ObjectiveA cardiovascular safety issue has been associated with JAK inhibitors (JAKi). This study compares the effects of distinct approved JAKi on endothelial cell (EC) dysfunction and apoptosis during inflammation.MethodsMassive inflammation was induced in human vascular ECs by tumor necrosis factor (TNF) with interleukin‐17A (IL‐17A) treated or not treated with tofacitinib, baricitinib, upadacitinib, peficitinib, ruxolitinib, and fedratinib at 1 or 10 μM. Levels of IL‐6 and IL‐8 were measured by enzyme‐linked immunosorbent assay. Variations in gene expression of adhesion molecules and factors of blood coagulation and fibrinolysis pathways were quantified by quantitative reverse transcriptase–polymerase chain reaction. Endothelial apoptosis was measured by Annexin V staining.ResultsAll JAKi decreased IL‐6 release of ECs stimulated with TNF+IL‐17A. In contrast, only baricitinib and fedratinib decreased IL‐8 overproduction, from 1 μM. Fedratinib decreased the up‐regulation of vascular adhesion molecule 1 (VCAM‐1) and E‐selectin expression at 1 and 10 μM. Tofacitinib reduced intercellular adhesion molecule 1 (ICAM‐1) and E‐selectin induction at 1 μM. However, at 10 μM, tofacitinib, baricitinib, upadacitinib, peficitinib, and ruxolitinib enhanced induction of VCAM‐1 and ICAM‐1 triggered by TNF+IL‐17A. Peficitinib and fedratinib at 1 and 10 μM decreased tissue factor up‐regulation induced by TNF+IL‐17A, whereas ruxolitinib was effective only at 1 μM. None of the JAKi could prevent the down‐regulation of the anticoagulant molecule thrombomodulin. Fedratinib and peficitinib were both proapoptotic and cytotoxic for ECs.ConclusionAll JAKi reduced EC inflammation but most JAKi could not prevent the up‐regulation of adhesion molecules or the increase in procoagulant and the decrease in anticoagulant factors triggered by proinflammatory cytokines. Peficitinib and fedratinib exhibited cytotoxic effects causing EC apoptosis.

Background: Chronic kidney disease (CKD) has been linked to elevated inflammatory biomarkers, yet few studies have evaluated these associations using iothalamate-based measures of kidney function, highlighting the need for further research. Research question: Is CKD associated with elevated inflammatory markers when defined by measured glomerular filtration rate (mGFR) and urinary albumin-to-creatinine ratio (UACR)? Methods: Participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) cohort were included if they had data available for at least one inflammatory marker at visit 2. 17 inflammatory markers were assessed, including C-reactive protein (CRP), interleukin-6 (IL-6), IL-18, tumor necrosis factor receptors 1 and 2 (TNFR1, TNFR2), serum amyloid A, intercellular and vascular adhesion molecules (ICAM, VCAM), E-selectin, P-selectin, monocyte chemoattractant protein (MCP), myeloperoxidase (MPO), receptor for advanced glycation end products (RAGE), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9), and tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1, TIMP-2). Kindey function was assessed using the urinary clearance of iothalamate. CKD was defined as mGFR < 60 mL/min/1.73 m 2 or UACR ≥ 30 mg/g. To further assess whether associations persisted without albuminuria, we also defined CKD solely by mGFR < 60 mL/min/1.73 m 2 . Generalized estimating equations (GEE) were used to assess associations between CKD status and inflammatory markers, accounting for familial clustering. Exponentiated beta coefficients from GEE models were used to present geometric mean (GM) ratios of each biomarker by CKD status, adjusted for demographics, lifestyle factors, cardiovascular risk factors, and medication use. Results: Among 1,010 participants (mean age 61 ± 10 years; 67% women; 48% Black adults), 207 were classified as having CKD. After adjusting for potential confounders, individuals with CKD had significantly higher levels of hsCRP, VCAM, TNFR1, and TNFR2 compared to those without CKD (GM ratios > 1; p < 0.05), while the remaining inflammatory markers showed no significant differences ( Figure 1 ). Importantly, these elevations remained significant when CKD was defined by mGFR alone ( Figure 2 ). Conclusion: Our findings suggest that CKD, defined by mGFR, is associated with specific inflammatory biomarkers, underscoring the need for mechanistic studies to investigate these associations.

BackgroundUlcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Chronic intestinal inflammation plays a critical role in the increased risk of developing colitis-associated cancer (CAC). CU06-1004, an endothelial dysfunction blocker, can alleviate acute colitis by suppressing inflammation and regulating colonic vascular dysfunction. However, whether CU06-1004 suppresses chronic intestinal inflammation and prevents the development of CAC remains unclear.MethodsIn this study, we investigated the protective effects of CU06-1004 by suppressing inflammation in both the dextran sulfate sodium (DSS)-induced chronic colitis model and the azoxymethane (AOM)/DSS-induced colorectal cancer mouse models. We evaluated the expression of key pro-inflammatory cytokines, assessed histological characteristics in the animals, and examined the expression of key genes associated with inflammation.ResultsIn the DSS-induced chronic colitis model, our results showed that CU06-1004 treatment suppressed inflammation, as evidenced by disease activity index scores, colon length, colon damage, and histological analysis. Furthermore, CU06-1004 administration reduced the levels of various inflammatory cytokines and factors (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase), decreased immune cell infiltration (F4/80+ macrophages and CD177+ neutrophils), and alleviated inflammation by inhibiting vascular adhesion molecules. Moreover, in the AOM/DSS-induced colorectal cancer model as well, CU06-1004 significantly reduced the severity of colitis. CU06-1004 treatment also significantly reduced both the number and size of AOM/DSS-induced colorectal tumors, suppressed inflammation, and inhibited the malignant proliferation of epithelial cells. Additionally, CU06-1004 treatment downregulated the expression of the key colorectal cancer marker β-catenin and its target gene c-Myc in AOM/DSS-induced mice, thereby inhibiting tumor growth.ConclusionOur findings suggest that CU06-1004 inhibits inflammation-induced tumorigenesis by modulating the inflammatory response in the colon. Consequently, CU06-1004 could represent a promising therapeutic candidate for the prevention of colorectal cancer through modulation of inflammation.

BackgroundCurrent evidence has linked peripheral biomarkers of vascular endothelial dysfunction (ED) with cognitive impairment in older adults.ObjectiveTo investigate the associations of vascular ED with cognitive function while considering the potential influence of lifelong cognitive reserve (CR).MethodsThis population-based cross-sectional study included 1540 dementia-free participants who were aged ≥60 years and living in a rural area of China. Cognitive function was assessed using a neuropsychological test battery. A composite CR score was calculated by integrating education, occupational complexity, mental activity, and social support using a structural equation model. A composite ED score was calculated by averaging the z-scores of serum intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1). Data were analyzed using multiple general linear regression models.ResultsAfter controlling for multiple potential confounders, higher serum ICAM-1 levels and the composite ED score were significantly associated with lower z-scores in global cognition, verbal fluency, attention, and executive function (p < 0.05), but not with episodic memory z-score (p > 0.05). Higher serum VCAM-1 levels were significantly related with lower z-scores in global cognition, attention, and executive function (p < 0.05), but not with episodic memory or verbal fluency z-score (p > 0.05). There were no statistically significant interactions between ED biomarkers and lifelong CR on cognitive outcomes.ConclusionsVascular ED is associated with worse cognitive performance in dementia-free older adults, independent of lifelong CR.

Intracerebral hemorrhage (ICH) is a lethal and highly morbid form of stroke for which there is no disease-specific therapy. Inflammation after ICH is an important mechanism of secondary damage, and the inflamed endothelium in ICH is a promising therapeutic target as it is the gateway for recruitment of peripheral inflammatory cells to the brain. Systemic therapies that target inflammation have been unsuccessful in stroke, in part due to side effects or poor brain delivery. We hypothesized that targeting mRNA encoding IL-10, a potent anti-inflammatory cytokine, to the brain vasculature would improve outcomes in an experimental mouse model of ICH. We manufactured lipid nanoparticles (LNPs) using microfluidics, packaged them with IL-10 mRNA, and conjugated them with antibodies against vascular cellular adhesion molecule (VCAM), which can bind the inflamed brain endothelium after ICH. VCAM LNPs distributed to the brain ~ 4x more than nonspecific LNPs and expressed their cargo in the brain at 10x higher levels. Treatment with VCAM-LNPs containing IL-10 mRNA led to ~ 69% reduction in hematoma size at 72 h by histology and decreased lesion size in MRI, and ~ 65% improvement in motor behavior in our model. Finally, we propose that VCAM-IL10-LNPs enact their therapeutic benefit via modulation of brain macrophage phenotype. Our data bring forth a promising therapeutic and delivery strategy for ICH, and shed light on the effects of acute targeting of inflammation in ICH lesion size and behavior. Future experiments will seek to understand how serial dosing affects LNP expression in our model and whether treatment at later time points after ICH can still confer therapeutic effects.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12974-025-03541-0.

Downregulation of heat shock protein 90 alpha family class A member 1 inhibits necroptosis in cardiac microvascular endothelial cells and alleviates sepsis-induced cardiomyopathy.

