Search

BACKGROUND: Although VCAM-1 (vascular cell adhesion molecule-1) and ICAM-1 (intercellular adhesion molecule-1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM-1 and ICAM-1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM-1, ICAM-1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. METHODS AND RESULTS: In MESA (Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM-1 and ICAM-1 at examination 2 (2002-2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010-2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM-1 or ICAM-1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM-1 or ICAM-1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM-1 and ICAM-1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2-30) of the relationship between VCAM-1 and HFpEF and 9% (95% CI, 2-21) of the relationship between VCAM-1 and AF. CONCLUSIONS: Higher VCAM-1 and ICAM-1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM-1 and ICAM-1 may promote HFpEF and AF risk through impaired LA reservoir function.

BACKGRUOUND: Phospholipase C-γ (PLC-γ) plays a crucial role in immune responses and is related to the pathogenesis of various inflammatory disorders. In this study, we investigated the role of PLC-γ and the therapeutic effect of the PLC-specific inhibitor U73122 using orbital fibroblasts from patients with Graves orbitopathy (GO). METHODS: The expression of phospholipase C gamma 1 (PLCG1) and phospholipase C gamma 2 (PLCG2) was evaluated using polymerase chain reaction in GO and normal orbital tissues/fibroblasts. The primary cultures of orbital fibroblasts were treated with non-toxic concentrations of U73122 with or without interleukin (IL)-1β to determine its therapeutic efficacy. The proinflammatory cytokine levels and activation of downstream signaling molecules were determined using Western blotting. RESULTS: PLCG1 and PLCG2 mRNA expression was significantly higher in GO orbital tissues than in controls (P

Introduction. Gamma-glutamyltransferase (GGT) is a liver enzyme involved in inflammation and oxidative stress. It is already known that MCP-1 (Monocyte Chemoattractant Protein-1) and TNF-α (tumour necrosis factor) as inflammatory markers, ICAM-1 (Intercellular Adhesion Molecule-1) as an endothelial dysfunctional marker, and glutathione, as an antioxidant, have abnormal levels in type 2 diabetic patients. The aim of this study was to evaluate the specific biological picture of type 2 diabetic patients that also associate higher GGT activity.

AIM: To investigate the effects and mechanism of Xin-Tong-Tai granule on oxidized low-density lipoprotein (ox-LDL), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in mice with atherosclerosis (AS). METHODS: A total of 72 SPF-grade healthy male ApoEmice aged 6-8 weeks were fed with high-fat diet for 12 weeks to replicate AS models, and 12 SPF-grade healthy male C57BL/6J wild mice were fed with ordinary diet as the control group. After the corresponding drugs were administered for 8 weeks, the body weight and general condition of mice in each group were observed. The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected by biochemical kits. The pathological structures of aorta were observed by HE and oil red O staining. The levels of serum ox-LDL and aortic ICAM-1 and VCAM-1 were detected by ELISA. The protein levels of NADPH oxidase 4 (NOX4), NOX subunit p22phox, inhibitor of kB kinase-a (IKK-a), IKK-p and nuclear factor-KB (NF-kB) in aorta were detected by Western blot. RESULTS: Compared with control group, the mice in model group showed increased body weight (P<0. 05), dull and local shedding hair, slow grasping response, increased serum TC, TG and LDL-C levels, decreased serum HDL-C level (P< 0.05), increased the levels of serum ox-LDL and aortic ICAM-1 and VCAM-1 (P<0. 05), and increased protein expressions of NOX4, p22phox, IKK-a, IKK-p and NF-kB in aorta (P<0. 05). Compared with model group, the body weight of mice in each treatment group decreased (P<0. 05), the hair loss and the response flexibility were also improved. The serum levels of TC, TG and LDL-C decreased and HDL-C increased (P<0. 05). The levels of serum ox-LDL and aortic ICAM-1 (except the low-dose Xin-Tong-Tai granule group) and VCAM-1 decreased (P<0. 05). The protein levels of NOX4, p22phox, IKK-a, IKK-p and NF-kB in aorta decreased (P<0. 05). HE and oil red O staining showed that typical AS plaques could be seen in blood vessels of the model group, and the red-stained areas were widely distributed. The above lesions were alleviated to different degrees in each treatment group compared with model group. CONCLUSION: Xin-Tong-Tai granule reduces the atherosclerotic plaque area of Apoh mice induced by high-fat diet, decreased serum TC, TG and LDL-C levels, increased HDL-C level, decreased the levels of serum ox-LDL and aorta ICAM-1 and VCAM- 1,and inhibited protein expression of NOX4, p22phox, IKK-a and IKK-p in the aorta, thereby attenuating AS. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the efficacy of modified Wendan decoction in the treatment of patients with acute stage of ischemic stroke of Qi-deficiency, blood-stasis and phlegm-obstruction and its effects on the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), intercellular adhesion molecule-1 ( ICAM-1) and monocyte chemoattractant protein-1 ( MCP-1). METHODS: A total of 100 patients with acute stage of ischemic stroke of Qi-deficiency, blood-stasis and phlegm-obstruction admitted into the hospital from May 2021 to May 2022 were selected as research objects, which were divided into control group and observation group using a random number table method, with 50 cases in each group. The control group was given conventional treatment, while the observation group received modified Wendan decoction based on the control group. The clinical efficacy, levels of NT-proBNP, NT-proBNP and MCP-1, the National Institutes of Health Stroke Scale ( NIHSS) score, Modified Rankin Scale ( mRS) score and traditional Chinese medicine (TCM) syndrome integral were compared between two groups. RESULTS: After 1 month of treatment, the total effective rate of the observation group was 94. 00% (47/ 50), which was significantly higher than 80. 00% (40/ 50) of the control group, with statistically significant difference (P<0. 05). After 1 month of treatment, the NT-proBNP, NT-proBNP and MCP-1 levels of the observation group were significantly lower than those of the control group, the various hemorheological indicators (plasma viscosity, blood low-shear viscosity, blood high-shear viscosity, fibrinogen and hematokrit) of the observation group were significantly lower than those of the control group, with statistically significant differences (P<0. 05). After 7 d and 1 month of treatment, the NIHSS scores of the observation group were lower than those of the control group; after 1 month of treatment, the mRS score and TCM integral of the observation group were lower than those of the control group, with statistically significant differences ( P<0. 05). CONCLUSIONS: The efficacy of modified Wendan decoction in the treatment of patients with acute stage of ischemic stroke of Qi-deficiency, blood-stasis and phlegm-obstruction is remarkable, which can significantly reduce the levels of NT-proBNP, NT-proBNP and MCP-1, improve blood circulation and disease recovery, promote patients’ quality of life. [ABSTRACT FROM AUTHOR]

In our previous study, two oleanane-type pentacyclic triterpenoids (oleanolic acid and maslinic acid) were reported to affect the N-glycosylation and intracellular trafficking of intercellular adhesion molecule-1 (ICAM-1). The present study was aimed at investigating the structure–activity relationship of 13 oleanane-type natural triterpenoids with respect to the nuclear factor κB (NF-κB) signaling pathway and the expression, intracellular trafficking, and N-glycosylation of the ICAM-1 protein in human lung adenocarcinoma A549 cells. Hederagenin, echinocystic acid, erythrodiol, and maslinic acid, which all possess two hydroxyl groups, decreased the viability of A549 cells. Celastrol and pristimerin, both of which possess an α,β-unsaturated carbonyl group, decreased cell viability but more strongly inhibited the interleukin-1α-induced NF-κB signaling pathway. Oleanolic acid, moronic acid, and glycyrrhetinic acid interfered with N-glycosylation without affecting the cell surface expression of the ICAM-1 protein. In contrast, α-boswellic acid and maslinic acid interfered with the N-glycosylation of the ICAM-1 protein, which resulted in the accumulation of high-mannose-type N-glycans. Among the oleanane-type triterpenoids tested, α-boswellic acid and maslinic acid uniquely interfered with the intracellular trafficking and N-glycosylation of glycoproteins. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.

PURPOSE: Physical inactivity and obesity increase risk for breast cancer recurrence and cardiovascular death; inflammation is hypothesized to mediate these associations. METHODS: In a four-arm randomized controlled trial, 318 breast cancer survivors with overweight or obesity were randomized to exercise alone, weight loss alone, exercise plus weight loss, or control for 12 months. Inflammation outcomes included C-reactive protein (CRP), serum amyloid A (SAA), intracellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). RESULTS: Compared with control, exercise alone increased ICAM-1 (9.3%; 95% confidence interval [CI] = 1.6-16.9) and VCAM-1 (8.6%; 95% CI = 2.6-14.5) but did not change CRP or SAA. Compared with control, weight loss alone reduced CRP (-35.2%; 95% CI = -49.9 to -20.7), and SAA (-25.6%; 95% CI = -39.8 to -11.9) but did not change ICAM-1 or VCAM-1. Compared with control, exercise plus weight loss reduced CRP (-44.1%; 95% CI = -57.1 to -31.1) and SAA (-26.6%; 95% CI = -40.5 to -12.6) but did not change ICAM-1 or VCAM-1. Among 194 participants with elevated CRP at baseline (e.g., >3 mg·L -1 ), compared with control, weight loss alone (0.17; 95% CI = 0.04-0.30) and exercise plus weight loss (0.31; 95% CI = 0.16-0.46) increased the probability of achieving normal CRP at month 12. In analyses that consolidated randomized groups, body weight and adiposity reductions, but not change in fitness level, correlated with decreased CRP, SAA, and ICAM-1 levels. CONCLUSIONS: In breast cancer survivors with overweight or obesity, weight loss or exercise plus weight loss reduced measures of inflammation that are associated with breast cancer recurrence and cardiovascular death.

