human endothelial CD40 significantly abated monocyte adhesion on ECs. Conclusion Endothelial deficiency of CD40 in mice promotes structural features associated with a stable plaque phenotype in humans and decreases leukocyte adhesion. These results suggest that endothelial-expressed CD40 contributes to inflammatory cell migration and consecutive plaque formation in atherogenesis.

Although coffee consumption has been historically associated with negative health outcomes, recent evidence suggests a lower risk of metabolic syndrome, obesity and diabetes among regular coffee drinkers. Among the plethora of minor organic compounds assessed as potential mediators of coffee health benefits, trigonelline and its pyrolysis product N-methylpyridinium (NMP) were preliminary shown to promote glucose uptake and exert anti-adipogenic properties. Against this background, we aimed at characterizing the effects of trigonelline and NMP in inflamed and dysfunctional human adipocytes. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with NMP or, for comparison, trigonelline, for 5 h before stimulation with tumor necrosis factor (TNF)-α. NMP at concentrations as low as 1 µmol/L reduced the stimulated expression of several pro-inflammatory mediators, including C-C Motif chemokine ligand (CCL)-2, C-X-C Motif chemokine ligand (CXCL)-10, and intercellular adhesion Molecule (ICAM)-1, but left the induction of prostaglandin G/H synthase (PTGS)2, interleukin (IL)-1β, and colony stimulating factor (CSF)1 unaffected. Furthermore, NMP restored the downregulated expression of adiponectin (ADIPOQ). These effects were functionally associated with downregulation of the adhesion of monocytes to inflamed adipocytes. Under the same conditions, NMP also reversed the TNF-α-mediated suppression of insulin-stimulated Ser473 Akt phosphorylation and attenuated the induction of TNF-α-stimulated lipolysis restoring cell fat content. In an attempt to preliminarily explore the underlying mechanisms of its action, we show that NMP restores the expression of the master regulator of adipocyte differentiation peroxisome proliferator-activated receptor (PPAR)γ and downregulates activation of the pro-inflammatory mitogen-activated protein jun N-terminal kinase (JNK). In conclusion, NMP reduces adipose dysfunction in pro-inflammatory activated adipocytes. These data suggest that bioactive NMP in coffee may improve the inflammatory and dysmetabolic milieu associated with obesity.

CD19‐target chimeric antigen receptor (CAR)‐T cell therapy is highly effective for relapsed/refractory (R/R) acute lymphoblastic leukaemia (ALL), but is often complicated by cytokine release syndrome (CRS), which is potentially life‐threatening. Endothelial cells are the core regulator of CRS in many infectious diseases and may also play a key role after CAR‐T cell therapy. We provided a detailed clinical, laboratory description and endothelial cell activation biomarkers in patients with CRS. Endothelial cell activation was associated with occurrence, development and severity of CRS, manifested by decreased serum angiopoietin (Ang)‐1 levels and increased levels of von Willebrand Factor (VWF), Ang‐2, Ang‐2:Ang‐1, sE‐selectin, soluble intercellular adhesion molecule (sICAM‐1) and soluble vascular cell adhesion molecule (sVCAM)‐1. Besides, the endothelial activation was correlated with the hepatic, kidney and hematopoietic dysfunction in CRS patients. After infusion of CAR‐T cells, we detected changes of endothelial activation‐related biomarkers within 36 hours in patients who subsequently developed CRS, especially severe CRS. Using top tree models, we could predict which patients would develop CRS, especially severe CRS, or identify the severity of CRS by certain biomarkers of endothelial activation. These data provide a new idea and will help identify new targets for early intervention and prevention of CRS.

Introduction: Cough is a debilitating symptom with a significant impact on quality of life. Patients with refractory chronic cough typically cough hundreds of times per day therefore we hypothesised that the associated pressures and shearing forces may lead to micro-injury of the pulmonary tissues. Aims: To compare lung and tissue injury biomarkers in the blood of refractory chronic cough patients (RCC) with healthy volunteers (HV). Methods: Serum from 64 RCC (75% female; mean age 54.3yrs) and 34 HV (62% female; mean age 36.7yrs) was assayed. Surfactant Protein-D (SP-D) and matrix metalloproteinase (MMP)-7 were measured using a commercial ELISA kit; C Reactive protein (CRP), Intercellular Adhesion Molecule (ICAM)-1, Serum amyloid A (SAA), Vascular cell adhesion protein (VCAM)-1 were measured using V-PLEX Vascular Injury Panel 2. Two tailed Mann-Whitney-U tests were performed. Results: All markers of micro-injury were significantly elevated in RCC patients compared with HV, with the most striking elevations seen in SP-D (302 vs 187 ng/mL, p Conclusion: Markers of epithelial damage (SP-D and MMP-7), vascular injury (VCAM-1 and ICAM-1) and peripheral tissue injury (CRP and SAA) were all elevated in the serum of chronic cough patients, supporting the hypothesis that cough is associated with lung micro-injury.