Patients with cardiogenic shock (CS) following acute myocardial infarction (AMI) are challenged by pro-inflammatory and pro-apoptotic cellular processes. Little is known about the effect of mild therapeutic hypothermia (MTH) on these alterations. Blood plasma from 40 patients included in the randomized SHOCK-COOL trial, which compared MTH (33°C) versus no hypothermia in AMI-CS without cardiac arrest, from the first 3days of hospitalization was used to determine interleukins (IL)-6 and IL-1β, tumor necrosis factor-alpha (TNF-α), intercellular and vascular soluble adhesion molecules (ICAM1 and VCAM1), TNF-receptor 1 (TNF-R1), TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), soluble FAS-ligand (sFASL), and soluble FAS (sFAS). These markers were also determined in 11 healthy controls. All markers except for TNF-R1 and sFASL reached their highest levels on day two or day three in both CS groups. IL-1β and sFAS reached higher maximum levels in the MTH group. IL-1β was higher in the MTH group on day 2 (+ 38%, p = 0.014) and on day 3 (+ 9%, p = 0.047), but the averaged group-wise individual maxima were comparable (24 [17-30] versus 20 [12-25], p = 0.138). The pro-apoptotic marker sFAS was also higher in the MTH group on day 2 (+ 85%, p = 0.004) and day 3 (+ 170%, p < 0.001); the averaged individual maxima were significantly higher in the MTH group (25 [15-38] versus 15 [10-21] ng/ml, p = 0.008). Hypothermia in AMI-CS without cardiac arrest has no moderating effect on the assessed pro-inflammatory cytokines. However, sFAS showed significantly higher individual peak maxima in the MTH group indicating enhancement of pro-apoptotic mechanisms via the soluble FAS/FASL pathway.

BackgroundThe role of neutrophils in mediating neurovascular vulnerability has been increasingly implicated in various acute inflammatory models of neuroimmune crosstalk between the periphery and the brain. Whether neurovascular vulnerability is similarly modulated in the context of frequent, but not acute, inflammatory activation in the periphery is the aim of our study. Such a model of frequent inflammatory irritation is pertinent to understanding the neurologic risk of constant exposure to aerosolized environmental hazards leading to progressive pulmonary disease.MethodsTo model repeated pulmonary inflammation, we applied a three-dose regimen of intranasal (i.n.) lipopolysaccharide (LPS) in C57BL/6J mice and studied the impact on the inflammatory environment of the brain, with a specific focus on neutrophil dynamics at the neurovascular unit (NVU). Tissue and circulatory inflammatory profiles were screened via bronchoalveolar lavage (BAL) protein content and cellularity, transcript analysis of brain tissue, and flow cytometry of peripheral blood. Intravital two-photon microscopy (2PM) of the brain vasculature identified neutrophil dynamics at the NVU. Immunofluorescence validated neutrophil dynamics and identified neuroinflammatory hallmarks and peripheral immune factor interactions at the NVU. In vivo findings were corroborated and replicated in murine and human microphysiological systems (MPS) modeling the blood-brain barrier as a proxy demonstration of the translational relevance of our findings.Results2PM of tdTomato-Ly6G+ neutrophils demonstrated increased levels of circulating neutrophils and corresponding engagement with the brain vasculature after the three-dose repeated i.n. exposure regimen. Neutrophilia at the NVU was corroborated with increased transcript levels of Ly6G and other pro-inflammatory markers. This coordination between endothelial physiology and neutrophil phenotypes was recapitulated in murine and human MPS models. System-wide neutrophilia in the lung and circulation was found to be cotemporaneous to neutrophilia at the NVU based on the cellularity of BAL and peripheral blood samples collected at the same endpoints. Immunohistochemical analysis of brain tissue implicates temporal coordination between vascular surface adhesion molecules with changes in neutrophil dynamics from adhesion, crawling, stalling, and transmigration. Extravasation of neutrophils was complemented by sustained paravascular deposition of fibrinogen and microgliosis up to 72 hours after the final i.n. dosing. Microglia-associated effector functions for synaptic pruning and regulation of neutrophil activity demonstrated distinct temporal profiles.ConclusionsOur results identify systemic levels of neutrophilia accompanied by ingress and extravascular accumulation in brain parenchyma that correlated with sustained microglial activation. This neutrophil-centric lung-brain interaction is complemented by the observation of paravascular fibrinogen deposition that alters synaptic metabolism. Thus, we propose a mechanistic role for neutrophilia and associated inflammatory dysregulation as essential mediators along the lung-brain neuroimmune axis in a generalizable model of repeated respiratory exposure to inflammatory agents.