Intercellular adhesion molecule-1 (ICAM-1) is identified as an initiator of neuroinflammatory responses that lead to neurodegeneration and cognitive and sensory-motor deficits in several pathophysiological conditions including traumatic brain injury (TBI). However, the underlying mechanisms of ICAM-1-mediated leukocyte adhesion and transmigration and its link with neuroinflammation and functional deficits following TBI remain elusive. Here, we hypothesize that blocking of ICAM-1 attenuates the transmigration of leukocytes to the brain and promotes functional recovery after TBI. The experimental TBI was induced in vivo by fluid percussion injury (25 psi) in male and female wild-type and ICAM-1-/- mice and in vitro by stretch injury (3 psi) in human brain microvascular endothelial cells (hBMVECs). We treated hBMVECs and animals with ICAM-1 CRISPR/Cas9 and conducted several biochemical analyses and demonstrated that CRISPR/Cas9-mediated ICAM-1 deletion mitigates blood-brain barrier (BBB) damage and leukocyte transmigration to the brain by attenuating the paxillin/focal adhesion kinase (FAK)-dependent Rho GTPase pathway. For analyzing functional outcomes, we used a cohort of behavioral tests that included sensorimotor functions, psychological stress analyses, and spatial memory and learning following TBI. In conclusion, this study could establish the significance of deletion or blocking of ICAM-1 in transforming into a novel preventive approach against the pathophysiology of TBI. [ABSTRACT FROM AUTHOR]

Donor-specific HLA Abs contribute to Ab-mediated rejection (AMR) by binding to HLA molecules on endothelial cells (ECs) and triggering intracellular signaling, leading to EC activation and leukocyte recruitment. The molecular mechanisms involving donor-specific HLA Ab-mediated EC activation and leukocyte recruitment remain incompletely understood. In this study, we determined whether TLRs act as coreceptors for HLA class I (HLA I) in ECs. We found that human aortic ECs express TLR3, TLR4, TLR6, and TLR10, but only TLR4 was detected on the EC surface. Consequently, we performed coimmunoprecipitation experiments to examine complex formation between HLA I and TLR4. Stimulation of human ECs with HLA Ab increased the amount of complex formation between HLA I and TLR4. Reciprocal coimmunoprecipitation with a TLR4 Ab confirmed that the crosslinking of HLA I increased complex formation between TLR4 and HLA I. Knockdown of TLR4 or MyD88 with small interfering RNAs inhibited HLA I Ab-stimulated P-selectin expression, von Willebrand factor release, and monocyte recruitment on ECs. Our results show that TLR4 is a novel coreceptor for HLA I to stimulate monocyte recruitment on activated ECs. Taken together with our previous published results, we propose that HLA I molecules form two separate signaling complexes at the EC surface, that is, with TLR4 to upregulate P-selectin surface expression and capture of monocytes to human ECs and integrin β4 to induce mTOR-dependent firm monocyte adhesion via ICAM-1 clustering on ECs, two processes implicated in Ab-mediated rejection.

Aims/hypothesisInduction of intercellular adhesion molecule-1 (ICAM-1) has been implicated in the development of macrovascular and microvascular diseases such as diabetic retinopathy. Lesions of diabetic retinopathy are unique to the retina but the reason for this is unclear, as all tissues are exposed to the same hyperglycaemic insult. We tested whether diabetes induces ICAM-1 on the luminal surface of endothelial cells to a greater extent in the retina than in other tissues and the role of vision itself in that induction.MethodsExperimental diabetes was induced in C57Bl/6J, P23H opsin mutant and Gnat1-/- × Gnat2-/- double knockout mice using streptozotocin. The relative abundance of ICAM-1 on the luminal surface of endothelial cells in retina and other tissues was determined by conjugating anti-ICAM-1 antibodies to fluorescent microspheres (2 μm), injecting them intravenously and allowing them to circulate for 30 min. After transcardial perfusion, quantification of microspheres adherent to the endothelium in tissues throughout the body was carried out by fluorescent microscopy or flow cytometry. Mice injected with lipopolysaccharide (LPS) were used as positive controls. The difference in leucostasis between retinal and non-retinal vasculature was evaluated.ResultsDiabetes significantly increased ICAM-1-mediated adherence of microspheres to retinal microvessels by almost threefold, independent of sex. In contrast, diabetes had a much smaller effect on endothelial ICAM-1 in other tissues, and more tissues showed a significant induction of endothelial ICAM-1 with LPS than with diabetes. The diabetes-induced increase in endothelial ICAM-1 in retinal vasculature was inhibited by blocking phototransduction in photoreceptor cells. Diabetes significantly increased leucostasis in the retina by threefold compared with a non-ocular tissue (cremaster).Conclusions/interpretationThe diabetes-induced upregulation of ICAM-1 on the luminal surface of the vascular endothelium varies considerably among tissues and is highest in the retina. Induction of ICAM-1 on retinal vascular endothelial cells in diabetes is influenced by vision-related processes in photoreceptor cells. The unique presence of photoreceptors in the retina might contribute to the greater susceptibility of this tissue to vascular disease in diabetes.

Background and Aim: Aging is often accompanied by inflammation and lipid abnormalities. This study aimed at investigating the effects of endurance training combined with Citrus aurantium L.var. amara Engl. (CAVAO) consumption on the lipid profile, intercellular adhesion molecules-1 (ICAM-1), and vascular cell adhesion molecules-1 (VCAM-1) in aged Sprague-Dawley rats. Methods: In this experimental study, 35 aged Sprague-Dawley rats were divided into 7 groups: high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), HIIT with CAVAO (HIIT+CA), MICT with CAVAO (MICT+CA), CAVAO alone (CA) (300 mg/kg/day), control, and sham. Over eight weeks, HIIT was conducted at 85-110% VO2max intensity, while MICT was performed at 65-75% VO2max intensity. Lipid profiles were assessed using a kit, and ICAM-1 and VCAM-1 gene expressions were analyzed via RT-PCR. Results: HIIT, MICT, HIIT+CA, MICT+CA, and CA resulted in a significant increase in HDL levels, with HIIT showing the most pronounced effect (P

BackgroundCognitive dysfunction in schizophrenia is the key predictor of functional disability and drives economic burden. Inflammation has been increasingly implicated in the pathogenesis of schizophrenia, yet its role in cognitive decline has not been evaluated. This study explores the association between inflammation and cognitive functioning in persons with schizophrenia.MethodsParticipants included 143 persons with schizophrenia (PwS) and 139 non-psychiatric comparison subjects (NCs) from an ongoing study of aging. Cognitive assessments included validated measures for executive functioning, processing speed, and visuospatial skills. Plasma levels of nine biomarkers associated with inflammation (high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, interleukin-8, interferon gamma-induced protein-10, monocyte chemotactic protein-1, fractalkine, and brain-derived neurotrophic factor) were quantified using commercially available, enzyme-linked immunosorbent assays. Partial least squares regression was used to develop a composite "inflammatory profile" to maximize correlations with the cognitive outcomes. We then constructed a best-fit model using these composites and their interactions with diagnosis and sex as the predictors, controlling for covariates.ResultsThe biomarker composite, which best correlated with scores on cognitive testing, included high sensitivity C-reactive protein, intercellular adhesion molecule 1, serum amyloid A, interleukin-6, and brain-derived neurotrophic factor, for a 5-biomarker "inflammatory profile." The best-fit model showed a significant biomarker composite by diagnosis by sex three-way interaction, for executive function and processing speed, but not visuospatial skill.ConclusionsThis approach to building an "inflammatory profile" may provide insight into inflammatory pathways affecting brain function and potential targets for anti-inflammatory interventions to improve cognition in schizophrenia.