Abstract The focus of this paper is inflammation of the endothelium – originating in situ or exogenous – in the context of general inflammatory diseases, including autoimmune, in which it is accelerated. The main triggers or accelerators include hypertension caused by the hyperexpression of angiotensin II, which triggers endothelial inflammation and dyslipidemia by LDL cholesterol in small, dense and oxidized fractions. Others include hyperapolipoprotein B, or an increase in lipoprotein(a); hyperthyroglyceridemia associated with hypoHDL, as in atherogenic dyslipidemia in diabetes mellitus; dysglycemia, more specifically hyperglycemic spikes; and hyperinsulinism, which has been implicated in the acceleration of endothelial inflammation, especially in middle-aged patients (39-56 years). New data is based not only on genetic information, but also on morphological studies and new markers of endothelial inflammation. In this case, the reaction of lymphocytokines, including blood components such as lympho-monocytes but also platelets, can contribute to the precipitation of atherothrombotic phenomena with a predominantly inflammatory-prothrombotic mechanism. Existing lipid-lowering therapies did not provide complete protection, even in secondary prophylaxis using maximum tolerated doses of potent statins + ezetimibe. We will be able to see, in the near future, the results of adequate therapies to control the values of lipoprotein(a) and apolipoprotein B, which have proven to be even more statistically strong ischemic risk factors than LDL cholesterol, especially non-HDL cholesterol. With regard to the control of lipid fractions, some do not appear in the prevention guidelines, and perhaps this is unjustified. These include antisense oligonucleotides (ASOs) and small-interfering RNA (siRNA). There are also agents still in the investigation stage: pelacarsen (ASO); olpasiran (siRNA); zerlasiran (siRNA); lepodisiran (siRNA); and muvalaplin (oral therapy). Favorable effects were also obtained with niacin and evolocumab, but not of the same magnitude. We quantify the inflammatory risk using either indirect markers – such as CRPhs, or the induction of endothelial alteration in association with lymphocytokines. We also do this directl, by dosing more reliable markers such as interleukin 1 and 6, and earlier interleukin 8 and MCP 1; then TNF α; interferon β 1; soluble vascular adhesion molecules (VCAM-1); phospholipase A2 associated with circulating lipoproteins (FLPA2); IGF-1 (insulin-like growth factor-1); soluble molecules of selectin-E and -P; glycation end products (PFG); blood level of NO; and increased serum content of peroxynitrite (ONOO-), which is the product of interaction product between NO and the superoxide anion. Several studies have evaluated the effect of colchicine in patients with coronary ischemic disease. This drug prevents the polymerization of microtubules by interfering with the function of leukocytes. LODOCO II, COLCOT, CLEAR16 studies, only the last inconclusive for the prophylactic effect of colchicine. Studies with interleukin inhibitors/chemokine inhibitors, CANTOS – with canakinumab; Virginia Commonwealth University-Anakinra remodeling trial 38, with anakinra; and RESCUE, with ziltivekimab. There are some sources of hope, including predominantly non-anti-inflammatory drugs, statins, and proprotein inhibitors that convert subtilisin/kexin type 9 (PCSK9); GLP1 agonists, small and interfering RNA-based therapies; and gene addition and editing (CRISPR), including regularly clustered short palindromic repeats and base editing. The major question, despite the current economic problems, is: wouldn’t systemic endothelial anti-inflammatory therapies (not necessarily those already tested), in patients at high risk and with evidence of inflammation, be effective in primary prophylaxis? Until now, no such studies have been done in significant batches, at least not randomized trials. Primary prophylaxis is, in the 21st century, another conceptual stage in the development of life-saving therapies, not only to prolong life, but also for the healthy living of the population.

High tumor budding and elevated systemic inflammation are adverse prognostic indicators in colorectal cancer. Its underlying mechanisms remain poorly understood. It is unclear whether systemic inflammation, angiogenesis, and cell-to-cell adhesion influence tumor budding. We investigated n = 132 stage I-III colorectal cancer patients recruited at Huntsman Cancer Institute enrolled in the ColoCare Study. Tumor budding was evaluated using an evidence-based scoring system, and patient sera were analyzed for nine circulating biomarkers using the Meso Scale Discovery platform. We examined associations between biomarkers and tumor budding using multivariable linear regression models adjusted for age, sex, neoadjuvant treatment, stage, and non-steroidal anti-inflammatory drug use. The study population was predominantly non-Hispanic White (95%), with a mean age of 61 years; 56% were male. Most tumors were stage III (47%), located in the colon (64%), and exhibited low-grade tumor budding (58%). Soluble intercellular adhesion molecule 1 was inversely associated with tumor budding overall (M1: β = -0.57, p = 0.03), among females (M1: β = -0.81, p-value = 0.03) and later-onset (≥ 50 years) colorectal cancer (M1: β = -0.71, p-value = 0.008). C-reactive protein was positively associated with tumor budding in males (M1: β = 0.23, p = 0.001), while interleukin-8 (M1: β = 0.96, p-value = 0.01) and soluble vascular adhesion molecule 1 (M2: β = 1.48, p-value = 0.04) were positively associated with tumor budding in early-onset patients. However, these associations did not remain statistically significant after correction for multiple testing. Overall, our findings do not provide evidence of a significant association between biomarkers of systemic inflammation, angiogenesis, and cell-to-cell adhesion with tumor budding count. We observed patterns for some biomarkers, yet none remained statistically significant after correction for multiple testing. These findings provide preliminary insights for future studies. ClinicalTrials.gov: NCT02328677.

Background/Objectives: Exposure to fine particulate matter (PM2.5) is linked to increased cardiovascular risk, particularly in individuals with hypertension. This study examined the association between dietary patterns, lifestyle factors, and vascular inflammation among individuals with hypertension living in rural and peri-urban areas of Chiang Mai Province, Thailand. Methods: A cross-sectional pilot study was conducted among 47 participants (23 rural, 24 peri-urban). Data on dietary intake, smoking, alcohol use, anthropometry, and blood chemistry were collected. Serum intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and interleukin-6 (IL-6) were measured. Partial correlation analysis was used to examine associations with lifestyle factors, adjusting for relevant covariates. Results: Peri-urban participants had significantly higher levels of ICAM-1 [83.0 vs. 50.1 ng/mL], VCAM-1 [639.3 vs. 376.5 ng/mL], and IL-6 [4.80 vs. 1.02 pg/mL] compared to rural participants. Rural individuals reported higher intakes of antioxidant-related nutrients (selenium, β-carotene, niacin, vitamins A, B6, and C), while peri-urban individuals had higher sugar intake. Sugar intake was positively associated with ICAM-1 and VCAM-1, whereas selenium and vitamin C were inversely associated with both ICAM-1 and VCAM-1, while vitamin B6 was inversely associated with VCAM-1 only. Although rural participants had a higher rate of current smoking (34.8% vs. 4.4%), smoking and alcohol use were not significantly associated with inflammatory markers. Conclusion: Rural dietary patterns may be linked to reduced vascular adhesion molecule levels. Further studies with larger samples are warranted to clarify these associations and guide lifestyle strategies for managing vascular inflammation in PM2.5-exposed individuals with hypertension.

BackgroundAging-related systemic cardiovascular changes can impair cerebrovascular circulation, contributing to hippocampal atrophy and cognitive decline. However, the mechanistic pathways by which systemic alterations may relate to hippocampal atrophy via hippocampal vascular features remain unclear.MethodsIn this study, 191 participants (aged 30–59 years, 115 female) underwent 7T MRI to segment hippocampal supply vessels and hippocampal volume from T1-weighted images. Twenty-three systemic parameters related to the metabolic syndrome, autonomic function, inflammation, vascular stiffness, and endothelial function were measured at rest. Mediation analysis examined whether hippocampal vessel velocity and size mediated the relationship between systemic factors and hippocampal volume.ResultsHippocampal volume was highly associated with hippocampal supply vessel velocity, showing a pronounced right lateralized effect. Indirect associations of vessel velocity with hippocampal volume were identified for circulating vascular and intercellular adhesion molecules, heart rate variability, fasting insulin, and spontaneous baroreflex sensitivity. No significant mediated relationships were found for blood pressure, adiposity, mean heart rate, cardiac output, pre-ejection period, reactive hyperemia, pulse wave velocity, mean carotid artery intimal medial thickness, fasting glucose, lipid levels, circulating interleukin-6, hemoglobin A1C, or blood pressure variability.ConclusionThese findings highlight the role of vascular inflammation, autonomic dysfunction, and metabolic disturbances in hippocampal atrophy, with hippocampal vessel velocity serving as a key mediator. This insight advances our understanding of cerebrovascular contributions to hippocampal structural integrity and cognitive health.