Background: The burden of cardiovascular diseases caused by ambient particulate air pollution is universal. An increasing number of studies have investigated the potential effects of exposure to particulate air pollution on endothelial function, which is one of the important mechanisms for the onset and development of cardiovascular disease. However, no previous study has conducted a summary analysis of the potential effects of particulate air pollution on endothelial function. Objectives: To summarize the evidence for the potential effects of short-term exposure to ambient particulate air pollution on endothelial function based on existing studies. Methods: A systematic literature search on the relationship between ambient particulate air pollution and biomarkers of endothelial function including endothelin-1 (ET-1), E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) was conducted in PubMed, Scopus, EMBASE, and Web of Science up to 20 May 2023. Subsequently, a meta-analysis was conducted using a random effects model. Results: A total of 18 studies were included in this meta-analysis. A 10 μg/m3 increase in short-term exposure to ambient PM2.5 was associated with a 1.55% (95% CI: 0.89%, 2.22%) increase in ICAM-1 and a 1.97% (95% CI: 0.86%, 3.08%) increase in VCAM-1. The associations of ET-1 (0.22%, 95% CI: −4.94%, 5.65%) and E-selectin (3.21%, 95% CI: −0.90% 7.49%) with short-term exposure to ambient PM2.5 were statistically insignificant. Conclusion: Short-term exposure to ambient PM2.5 pollution may significantly increase the levels of typical markers of endothelial function, including ICAM-1 and VCAM-1, suggesting potential endothelial dysfunction following ambient air pollution exposure. [ABSTRACT FROM AUTHOR]

Sleep apnea syndrome (SAS) exposes cells throughout the body to intermittent hypoxia (IH). Intermittent hypoxia is a risk factor not only for hypertension and insulin resistance but also for vascular dysfunction. We have reported correlations between IH, insulin resistance and hypertension. However, the details of why IH leads to vascular dysfunction remain unclear. In this study, we investigated inflammation‐related transcripts in vascular endothelial cells (human HUEhT‐1 and mouse UV2) exposed to IH by real‐time RT‐PCR and found that intercellular adhesion molecule‐1 (ICAM‐1) and endothelial cell‐specific molecule‐1 (ESM1) mRNAs were significantly increased. ELISA confirmed that, in the UV2 cell medium, ICAM‐1 and ESM1 were significantly increased by IH. However, the promoter activities of ICAM‐1 and ESM1 were not upregulated. On the other hand, IH treatment significantly decreased microRNA (miR)‐181a1 in IH‐treated cells. The introduction of miR‐181a1 mimic but not miR‐181a1 mimic NC abolished the IH‐induced upregulation of Ican‐1 and ESM1. These results indicated that ICAM‐1 and ESM1 were upregulated by IH via the IH‐induced downregulation of miR‐181a1 in vascular endothelial cells and suggested that SAS patients developed atherosclerosis via the IH‐induced upregulation of ICAM‐1 and ESM1. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still a global concern with high morbidity and mortality rates. The role of endothelial cells in the progress of COVID-19 is well established. Therefore, the current study aimed to measure the endothelial markers and their correlation with the hematological parameters in intensive care unit-admitted COVID-19 patients. This study involved 111 adult participants, including 55 ICU-admitted patients with COVID-19 and 56 healthy controls. Levels of E-selectin, ICAM-1, and VCAM-1 in the plasma of the study participants were measured and correlated with hematological parameters. The study demonstrates that COVID-19 patients admitted to the ICU have higher levels of E-selectin, ICAM-1, and VCAM-1 compared to healthy controls (p <.05). These elevated levels can serve as reliable indicators of endothelial dysfunction and early markers for the detection and prediction of endothelial cell involvement in COVID-19 complications. The findings of this study suggest that increased levels of E-selectin, VCAM-1, and ICAM-1 in patients with COVID-19 are indicative of the participation of endothelial cells in the pathogenesis of COVID-19 complications. Consequently, these endothelial markers are proposed as potential early indicators for predicting the severity of COVID-19. [ABSTRACT FROM AUTHOR]

Altered glycosylation profiles have been correlated with potential drug targets in various diseases, including Alzheimer’s disease (AD). In this area, the linkage between bisecting N-acetylglucosamine (GlcNAc), a product of N-acetylglucosaminyltransferase III (GnT-III), and AD has been recognized, however, our understanding of the cause and the causative role of this aberrant glycosylation in AD are far from completion. Moreover, the effects and mechanisms of glycosylation-targeting interventions on memory and cognition, and novel targeting strategies are worth further study. Here, we showed the characteristic amyloid pathology-induced and age-related changes of GnT-III, and identified transcription factor 7-like 2 as the key transcription factor responsible for the abnormal expression of GnT-III in AD. Upregulation of GnT-III aggravated cognitive dysfunction and Alzheimer-like pathologies. In contrast, loss of GnT-III could improve cognition and alleviate pathologies. Furthermore, we found that an increase in bisecting GlcNAc modified ICAM-1 resulted in impairment of microglial responses, and genetic inactivation of GnT-III protected against AD mechanistically by blocking the aberrant glycosylation of ICAM-1 and subsequently modulating microglial responses, including microglial motility, phagocytosis ability, homeostatic/reactive state and neuroinflammation. Moreover, by target-based screening of GnT-III inhibitors from FDA-approved drug library, we identified two compounds, regorafenib and dihydroergocristine mesylate, showing pharmacological potential leading to modulation of aberrant glycosylation and microglial responses, and rescue of memory and cognition deficits.

Introduction: The available literature on vascular risk and endothelial dysfunction in patients with Chronic Migraine (CM) is limited. CM patients are known to have a higher risk of cardiovascular and cerebrovascular events. The present study aims to characterise the vascular risk and endothelial dysfunctions in CM patients and compare them with Healthy Controls (HC). Aim: To assess the vascular risk factors and biomarkers of endothelial dysfunction in CM patients and compare them with healthy non-headache controls. Materials and Methods: This cross-sectional study was conducted from October 2021 to January 2023 at the headache clinic of GB Pant Institute of Postgraduate Medical Education and Research in Delhi, India. The patients were diagnosed with CM using the International Classification of Headache Disorders-3 (ICHD-3) criteria. The patients were drug-naïve for preventive medications and did not have medication overuse headache. Clinical vascular risk factors such as Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Ankle Brachial Index (ABI), Body Mass Index (BMI), and Waist Hip Ratio (WHR) were measured. A battery of biochemical vascular risk factors, including serum C-reactive protein, leptin, insulin, fasting and post-prandial glucose, Glycosylated Haemoglobin (HbA1c), lipid profile, lipoprotein-A, pro-Brain Natriuretic Peptide (proBNP), and serum biomarkers of endothelial dysfunction like Intercellular Adhesion Molecules-1 (ICAM-1), Myeloperoxidase (MPO), Interleukin-6 (IL-6), Tumour Necrosis Factor-Alpha (TNFalpha), Asymmetric Dimethyl Arginine (ADMA), fibrinogen, and von Willebrand’s factor were measured in all patients during the interictal period. Statistical analysis was done using the Statistical Package for Social Sciences (SPSS) version 25.0, and the Mann-Whitney U test, student’s t-test, and Chi-square tests were applied. Results: Thirty-two patients with CM and thirty-two nonheadache healthy subjects were included in the study (age 30.6±8.8 years; 29 females and 3 males) vs. (31.7±7.9 years; 19 females and 13 males, respectively). Compared to HC, CM patients had significantly higher DBP (81.0±8.0 mmHg vs. 66.2±6.2 mmHg; p

The obligate intracellular parasite Toxoplasma gondii makes use of infected leukocytes for systemic dissemination. Yet, how infection impacts the processes of leukocyte diapedesis has remained unresolved. Here, we addressed the effects of T. gondii infection on the trans-endothelial migration (TEM) of dendritic cells (DCs) across polarised brain endothelial monolayers. We report that upregulated expression of leukocyte ICAM-1 is a feature of the enhanced TEM of parasitised DCs. The secreted parasite effector GRA15 induced an elevated expression of ICAM-1 in infected DCs that was associated with enhanced cell adhesion and TEM. Consequently, gene silencing of Icam-1 in primary DCs or deletion of parasite GRA15 reduced TEM. Further, the parasite effector TgWIP, which impacts the regulation of host actin dynamics, facilitated TEM across polarised endothelium. The data highlight that the concerted action of the secreted effectors GRA15 and TgWIP modulate the leukocyte-endothelial interactions of TEM in a parasite genotype-related fashion to promote dissemination. In addition to the canonical roles of endothelial ICAM-1, this study identifies a previously unappreciated role for leukocyte ICAM-1 in infection-related TEM.

On arrested neutrophils a focal adhesive cluster of ~200 high affinity (HA) β2-integrin bonds under tension is sufficient to trigger Ca2+ flux that signals an increase in activation in direct proportion to increments in shear stress. We reasoned that a threshold tension acting on individual β2-integrin bonds provides a mechanical means of transducing the magnitude of fluid drag force into signals that enhance the efficiency of neutrophil recruitment and effector function. Tension gauge tethers (TGT) are a duplex of DNA nucleotides that rupture at a precise shear force, which increases with the extent of nucleotide overlap, ranging from a tolerance of 54pN to 12pN. TGT annealed to a substrate captures neutrophils via allosteric antibodies that stabilize LFA-1 in a high- or low-affinity conformation. Neutrophils sheared on TGT substrates were recorded in real time to form HA β2-integrin bonds and flux cytosolic Ca2+, which elicited shape change and downstream production of reactive oxygen species. A threshold force of 33pN triggered consolidation of HA β2-integrin bonds and triggered membrane influx of Ca2+, whereas an optimum tension of 54pN efficiently transduced activation at a level equivalent to chemotactic stimulation on ICAM-1. We conclude that neutrophils sense the level of fluid drag transduced through individual β2-integrin bonds, providing an intrinsic means to modulate inflammatory response in the microcirculation.