Neuregulin-1 (NRG-1), a stress-mediated paracrine transmembrane growth factor, plays vital roles in the pathophysiology of atherosclerosis, myocardial infarction, ischemia-reperfusion, heart failure (HF), cardiomyopathy and other cardiovascular diseases. This study aimed to assess plasma NRG-1 levels in atherosclerotic cardiovascular disease (ASCVD) patients and explore the relationship between NRG-1 levels and patient outcomes. Plasma NRG-1, monocyte chemotactic protein-1 (MCP-1), myeloperoxidase (MPO) and vascular cellular adhesion molecule-1 (VCAM-1) concentrations were quantified in 185 ASCVD patients and 185 age- and sex-matched controls. All ASCVD patients were followed up for 14-16 months, and major adverse cardiovascular and cerebrovascular events (MACCEs), including angina pectoris, nonfatal myocardial infarction, nonfatal stroke, new HF symptoms, and CVD-related death, were recorded. ASCVD patients presented notably lower NRG-1 levels (123.45 ± 0.87 pg/ml, vs. 139.76 ± 0.83 pg/ml for controls, P < 0.001) and higher MCP-1, MPO and VCAM-1 levels. Circulating NRG-1 levels were negatively associated with MCP-1 (-0.278, P < 0.001), MPO (-0.171, P = 0.001) `and VCAM-1 (-0.351, P < 0.001) levels. Logistic regression analysis revealed that a high NRG-1 level was a significant protective effect against ASCVD (OR = 0.859, 95% CI = 0.821-0.900; P < 0.001). In the mediation analysis, MCP-1, MPO, and VCAM-1 explained 20.2%, 8.8%, and 30.1%, respectively, of NRG-1's association with ASCVD. After an average follow-up of 13.8 ± 1.7 months, the mean NRG-1 level was lower in patients with MACCEs than in patients without MACCEs (112.04 ± 1.24 pg/ml vs. 125.93 ± 0.90 pg/ml, P < 0.001). Kaplan-Meier survival analysis revealed that patients with plasma NRG-1 concentration <122.5 pg/ml had a lower survival rate than those with higher levels (P < 0.001). According to the adjusted models, NRG-1 was independently associated with a decreased risk of MACCEs [adjusted HR 0.857 (95% CI 0.809-0.908), P < 0.001]. Reduced NRG-1 levels in ASCVD patients increased the risk of MACCEs. NRG-1 levels may serve as useful laboratory markers of ASCVD prognosis.

ABSTRACTObjectiveDuring skin inflammation, inhibition of adhesion of regulatory T cells (Tregs) to the dermal microvascular endothelium leads to exacerbation of inflammation, evidence that the dermal endothelium is a key target of the anti‐inflammatory actions of Tregs. The aim of this study was to investigate the capacity of Tregs to control the expression of endothelial adhesion molecules in inflamed and resting skin.MethodsTreg function was assessed in a two‐challenge contact hypersensitivity (CHS) model, measuring dermal adhesion molecule expression via imaging of cleared skin. Treg depletion was achieved using Foxp3DTR mice.ResultsCHS induced upregulation of E‐selectin and ICAM‐1 but not P‐selectin and VCAM‐1. Elimination of Tregs following CHS challenge resulted in exacerbated skin inflammation and enhanced expression of E‐selectin, P‐selectin and ICAM‐1 in the dermal microvasculature. Multiphoton imaging revealed that at this phase of the response, Tregs were enriched near blood vessels and underwent dynamic migration adjacent to the microvasculature. Additionally, in skin that was not undergoing hapten challenge, absence of Tregs also resulted in upregulation of E‐selectin and ICAM‐1 in skin vessels.ConclusionsThese observations demonstrate that the microvascular endothelium is a target of the anti‐inflammatory actions of Tregs in the skin, both during CHS and in steady‐state skin.

BackgroundMyocardial ischemia/reperfusion (I/R) injury is a leading cause of myocardial dysfunction and is associated with inflammation, apoptosis, and fibrosis. The integrin subunit ITGAM (also known as CD11b) mainly mediates leukocyte infiltration in the inflammatory process. However, the importance of CD11b in the development of myocardial I/R injury is unclear. The goal of this study is to investigate the role of CD11b+ immune cells, particularly neutrophils and macrophages, in mediating myocardial I/R injury and to evaluate the therapeutic potential of CD11b inhibition.MethodsWild‐type mice were administered an anti‐CD11b neutralizing antibody before myocardial I/R surgery. Echocardiography and histological staining were used to evaluate cardiac function and injury, respectively. Inflammatory cells were analyzed by flow cytometry in mice and patients with myocardial infarction who underwent percutaneous coronary intervention. Activated fibroblasts from patients with myocardial infarction were detected by positron emission tomography/computed tomography with a [(18)F]‐labeled fibroblast activation protein inhibitor.ResultsOur results indicated that CD11b expression and the number of CD45+CD11b+ bone marrow mononuclear cells were dramatically increased in the heart tissues of I/R‐treated mice. Moreover, compared with immunoglobulin G treatment, the pharmacological inhibition of CD11b in mice greatly alleviated cardiac dysfunction, infarct size, myocyte apoptosis, CD11b+ neutrophils and macrophage infiltration, cardiac fibrosis and fibroblast activation, accompanied by the inhibition of multiple signaling pathways (Bax, caspase‐3, nuclear factor‐κB, and transforming growth factor‐β/Smad2/3) 3 days after I/R surgery. In addition, the numbers of CD15+CD11b+ neutrophils and CD14+CD11b+ monocytes and the levels of inflammatory cytokines (intercellular adhesion molecule ‐1, vascular adhesion molecule ‐1, interleukin‐1β, and interleukin‐6) as well as the levels of fibroblast activation protein inhibitor in patients with myocardial infarction were also significantly greater than those in normal controls.ConclusionsOur data demonstrate that CD11b plays an important role in promoting myocardial I/R injury through multiple signaling pathways and that targeting CD11b may represent a promising option for treating heart I/R injury.