In our previous study, two oleanane-type pentacyclic triterpenoids (oleanolic acid and maslinic acid) were reported to affect the N-glycosylation and intracellular trafficking of intercellular adhesion molecule-1 (ICAM-1). The present study was aimed at investigating the structure–activity relationship of 13 oleanane-type natural triterpenoids with respect to the nuclear factor κB (NF-κB) signaling pathway and the expression, intracellular trafficking, and N-glycosylation of the ICAM-1 protein in human lung adenocarcinoma A549 cells. Hederagenin, echinocystic acid, erythrodiol, and maslinic acid, which all possess two hydroxyl groups, decreased the viability of A549 cells. Celastrol and pristimerin, both of which possess an α,β-unsaturated carbonyl group, decreased cell viability but more strongly inhibited the interleukin-1α-induced NF-κB signaling pathway. Oleanolic acid, moronic acid, and glycyrrhetinic acid interfered with N-glycosylation without affecting the cell surface expression of the ICAM-1 protein. In contrast, α-boswellic acid and maslinic acid interfered with the N-glycosylation of the ICAM-1 protein, which resulted in the accumulation of high-mannose-type N-glycans. Among the oleanane-type triterpenoids tested, α-boswellic acid and maslinic acid uniquely interfered with the intracellular trafficking and N-glycosylation of glycoproteins.

This study tested the hypothesis that diabetes promotes a greater than normal cytosolic calcium level in rod cells that activates a Ca2+-sensitive protease, calpain, resulting in oxidative stress and inflammation, two pathogenic factors of early diabetic retinopathy. Nondiabetic and 2-month diabetic C57Bl/6J and calpain1 knockout (Capn1-/-) mice were studied; subgroups were treated with a calpain inhibitor (CI). Ca2+ content was measured in photoreceptors using Fura-2. Retinal calpain expression was studied by quantitative RT-PCR and immunohistochemistry. Superoxide and expression of inflammatory proteins were measured using published methods. Proteomic analysis was conducted on photoreceptors isolated from untreated diabetic mice or treated daily with CI for 2 months. Cytosolic Ca2+ content was increased twofold in photoreceptors of diabetic mice as compared with nondiabetic mice. Capn1 expression increased fivefold in photoreceptor outer segments of diabetic mice. Pharmacologic inhibition or genetic deletion of Capn1 significantly suppressed diabetes-induced oxidative stress and expression of proinflammatory proteins in retina. Proteomics identified a protein (WW domain-containing oxidoreductase [WWOX]) whose expression was significantly increased in photoreceptors from mice diabetic for 2 months and was inhibited with CI. Knockdown of Wwox using specific siRNA in vitro inhibited increase in superoxide caused by the high glucose. These results suggest that reducing Ca2+ accumulation, suppressing calpain activation, and/or reducing Wwox up-regulation are novel targets for treating early diabetic retinopathy.

Abstract Introduction The humanized anti-α4 integrin blocking antibody natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS) that is associated with the risk of progressive multifocal leukoencephalopathy (PML). While extended interval dosing (EID) of NTZ reduces the risk for PML, the minimal dose of NTZ required to maintain its therapeutic efficacy remains unknown. Objective Here we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector/memory CD4+ T cell subsets or of PBMCs to the blood–brain barrier (BBB) under physiological flow in vitro. Results Making use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of α4-integrins failed to abrogate T cell arrest to the inflamed BBB under physiological flow. Complete inhibition of shear resistant T cell arrest required additional inhibition of β2-integrins, which correlated with a strong upregulation of endothelial intercellular adhesion molecule (ICAM)-1 on the respective BBB models investigated. Indeed, NTZ mediated inhibition of shear resistant T cell arrest to combinations of immobilized recombinant vascular cell adhesion molecule (VCAM)-1 and ICAM-1 was abrogated in the presence of tenfold higher molar concentrations of ICAM-1 over VCAM-1. Also, monovalent NTZ was less potent than bivalent NTZ in inhibiting T cell arrest to VCAM-1 under physiological flow. In accordance with our previous observations ICAM-1 but not VCAM-1 mediated T cell crawling against the direction of flow. Conclusion Taken together, our in vitro observations show that high levels of endothelial ICAM-1 abrogate NTZ mediated inhibition of T cell interaction with the BBB. EID of NTZ in MS patients may thus require consideration of the inflammatory status of the BBB as high levels of ICAM-1 may provide an alternative molecular cue allowing for pathogenic T cell entry into the CNS in the presence of NTZ.

Introduction: The available literature on vascular risk and endothelial dysfunction in patients with Chronic Migraine (CM) is limited. CM patients are known to have a higher risk of cardiovascular and cerebrovascular events. The present study aims to characterise the vascular risk and endothelial dysfunctions in CM patients and compare them with Healthy Controls (HC). Aim: To assess the vascular risk factors and biomarkers of endothelial dysfunction in CM patients and compare them with healthy non-headache controls. Materials and Methods: This cross-sectional study was conducted from October 2021 to January 2023 at the headache clinic of GB Pant Institute of Postgraduate Medical Education and Research in Delhi, India. The patients were diagnosed with CM using the International Classification of Headache Disorders-3 (ICHD-3) criteria. The patients were drug-naïve for preventive medications and did not have medication overuse headache. Clinical vascular risk factors such as Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Ankle Brachial Index (ABI), Body Mass Index (BMI), and Waist Hip Ratio (WHR) were measured. A battery of biochemical vascular risk factors, including serum C-reactive protein, leptin, insulin, fasting and post-prandial glucose, Glycosylated Haemoglobin (HbA1c), lipid profile, lipoprotein-A, pro-Brain Natriuretic Peptide (pro-BNP), and serum biomarkers of endothelial dysfunction like Intercellular Adhesion Molecules-1 (ICAM-1), Myeloperoxidase (MPO), Interleukin-6 (IL-6), Tumour Necrosis Factor-Alpha (TNFalpha), Asymmetric Dimethyl Arginine (ADMA), fibrinogen, and von Willebrand's factor were measured in all patients during the interictal period. Statistical analysis was done using the Statistical Package for Social Sciences (SPSS) version 25.0, and the Mann-Whitney U test, student's t-test, and Chi-square tests were applied. Results: Thirty-two patients with CM and thirty-two non-headache healthy subjects were included in the study (age 30.6±8.8 years; 29 females and 3 males) vs. (31.7±7.9 years; 19 females and 13 males, respectively). Compared to HC, CM patients had significantly higher DBP (81.0±8.0 mmHg vs. 66.2±6.2 mmHg; p<0.001). Among the biochemical parameters, CM patients had higher post-prandial blood sugar (mg/dL) (140.2±10.7 vs. 136.6±7.0; p=0.021), HbA1c (%) (5.8±0.8 vs. 5.6±0.4; p=0.034), serum cholesterol (mg/dL) (146.9±36.2 vs. 131±20.8), and Triglyceride (TG) levels (mg/dL) (93.2±10.8 vs. 88.5±13.0; p=0.001) compared to HCs. Among the biomarkers of endothelial dysfunction studied, levels of ICAM-1 (pg/mL) (4.5±3.8 vs. 1.3±0.62; p<0.001), MPO (pg/mL) (415.4±266.0 vs. 108.9±141.4; p=0.001), IL-6 (pg/mL) (10.8±4.9 vs. 4.2±1.5; p<0.001), and ADMA (ng/mL) (32.6±28.3 vs. 23.5±22.1; p=0.008) were higher in the CM group compared to non-headache controls. Conclusion: This study found that patients with CM have significantly higher vascular risk and evidence of endothelial dysfunction compared to healthy non-headache controls. The significantly elevated biomarkers of endothelial dysfunction may possibly be related to persistent neurogenic inflammation in CM and require further exploration through larger studies. [ABSTRACT FROM AUTHOR]

Lymphocyte function-associated antigen-1 (LFA-1) and its endothelial ligand intercellular adhesion molecule-1 (ICAM-1) are important for the migration of lymphocytes from blood vessels into lymph nodes. However, it is largely unknown whether these molecules mediate the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes through lymphatic vessels. In this study, we find that, in naive mice, ICAM-1 is expressed on the sinus endothelia of lymph nodes, but not on the lymphatic vessels of peripheral tissues. In in vivo lymphocyte migration assays, memory CD4+ T cells migrated to lymph nodes from peripheral tissues much more efficiently than from blood vessels, as compared to naive CD4+ T cells. Moreover, ICAM-1 deficiency in host mice significantly inhibited the migration of adoptively transferred wild-type donor lymphocytes from peripheral tissues, but not from blood vessels, into lymph nodes. The migration of LFA-1-deficient donor lymphocytes from peripheral tissues into the lymph nodes of wild-type host mice was also significantly reduced as compared to wild-type donor lymphocytes. Furthermore, the number of memory T cells in lymph nodes was significantly reduced in the absence of ICAM-1 or LFA-1. Thus, our study extends the functions of the LFA-1/ICAM-1 adhesion pathway, indicating its novel role in controlling the homeostatic migration of lymphocytes from peripheral tissues into lymph nodes and maintaining memory T cellularity in lymph nodes. [ABSTRACT FROM AUTHOR]