The tumor microenvironment, comprising elements such as endothelial cells (ECs) and immune cells, plays a critical role in cancer progression, therapy resistance, and metastasis. Adhesion of cancer cells to the endothelium, their transendothelial migration, and immune evasion by cancer cells contribute to these processes. In this study, we investigated the effect of the polysaccharide-rich fraction derived from bioprocessed black rice bran extract (BRB-F-P) on the interaction between triple-negative breast cancer (TNBC) and radiotherapy-resistant TNBC (RT-R-TNBC) cells with ECs, as well as on the cytolytic function of natural killer (NK) cells. BRB-F-P treatment did not affect the viability of ECs, TNBC, or RT-R-TNBC cells. However, BRB-F-P (50 and 100 µg/mL) significantly suppressed the clonogenicity of TNBC and RT-R-TNBC cells and attenuated ATP-induced expression of vascular adhesion molecule-1, intercellular adhesion molecule-1, and Vimentin, along with the phosphorylation of vascular endothelial cadherin in ECs. Additionally, BRB-F-P markedly reduced cancer cell adhesion to ECs and inhibited their ability to transmigrate through ECs. Interestingly, BRB-F-P increased NK cell-mediated cytotoxicity against TNBC and RT-R-TNBC cells by inducing granzyme B release and downregulating human leukocyte antigen-E expression in target cancer cells. These results suggest that BRB-F-P exerts anticancer effects in TNBC and RT-R-TNBC by inhibiting interactions with ECs and inducing NK cell activity without cytotoxicity.

Background: Epidemiological research has shown that regular walnut (from Juglans regia L.) consumption is associated with a reduced risk of cardiovascular disease (CVD), potentially attributable to their antioxidant and anti-inflammatory properties. The vascular cellular adhesion molecule-1 (VCAM-1), a protein upregulated in CVD, has been previously examined in relation to walnut consumption. However, the clinical findings regarding the effects of walnuts on endothelial function among middle-aged individuals susceptible to metabolic syndrome (MetS) remain inconclusive. Objective: This study examined the effects of daily walnut consumption over a four-week period on cardiometabolic parameters (lipid and glycemic profiles, as well as soluble VCAM-1 levels) and anthropometric measurements in middle-aged individuals with at least one altered MetS parameter and no medication. Methods: In a randomized controlled cross-over trial, 22 eligible Caucasian participants (48.81 ± 4.3 years) were selected and randomly assigned to receive either 45 g of walnuts per day or no walnuts within a controlled diet. There were two 28-day intervention periods, with a one-month washout period in between. Clinical and biochemical evaluations were conducted at the beginning and end of each intervention period. Results: A total of 20 participants completed the intervention and were analyzed, with walnuts being well tolerated. A significant decrease in waist circumference (p = 0.049) and a slight change in fasting blood glucose (p = 0.089) were noted following walnut intake. Conclusions: Short-term (4 weeks) dietary supplementation with walnuts resulted in a statistically significant reduction in waist circumference while not impacting the overall health status of participants. Longer-term studies are necessary to investigate the benefits of daily walnut consumption and its impact on the onset and development of MetS in this age group.

Introduction and Objective: We have discovered that verapamil inhibits pancreatic islet expression of beta cell toxic thioredoxin-interacting protein (TXNIP) and preserves beta cell function in mice and in subjects with T1D and these clinical findings have been independently validated. However, as a calcium channel blocker, verapamil has many additional effects. We therefore aimed to explore the genes/proteins regulated by verapamil in the context of diabetes. Methods: We performed proteomics on serum samples of T1D subjects treated with placebo or verapamil. We also conducted transcriptomics on human islets treated with or without verapamil. Common genes/proteins significantly downregulated by verapamil in both omics were selected and analyzed in islets in the context of diabetes and inflammation. In addition, we analyzed the effect of verapamil on these genes in islets and islet endothelial cells. Results: We found five common proteins/genes (VCAM1, SPINK1, SYCN, PI16 and CD14) significantly decreased by verapamil in both omics. Besides its important role in immune cell transmigration and in diabetes, we chose VCAM1 for further study because SPINK1 is exclusively expressed in exocrine cells while the other genes are very lowly expressed in islets. We found that the serum levels of VCAM1 were significantly decreased in T1D subjects after 1 year of verapamil but not placebo treatment. In addition, VCAM1 expression was increased in islets of diabetic NOD mice, T2D subjects and in human islets treated with T1D-associated cytokines. Furthermore, we demonstrated that the expression of VCAM1 and two other adhesion molecules (PECAM1 and ESAM) was significantly decreased by verapamil in human islets and mouse islet endothelial cells. Conclusion: VCAM1 is significantly increased in islets in the context of diabetes and inflammation, which may play an important role in T cell infiltration into islets in T1D. The inhibition of VCAM1 and other vascular adhesion molecules by verapamil may contribute to the potential protective effects of this drug against islet inflammation. Disclosure G. Xu: None. J. Chen: None. B. Lu: None. A. Shalev: Other Relationship; TIXiMED, Inc.