• Of 3 identified missense genetic variants in ICAM1, rs5491 was common in individuals of Black race/ethnicity and rare in other race/ethnic groups. • Among Black individuals, rs5491 was associated with higher circulating ICAM-1 levels. • In Black individuals, the presence of rs5491 was associated with an increased risk of incident heart failure with preserved ejection fraction in our primary cohort and with overall heart failure in a separate cohort. These findings suggest that a common missense variant of ICAM1 in individuals of Black race/ethnicity is associated with risk of heart failure. Intercellular adhesion molecule-1 (ICAM-1) is a cell surface protein that participates in endothelial activation and is hypothesized to play a central role in heart failure (HF). We evaluated associations of ICAM1 missense genetic variants with circulating ICAM-1 levels and with incident HF. We identified 3 missense variants within ICAM1 (rs5491, rs5498 and rs1799969) and evaluated their associations with ICAM-1 levels in the Coronary Artery Risk Development in Young Adults Study and the Multi-Ethnic Study of Atherosclerosis (MESA). We determined the association among these 3 variants and incident HF in MESA. We separately evaluated significant associations in the Atherosclerosis Risk in Communities (ARIC) study. Of the 3 missense variants, rs5491 was common in Black participants (minor allele frequency [MAF] > 20%) and rare in other race/ethnic groups (MAF < 5%). In Black participants, the presence of rs5491 was associated with higher levels of circulating ICAM-1 at 2 timepoints separated by 8 years. Among Black participants in MESA (n = 1600), the presence of rs5491 was associated with an increased risk of incident HF with preserved ejection fraction (HFpEF; HR = 2.30; [95% CI 1.25–4.21; P = 0.007]). The other ICAM1 missense variants (rs5498 and rs1799969) were associated with ICAM-1 levels, but there were no associations with HF. In ARIC, rs5491 was significantly associated with incident HF (HR = 1.24 [95% CI 1.02 – 1.51]; P = 0.03), with a similar direction of effect for HFpEF that was not statistically significant. A common ICAM1 missense variant among Black individuals may be associated with increased risk of HF, which may be HFpEF-specific. Visual Take Home Graphic: Missense Genetic Variation in ICAM1 and Incident HF. We identified 3 missense genetic variants of ICAM1. Of these 3 variants, 1 (rs5491) was common in individuals of Black race/ethnicity and rare in other race/ethnic cohorts. The presence of rs5491 was associated with higher circulating ICAM-1 levels. In Black individuals in MESA, rs5491 was associated with incident HFpEF. In a separate cohort of Black individuals, rs5491 was associated with incident HF. [Display omitted] [ABSTRACT FROM AUTHOR]

PurposeTo compare rates of tau biomarker positivity (T-status) per the 2018 Alzheimer's Disease (AD) Research Framework derived from [18F]flortaucipir (FTP) PET visual assessment, FTP quantification, and cerebrospinal fluid (CSF) phosphorylated Tau-181 (PTau181).MethodsWe included 351 subjects with varying clinical diagnoses from three cohorts with available FTP PET and CSF PTau181 within 18 months. T-status was derived from (1) FTP visual assessment by two blinded raters; (2) FTP standardized uptake value ratio (SUVR) quantification from a temporal meta-ROI (threshold: SUVR ≥1.27); and (3) Elecsys® Phospho-Tau (181P) CSF (Roche Diagnostics) concentrations (threshold: PTau181 ≥ 24.5 pg/mL).ResultsFTP visual reads yielded the highest rates of T+, while T+ by SUVR increased progressively from cognitively normal (CN) through mild cognitive impairment (MCI) and AD dementia. T+ designation by CSF PTau181 was intermediate between FTP visual reads and SUVR values in CN, similar to SUVR in MCI, and lower in AD dementia. Concordance in T-status between modality pairs ranged from 68 to 76% and varied by clinical diagnosis, being highest in patients with AD dementia. In discriminating Aβ + MCI and AD subjects from healthy controls and non-AD participants, FTP visual assessment was most sensitive (0.96) but least specific (0.60). Specificity was highest with FTP SUVR (0.91) with sensitivity of 0.89. Sensitivity (0.73) and specificity (0.72) were balanced for PTau181.ConclusionThe choice of tau biomarker may differ by disease stage and research goals that seek to maximize sensitivity or specificity. Visual interpretations of tau PET enhance sensitivity compared to quantification alone, particularly in early disease stages.

The increased incidence of whooping cough worldwide suggests that current vaccination against Bordetella pertussis infection has limitations in quality and duration of protection. The resurgence of infection has been linked to the introduction of acellular vaccines (aP), which have an improved safety profile compared with the previously used whole-cell (wP) vaccines. To determine immunological differences between aP and wP priming in infancy, we performed a systems approach of the immune response to booster vaccination. Transcriptomic, proteomic, cytometric, and serologic profiling revealed multiple shared immune responses with different kinetics across cohorts, including an increase of blood monocyte frequencies and strong antigen-specific IgG responses. Additionally, we found a prominent subset of aP-primed individuals (30%) with a strong differential signature, including higher levels of expression for CCL3, NFKBIA, and ICAM1. Contrary to the wP individuals, this subset displayed increased PT-specific IgE responses after boost and higher antigen-specific IgG4 and IgG3 antibodies against FHA and FIM2/3 at baseline and after boost. Overall, the results show that, while broad immune response patterns to Tdap boost overlap between aP- and wP-primed individuals, a subset of aP-primed individuals present a divergent response. These findings provide candidate targets to study the causes and correlates of waning immunity after aP vaccination.

PurposeNew therapies have changed the outlook for patients with multiple myeloma, but novel agents are needed for patients who are refractory or relapsed on currently approved drug classes. Novel targets other than CD38 and BCMA are needed for new immunotherapy development, as resistance to daratumumab and emerging anti-BCMA approaches appears inevitable. One potential target of interest in myeloma is ICAM1. Naked anti-ICAM1 antibodies were active in preclinical models of myeloma and safe in patients, but showed limited clinical efficacy. Here, we sought to achieve improved targeting of multiple myeloma with an anti-ICAM1 antibody-drug conjugate (ADC).Experimental designOur anti-ICAM1 human mAb was conjugated to an auristatin derivative, and tested against multiple myeloma cell lines in vitro, orthotopic xenografts in vivo, and patient samples ex vivo. The expression of ICAM1 was also measured by quantitative flow cytometry in patients spanning from diagnosis to the daratumumab-refractory state.ResultsThe anti-ICAM1 ADC displayed potent anti-myeloma cytotoxicity in vitro and in vivo. In addition, we have verified that ICAM1 is highly expressed on myeloma cells and shown that its expression is further accentuated by the presence of bone marrow microenvironmental factors. In primary samples, ICAM1 is differentially overexpressed on multiple myeloma cells compared with normal cells, including daratumumab-refractory patients with decreased CD38. In addition, ICAM1-ADC showed selective cytotoxicity in multiple myeloma primary samples.ConclusionsWe propose that anti-ICAM1 ADC should be further studied for toxicity, and if safe, tested for clinical efficacy in patients with relapsed or refractory multiple myeloma.

Background & aimsEosinophilic esophagitis (EoE) is an antigen-mediated eosinophilic disease of the esophagus that involves fibroblast activation and progression to fibrostenosis. Cytokines produced by T-helper type 2 cells and transforming growth factor beta 1 (TGFβ1) contribute to the development of EoE, but other cytokines involved in pathogenesis are unknown. We investigate the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE.MethodsWe analyzed publicly available esophageal CD3+ T-cell single-cell sequencing data for expression of LIGHT. Esophageal tissues were obtained from pediatric patients with EoE or control individuals and analyzed by immunostaining. Human primary esophageal fibroblasts were isolated from esophageal biopsy samples of healthy donors or patients with active EoE. Fibroblasts were cultured; incubated with TGFβ1 and/or LIGHT; and analyzed by RNA sequencing, flow cytometry, immunoblots, immunofluorescence, or reverse transcription polymerase chain reaction. Eosinophils were purified from peripheral blood of healthy donors, incubated with interleukin 5, cocultured with fibroblasts, and analyzed by immunohistochemistry.ResultsLIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals, and expressed by several T-cell populations, including T-helper type 2 cells. TNF receptor superfamily member 14 (TNFRSF14, also called HVEM) and lymphotoxin beta receptor are receptors for LIGHT that were expressed by fibroblasts from healthy donors or patients with active EoE. Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription, whereas stimulation with TGFβ1 induced transcription of genes associated with a myofibroblast phenotype. Stimulation of fibroblasts with TGFβ1 increased expression of HVEM; subsequent stimulation with LIGHT resulted in their differentiation into cells that express markers of myofibroblasts and inflammatory chemokines and cytokines. Eosinophils tethered to esophageal fibroblasts after LIGHT stimulation via intercellular adhesion molecule-1.ConclusionsT cells in esophageal tissues from patients with EoE express increased levels of LIGHT compared with control individuals, which induces differentiation of fibroblasts into cells with inflammatory characteristics. TGFβ1 increases fibroblast expression of HVEM, a receptor for LIGHT. LIGHT mediates interactions between esophageal fibroblasts and eosinophils via ICAM1. This pathway might be targeted for the treatment of EoE.