BackgroundFerulic acid (FA) is an antioxidant compound present in cereals, fruits, and vegetables. Chronic consumption of a high-fat and high-carbohydrate (HFHC) diet can lead to metabolic syndrome and increase the risk of atherosclerotic cardiovascular disease. This study examined whether FA could mitigate vascular inflammation, aortic stiffness, and cardiovascular remodeling in rats fed a HFHC diet.MethodsMale Sprague–Dawley rats were divided into five groups (eight rats/group): one group was fed a standard chow diet with or without FA supplementation, while the others were fed a HFHC diet plus a 15% fructose solution for 16 weeks. Rats on the HFHC diet received FA at doses of 0, 30, or 60 mg/kg/day during the final 6 weeks of the study. Various cardiovascular parameters, plasma biochemical markers, and the expression of biomarker proteins were measured.ResultsFA administration alleviated the metabolic disturbances caused by the HFHC diet. FA reduced arterial blood pressure, aortic pulse wave velocity, oxidative stress, vascular inflammation, and angiotensin-mediated myocardial fibrosis and cardiac hypertrophy, as evidenced by decreases in ventricular interstitial fibrosis and cross-sectional area. These beneficial effects were associated with reduced vascular superoxide production and lower plasma levels of angiotensin-converting enzyme and tumor necrosis factor α. FA also suppressed the expression of Ang II type 1 receptor, gp91phox, and vascular-adhesion molecule 1 proteins and prevented hypertrophic remodeling of the aortic wall by reducing protein expression of matrix metalloproteinases 2 and 9.ConclusionThis study provides insightful findings on the beneficial effects of FA in reducing aortic stiffness and cardiovascular remodeling associated with metabolic syndrome.

Canine angiostrongylosis, caused by Angiostrongylus vasorum, affects dogs and red foxes, with dogs developing cardiopulmonary and coagulation disorders, while foxes remain mostly subclinical. This study examined aortic endothelial cell responses from both species to A. vasorum adult full somatic antigen extracts, first-stage larval (L1) antigen, and adult excretory-secretory products (ESP). Differential gene expression of interleukins (IL) -6, -10, and -33, intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), endothelial selectin (E-selectin), platelet selectin (P-selectin), vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein 1 (MCP-1) was assessed via reverse transcription quantitative PCR (RT qPCR) after four and 24 hours of antigen exposure. Four hours post ESP stimulation, IL-10 increased in dogs (1.8-fold) but decreased in foxes (0.4-fold). IL-33 declined in both, (0.9-fold vs. 0.7-fold, respectively). VCAM-1 was upregulated more in foxes (3.5-fold vs. 1.2 in dogs). Following adult antigen exposure, P-selectin, ICAM-1, and VCAM-1 increased in fox more than in dog cells (1.4, 1.7, and 3.1-fold vs. 0.9, 0.5, and 0.7-fold, respectively). L1 antigen downregulated IL-10 and MCP-1 in dogs (0.7 and 0.8-fold) but upregulated them in foxes (2.1 and 1.1-fold). Twenty-four hours after ESP stimulation, ICAM-1 decreased in dogs (0.8-fold) but increased in foxes (1.4-fold). VCAM-1 was downregulated in dogs (0.6-fold) but upregulated in foxes (12.9-fold). Adult antigen exposure upregulated P-selectin in both species, more in foxes (4.8-fold) than in dogs (1.9-fold). ICAM-1 was downregulated in dogs (0.8-fold) but upregulated 7.5-fold in foxes. L1 antigen stimulation caused the most substantial differences between species: IL-6 was upregulated more in dogs (4.7-fold) than foxes (1.2-fold). E-Selectin was upregulated in dogs (12.8-fold) but downregulated in foxes (0.2-fold). P-selectin increased more in dogs (10.0-fold) than in foxes (1.7-fold). ICAM-1 was downregulated in dogs (0.6-fold) but upregulated in foxes (2.6-fold), as was VCAM-1 (0.7-fold and 3.1-fold). VEGF was upregulated 9.5-fold in dogs after adult antigen exposure, and 7.6-fold after L1 antigen exposure, while it remained rather unchanged in foxes (0.9-fold and 1.0-fold, respectively). These findings corroborate that foxes have developed mechanisms for a regulated immune response following A. vasorum exposure, while dogs exhibit a higher pro-inflammatory reaction, contributing to severe clinical outcomes. Host-parasite co-evolution may explain differences in the pathogenesis and clinical presentation of canid angiostrongylosis.