Objective: To investigate the clinical changes of serum melatonin and intercellular adhesion molecule-1 (ICAM-1) levels in patients with basal ganglia hypertensive intracerebral hemorrhage (HICH). Methods: In this retrospective observational study, patients with HICH in Suzhou Hospital of Traditional Chinese and Western Medicine from January 2020 to January 2021 were included as the observation group (n=120), and 120 healthy volunteers who underwent physical examination were included as the control group. According to the Glasgow Coma Scale (GCS), the observation group was divided into four subgroups: normal group (n=27), mild group (n=51), moderate group (n=24), and severe group (n=18). Differences in serum melatonin and ICAM-1 were compared between the observation group and the control group, and between the subgroups. Logistic regression was used to analyze the risk factors of poor prognosis, and the ROC curve was used to analyze the influence of melatonin and ICAM-1 levels on patient prognosis. Results: Serum melatonin levels were lower in the observation group compared to the control group, while ICAM-1 levels were higher (P<0.05). With the aggravation of brain injury, serum melatonin decreased and ICAM increased (P<0.05). Decreased serum melatonin and increased ICAM-1 were independent risk factors for poor prognosis in patients with HICH. The combined AUC of serum melatonin and ICAM-1 for the detection of poor prognosis in patients with HICH was 0.860, which was higher than that of the two alone (P<0.05). Conclusions: Low serum melatonin levels and high ICAM-1 levels are associated with poor prognosis in patients with HICH and can be used as predictors of patients' prognosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heatstroke is a highly fatal syndrome characterized by extensive endothelial cell injury and multiple organ failure caused by high temperature. The common complication is abnormal coagulation function, and vascular endothelial disease plays a key role in the coagulation disorder caused by severe heatstroke. OBJECTIVE: To observe the pathological changes of vascular endothelial cell injury in severe heatstroke pigs and the expression of intercellular cell adhesion molecule-1. METHODS: Twelve healthy male Bama miniature pigs (conventional animals) weighing 15-20 kg were randomly divided into normal temperature control group (n=6) and heatstroke group (n=6). Severe heatstroke pig model was made in the heatstroke group under high temperature and humidity environment. The pigs in the normal temperature control group were placed in a constant temperature humidity chamber. Venous blood samples before and after the experiment was collected for blood routine and coagulation function examinations in the two groups. The abdominal aorta, coronary artery and lung tissue samples at the same position were taken, and the pathological changes of the samples in the two groups were observed by hematoxylin-eosin staining. Immunohistochemical staining was used to observe the level of intercellular adhesion molecule-1 in the two groups. The ultrastructural changes of the coronary artery and lung were observed by high-power transmission electron microscope. RESULTS AND CONCLUSION: There were no significant changes in activated partial thromboplastin time, prothrombin time, plasma D-dimer, fibrinogen degradation product level and red blood cell and platelet counts in the normal temperature control group before and after the experiment (P > 0.05). The red blood cell count, activated partial thromboplastin time, prothrombin time, plasma D-dimer and fibrinogen degradation products in the heatstroke group increased significantly after the experiment and were higher than those in the normal temperature control group. Whereas, the platelet count decreased in the heatstroke group after the experimental and was significantly lower than that in the normal temperature control group (P < 0.05). Hematoxylin-eosin staining revealed that the pathological structure of abdominal aorta, coronary artery and pulmonary microvessels in the normal temperature control group was normal. Abdominal aortic endothelial cells in the heatstroke group were slightly edematous without obvious abnormalities; thrombosis, endothelial cell abscission, and necrosis were observed in the coronary artery, and the cell number decreased; and pulmonary microvascular diffuse hemorrhage and the number of endothelial cells decreased significantly. Immunohistochemical staining showed that the positive expression of intercellular adhesion molecule-1 with a large number of brownish yellow lines on the serosa of endothelial cells was observed in the abdominal aorta, coronary artery and lung of normal temperature control group; the number of endothelial cells on the serosa decreased significantly or the expression was absent and the light yellow intercellular adhesion molecule-1 was weakly positive in the heatstroke group; the average absorbance value of intercellular adhesion molecule-1 in vascular tissue in the heatstroke group was significantly lower than that in the normal temperature control group (P < 0.05). Under the electron microscope, irregular nuclei and swollen mitochondria were observed in coronary artery tissue in the heatstroke group, as well as a small amount of swollen nuclei and mitochondria observed in the lung tissue. To conclude, heatstroke can cause an injury to vascular endothelial cells, especially microvascular injury, in miniature pigs. [ABSTRACT FROM AUTHOR]

Interleukin-32 (IL-32), first reported in 2005, and its isoforms have been the subject of numerous studies investigating their functions in virus infection, cancer, and inflammation. IL-32θ, one of the IL-32 isoforms, has been shown to modulate cancer development and inflammatory responses. A recent study identified an IL-32θ mutant with a cytosine to thymine replacement at position 281 in breast cancer tissues. It means that alanine was also replaced to valine at position 94 in amino acid sequence (A94V). In this study, we investigated the cell surface receptors of IL-32θA94V and evaluated their effect on human umbilical vein endothelial cells (HUVECs). Recombinant human IL-32θA94V was expressed, isolated, and purified using Ni-NTA and IL-32 mAb (KU32-52)-coupled agarose columns. We observed that IL-32θA94V could bind to the integrins αVβ3 and αVβ6, suggesting that integrins act as cell surface receptors for IL-32θA94V. IL-32θA94V significantly attenuated monocyte-endothelial adhesion by inhibiting the expression of Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor (TNF)-α-stimulated HUVECs. IL-32θA94V also reduced the TNF-α-induced phosphorylation of protein kinase B (AKT) and c-jun N-terminal kinases (JNK) by inhibiting phosphorylation of focal adhesion kinase (FAK). Additionally, IL-32θA94V regulated the nuclear translocation of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), which are involved in ICAM-1 and VCAM-1 expression. Monocyte-endothelial adhesion mediated by ICAM-1 and VCAM-1 is an important early step in atherosclerosis, which is a major cause of cardiovascular disease. Our findings suggest that IL-32θA94V binds to the cell surface receptors, integrins αVβ3 and αVβ6, and attenuates monocyte-endothelial adhesion by suppressing the expression of ICAM-1 and VCAM-1 in TNF-α-stimulated HUVECs. These results demonstrate that IL-32θA94V can act as an anti-inflammatory cytokine in a chronic inflammatory disease such as atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: The humanized anti-α4 integrin blocking antibody natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS) that is associated with the risk of progressive multifocal leukoencephalopathy (PML). While extended interval dosing (EID) of NTZ reduces the risk for PML, the minimal dose of NTZ required to maintain its therapeutic efficacy remains unknown. Objective: Here we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector/memory CD4+ T cell subsets or of PBMCs to the blood–brain barrier (BBB) under physiological flow in vitro. Results: Making use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of α4-integrins failed to abrogate T cell arrest to the inflamed BBB under physiological flow. Complete inhibition of shear resistant T cell arrest required additional inhibition of β2-integrins, which correlated with a strong upregulation of endothelial intercellular adhesion molecule (ICAM)-1 on the respective BBB models investigated. Indeed, NTZ mediated inhibition of shear resistant T cell arrest to combinations of immobilized recombinant vascular cell adhesion molecule (VCAM)-1 and ICAM-1 was abrogated in the presence of tenfold higher molar concentrations of ICAM-1 over VCAM-1. Also, monovalent NTZ was less potent than bivalent NTZ in inhibiting T cell arrest to VCAM-1 under physiological flow. In accordance with our previous observations ICAM-1 but not VCAM-1 mediated T cell crawling against the direction of flow. Conclusion: Taken together, our in vitro observations show that high levels of endothelial ICAM-1 abrogate NTZ mediated inhibition of T cell interaction with the BBB. EID of NTZ in MS patients may thus require consideration of the inflammatory status of the BBB as high levels of ICAM-1 may provide an alternative molecular cue allowing for pathogenic T cell entry into the CNS in the presence of NTZ. [ABSTRACT FROM AUTHOR]

Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 is a newly recognized condition in children with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. These children and adult patients with severe hyperinflammation present with a constellation of symptoms that strongly resemble toxic shock syndrome, an escalation of the cytotoxic adaptive immune response triggered upon the binding of pathogenic superantigens to T cell receptors (TCRs) and/or major histocompatibility complex class II (MHCII) molecules. Here, using structure-based computational models, we demonstrate that the SARS-CoV-2 spike (S) glycoprotein exhibits a high-affinity motif for binding TCRs, and may form a ternary complex with MHCII. The binding epitope on S harbors a sequence motif unique to SARS-CoV-2 (not present in other SARS-related coronaviruses), which is highly similar in both sequence and structure to the bacterial superantigen staphylococcal enterotoxin B. This interaction between the virus and human T cells could be strengthened by a rare mutation (D839Y/N/E) from a European strain of SARS-CoV-2. Furthermore, the interfacial region includes selected residues from an intercellular adhesion molecule (ICAM)-like motif shared between the SARS viruses from the 2003 and 2019 pandemics. A neurotoxin-like sequence motif on the receptor-binding domain also exhibits a high tendency to bind TCRs. Analysis of the TCR repertoire in adult COVID-19 patients demonstrates that those with severe hyperinflammatory disease exhibit TCR skewing consistent with superantigen activation. These data suggest that SARS-CoV-2 S may act as a superantigen to trigger the development of MIS-C as well as cytokine storm in adult COVID-19 patients, with important implications for the development of therapeutic approaches.

RationalePatients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state.ObjectiveWe hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism.Methods and resultsWe evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3-mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration.ConclusionsCollectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.

β2 integrins are the main adhesion molecules in neutrophils and other leukocytes and are rapidly activated by inside-out signaling, which results in conformational changes that are transmitted through the transmembrane domain (TMD). Here, we investigated the biologic effect of introducing a proline mutation in the β2 integrin TMD to create a flexible kink that uncouples the topology of the inner half of the TMD from the outer half and impairs integrin activation. The β2 integrin alpha chains, αL, αM, αX, and αD, all contain an inserted (I) domain with homology to von Willebrand factor A domain. β2 activation was monitored in a homogenous binding assay of 2 reporter monoclonal antibodies: KIM127 reporting extension (E+ ) and mAb24 reporting the high-affinity (H+ ) conformation of the β2 I-like domain. The proline mutation partially diminished chemokine-induced extension, but not the high-affinity conformation. The proline mutation in the TMD of β2 completely inhibited arrest of rolling HL-60 cells in response to the chemokine IL-8. TMD mutant HL-60 cells rolling on P-selectin and ICAM-1 were unable to reduce their rolling velocity in response to IL-8. Quantitative dynamic footprinting live-cell imaging showed that blocking TMD topology transmission impaired the chemokine-induced activation of β2, limiting the appearance of extended high-affinity (E+ H+ ) β2. This also resulted in a defect in early spreading (3 min after arrest), which could be overcome by forced integrin activation using Mn2+ . We conclude that the TMD proline mutation severely impairs β2 integrin extension, cell arrest, and early spreading.

BackgroundFeline adipose-derived mesenchymal stem cells (ASCs) have been successfully used in clinical trials for the treatment of immune-mediated diseases with T cell dysregulation. However, the immunomodulatory pathways utilized by feline ASCs to suppress T cell activation have not been fully determined. We investigated the mechanisms used by feline ASCs to inhibit T cell proliferation, including the soluble factors and the cell-cell contact ligands responsible for ASC-T cell interaction.MethodsThe immunomodulatory activity of feline ASCs was evaluated via cell cycle analysis and in vitro mixed leukocyte reaction using specific immunomodulatory inhibitors. Cell-cell interactions were assessed with static adhesion assays, also with inhibitors.ResultsFeline ASCs decrease T cell proliferation by causing cell cycle arrest in G0-G1. Blocking prostaglandin (PGE2), but not IDO, partially restored lymphocyte proliferation. Although PDL-1 and CD137L are both expressed on activated feline ASCs, only the interaction of intercellular adhesion molecule 1 (ICAM-1, CD54) with its ligand, lymphocyte function-associated antigen 1 (LFA-1, CD11a/CD18), was responsible for ASC-T cell adhesion. Blocking this interaction reduced cell-cell adhesion and mediator (IFN-γ) secretion and signaling.ConclusionsFeline ASCs utilize PGE2 and ICAM-1/LFA-1 ligand interaction to inhibit T cell proliferation with a resultant cell cycle arrest in G0-G1. These data further elucidate the mechanisms by which feline ASCs interact with T cells, help define appropriate T cell-mediated disease targets in cats that may be amenable to ASC therapy, and may also inform potential translational models for human diseases.

Jieying Chen,1,&ast; Mingchen Lv,2,&ast; Xiaolian Su,1 Sizhu Wang,1 Yitong Wang,1 Zhen Fan,2,3 Lin Zhang,1 Guangyu Tang1 1Department of Radiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 2Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai, People’s Republic of China; 3Institute for Advanced Study, Tongji University, Shanghai, China; Department of Orthopedics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guangyu Tang; Lin Zhang, Tel +86-18917683528, Email tgy17@tongji.edu.cn; lynn122500@hotmail.comPurpose: Owing to the lack of effective biomarkers, triple-negative breast cancer (TNBC) has the worst prognosis among all subtypes of breast cancer. Meanwhile, tremendous progress has been made to identify biomarkers for TNBC. However, limited number of biomarkers still restrain the specifically targeting outcomes against TNBC. Here, to solve the obstacle, we designed and synthesized a new type of biocompatible nanoparticles to amplify the targeting effects for TNBC theranostics.Methods: To identify the biomarker of TNBC, the expression of intercellular adhesion molecule-1 (ICAM1) was assessed by real-time polymerase chain reaction and western blot among all subtypes of breast cancer and normal breast epithelium. Then, vesicular nanoparticles based on poly(ethylene glycol)-poly(&epsiv;-caprolactone) copolymers were prepared by the double emulsion method and modified with anti-ICAM1 antibodies through click chemistry to conjugate with related antigens on TNBC cell membranes and then loaded with magnetic resonance imaging (MRI) contrast agent gadolinium and chemotherapeutic drug doxorubicin. The targeting capability, diagnostic and therapeutic efficacy of this nanoparticle were validated through cell-based and tumor model-based experiments.Results: ICAM1 was expressed significantly higher on TNBC than on other subtypes of breast cancer and normal breast epithelium in both mRNA and protein level. Theranostic nanoparticle modified with anti-ICAM1 was proved to be able to specifically target to TNBC in vitro experiments. Such theranostic nanoparticle also displayed enhanced diagnostic and therapeutic efficacy by specifically targeting capability and extending circulation time in tumor models. The biocompatibility and biosafety of this nanoparticle was also confirmed in vitro and in vivo.Conclusion: Overall, this new nanoparticle has been demonstrated with effective therapeutic outcomes against TNBC, providing a promising theranostic approach for MRI-guided therapy of TNBC.Keywords: breast carcinoma, nanoparticles, magnetic resonance imaging, theranostics, intercellular adhesion molecule-1

Introduction: Hepatic inflammation is considered key driver of hepatic tissue impairment.We aimed to explore the interaction of Halamphora coffeaeformis (Amph.) with low dose ionizing γ radiation (γ R) exposure against D-galactosamine (D-GaIN)-induced chronic hepatitis in Albino rats. Methods: Chronic hepatitis was induced with single dose of D-GalN (400 mg/kg BW i.p.). Rats received 400 mg Amph /kg BW daily by gastric gavage concomitant with.25 Gy γ -R. Liver oxidative stress and inflammatory status were assessed. Gene expression levels of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NFKB) were estimated by q-PCR. D-Galactosamine injection significantly encouraged hepatic oxidative damage and inflammatory disturbance accompanied with improved intercellular adhesion molecule-1 level (ICAM-1). Results: messenger RNA gene expression levels of STAT3 and NF-kB were expressively higher in D-GaIN-treated animals. Histopathological examination supported results. Interestingly, Amph treatment with γ -radiation (γ -R) subjection displayed significant improvement of oxidative and inflammatory status along with controlled signaling molecular factors which was supported by amended histological structure of induced liver hepatitis. Conclusion: Results conclude the efficacious control of liver hepatitis progression by dual collaboration of Amph. with low dose γ -R via control of vital growth signaling factors linked with inflammation thru anti-inflammation, antioxidative and anti-proliferative activities. [ABSTRACT FROM AUTHOR]

Malignant pleural mesothelioma (MPM) is an aggressive solid cancer with a poor prognosis, whereas coxsackievirus A11 (CVA11) is a potential oncolytic virus for cancer treatment. We here investigated the oncolytic activity of CVA11 with human MPM cell lines. CVA11 infection was cytotoxic in all six MPM cell lines examined and showed no or minimal cytotoxicity toward normal human normal cell lines. MPM cells with a higher surface level of intercellular adhesion molecule‐1 (ICAM‐1) expression tended to be more susceptible to CVA11‐induced cytotoxicity, and a neutralizing antibody to ICAM‐1 attenuated such cytotoxicity. CVA11 infection activated signaling by Akt and extracellular signal‐regulated kinase (ERK) pathways, and inhibitors of such signaling also abrogated CVA11‐mediated cytotoxicity. Furthermore, CVA11 infection‐triggered multiple modes of tumor cell death including apoptosis, pyroptosis, and necroptosis, and such death was accompanied by the release or exposure of the proinflammatory cytokine interleukin‐1β and damage‐associated molecular patterns such as calreticulin, high‐mobility group box‐1, annexin A1, and heat shock protein 70, which are hallmarks of immunogenic cell death. Notably, in vivo treatment of human MPM xenografts with intratumoral CVA11 injection resulted in significant suppression of tumor growth in SCID mice, and all mice infected with CVA11 showed no significant change in body weight. Our findings collectively suggest that the oncolytic activity of CVA11 for MPM is dependent on ICAM‐1 as a virus receptor, as well as on Akt and ERK signaling, and that oncolytic virotherapy with CVA11 is a promising treatment modality with immunostimulatory activity for human MPM. [ABSTRACT FROM AUTHOR]

Interleukin-32 (IL-32), first reported in 2005, and its isoforms have been the subject of numerous studies investigating their functions in virus infection, cancer, and inflammation. IL-32θ, one of the IL-32 isoforms, has been shown to modulate cancer development and inflammatory responses. A recent study identified an IL-32θ mutant with a cytosine to thymine replacement at position 281 in breast cancer tissues. It means that alanine was also replaced to valine at position 94 in amino acid sequence (A94V). In this study, we investigated the cell surface receptors of IL-32θA94V and evaluated their effect on human umbilical vein endothelial cells (HUVECs). Recombinant human IL-32θA94V was expressed, isolated, and purified using Ni-NTA and IL-32 mAb (KU32-52)-coupled agarose columns. We observed that IL-32θA94V could bind to the integrins αVβ3 and αVβ6, suggesting that integrins act as cell surface receptors for IL-32θA94V. IL-32θA94V significantly attenuated monocyte-endothelial adhesion by inhibiting the expression of Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor (TNF)-α-stimulated HUVECs. IL-32θA94V also reduced the TNF-α-induced phosphorylation of protein kinase B (AKT) and c-jun N-terminal kinases (JNK) by inhibiting phosphorylation of focal adhesion kinase (FAK). Additionally, IL-32θA94V regulated the nuclear translocation of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), which are involved in ICAM-1 and VCAM-1 expression. Monocyte-endothelial adhesion mediated by ICAM-1 and VCAM-1 is an important early step in atherosclerosis, which is a major cause of cardiovascular disease. Our findings suggest that IL-32θA94V binds to the cell surface receptors, integrins αVβ3 and αVβ6, and attenuates monocyte-endothelial adhesion by suppressing the expression of ICAM-1 and VCAM-1 in TNF-α-stimulated HUVECs. These results demonstrate that IL-32θA94V can act as an anti-inflammatory cytokine in a chronic inflammatory disease such as atherosclerosis.

Background: The burden of cardiovascular diseases caused by ambient particulate air pollution is universal. An increasing number of studies have investigated the potential effects of exposure to particulate air pollution on endothelial function, which is one of the important mechanisms for the onset and development of cardiovascular disease. However, no previous study has conducted a summary analysis of the potential effects of particulate air pollution on endothelial function. Objectives: To summarize the evidence for the potential effects of short-term exposure to ambient particulate air pollution on endothelial function based on existing studies. Methods: A systematic literature search on the relationship between ambient particulate air pollution and biomarkers of endothelial function including endothelin-1 (ET-1), E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) was conducted in PubMed, Scopus, EMBASE, and Web of Science up to 20 May 2023. Subsequently, a meta-analysis was conducted using a random effects model. Results: A total of 18 studies were included in this meta-analysis. A 10 μg/m3 increase in short-term exposure to ambient PM2.5 was associated with a 1.55% (95% CI: 0.89%, 2.22%) increase in ICAM-1 and a 1.97% (95% CI: 0.86%, 3.08%) increase in VCAM-1. The associations of ET-1 (0.22%, 95% CI: −4.94%, 5.65%) and E-selectin (3.21%, 95% CI: −0.90% 7.49%) with short-term exposure to ambient PM2.5 were statistically insignificant. Conclusion: Short-term exposure to ambient PM2.5 pollution may significantly increase the levels of typical markers of endothelial function, including ICAM-1 and VCAM-1, suggesting potential endothelial dysfunction following ambient air pollution exposure.

Rationale: Impaired lung function is a potent independent predictor of coronary artery disease (CAD) in individuals without human immunodeficiency virus (HIV) infection; however, the relationship between lung function and CAD in HIV remains undefined. Objectives: To examine the relationship between lung function, CAD, mortality, and circulating biomarkers in HIV. Methods: Spirometry, diffusing capacity of the lung for carbon monoxide (DlCO), emphysema, coronary artery calcium, mortality, cause of death, and biomarkers were examined in HIV-infected and uninfected individuals enrolled in a cohort study at the University of Pittsburgh. Results were then validated in the Multicenter AIDS Cohort Study (MACS) cohort. Results: We examined data on 234 participants in the Pittsburgh cohort. The mean ± standard deviation age was 49.5 ± 10.2 years old, 82.1% were male, and 67.5% were ever smokers. Among the 177 of 234 individuals with HIV infection, lower DlCO (not forced expiratory volume in 1 second or emphysema) was independently associated with greater coronary artery calcium (odds ratio, 1.43 per 10% lower DlCO; 95% confidence interval, 1.14-1.81). HIV-infected individuals with both reduced DlCO and coronary artery calcium had a much higher mortality than those with either low DlCO or coronary calcium alone or with neither condition. Endothelin-1, a circulating biomarker of endothelial dysfunction, was associated with both lower DlCO and greater coronary artery calcium in those with HIV infection. Results were reproducible in 144 individuals enrolled in the MACS cohort; intercellular adhesion molecule 1 was the biomarker of endothelial dysfunction assessed in the MACS cohort. Conclusions: Impaired DlCO and CAD were associated with each other and with higher mortality in individuals with HIV infection.

BackgroundDyslipidaemia is frequent in non-alcoholic steatohepatitis (NASH); however, it is unclear if improvement in liver histology is associated with favourable changes in cardiovascular disease (CVD) risk.AimsTo evaluate the relationship of NASH resolution and lipoprotein subfraction levels, markers of endothelial dysfunction, and macrophage activation.MethodsOne hundred and seventeen individuals with NASH who participated in the Pioglitazone vs Vitamin E vs Placebo for the Treatment of Nondiabetic Patients with NASH (PIVENS) trial with paired liver biopsies and serum samples available at baseline and after 96 weeks of treatment were included. Participants in the PIVENS trials received vitamin E, pioglitazone, or placebo for 96 weeks. Lipoprotein subfraction levels, intracellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), E-selectin, and sCD163 levels were assessed at baseline and week 96 and their relationship with NASH resolution was examined.ResultsFifty-seven individuals had NASH resolution and 60 individuals did not have resolution of NASH. NASH resolution was associated with favourable changes in lipoprotein subfraction levels compared to those without NASH resolution. Individuals with resolution of NASH had a significantly increased mean peak LDL diameter (ratio of geometric means [96 weeks vs baseline] 1.007 vs 0.996, P = 0.004), and higher frequency of LDL phenotype A (58% vs 33%, P = 0.003) at week 96, after adjustment for relevant co-variates including treatment group. No differences in VCAM, ICAM, E-selectin, or sCD163 levels by NASH resolution were found.ConclusionsNASH resolution is associated with favourable changes in a subset of serum lipoprotein levels. More studies are warranted to understand if these favourable changes are associated with decreased risk of CVD.

PURPOSE: Recent evidence suggests that retinal photoreceptor cells have an important role in the pathogenesis of retinal microvascular lesions in diabetes. We investigated the role of rod cell phototransduction on the pathogenesis of early diabetic retinopathy (DR) using Gnat1-/- mice (which causes permanent inhibition of phototransduction in rod cells without degeneration). METHODS: Retinal thickness, oxidative stress, expression of inflammatory proteins, electroretinograms (ERG) and optokinetic responses, and capillary permeability and degeneration were evaluated at up to 8 months of diabetes. RESULTS: The diabetes-induced degeneration of retinal capillaries was significantly inhibited in the Gnat1-/- diabetics. The effect of the Gnat1 deletion on the diabetes-induced increase in permeability showed a nonuniform accumulation of albumin in the neural retina; the defect was inhibited in diabetic Gnat1-/- mice in the inner plexiform layer (IPL), but neither in the outer plexiform (OPL) nor inner nuclear (INL) layers. In Gnat1-deficient animals, the diabetes-induced increase in expression of inflammatory associated proteins (iNOS and ICAM-1, and phosphorylation of IĸB) in the retina, and the leukocyte mediated killing of retinal endothelial cells were inhibited, however the diabetes-mediated induction of oxidative stress was not inhibited. CONCLUSIONS: In conclusion, deletion of transducin1 (and the resulting inhibition of phototransduction in rod cells) inhibits the development of retinal vascular pathology in early DR.

ObjectiveHIV-infected (HIV+) individuals may be at increased risk for sudden arrhythmic cardiac death. Some studies have reported an association between HIV infection and prolongation of the electrocardiographic QT interval, a measure of ventricular repolarisation, which could potentiate ventricular arrhythmias. We aimed to assess whether HIV+ men have longer QT intervals than HIV-uninfected (HIV-) men and to determine factors associated with QT duration.MethodsWe performed resting 12-lead ECGs in 774 HIV+ and 652 HIV- men in the Multicenter AIDS Cohort Study (MACS). We used multivariable linear and logistic regression analyses to assess associations between HIV serostatus and Framingham corrected QT interval (QTc), after accounting for potential confounders. We also determined associations among QTc interval and HIV-related factors in HIV+ men. In a subgroup of participants, levels of serum markers of inflammation were also assessed.ResultsAfter adjusting for demographics and risk factors, QTc was 4.0 ms longer in HIV+ than HIV- men (p

Helicobacter pylori infection induces a number of pro-inflammatory signaling pathways contributing to gastric inflammation and carcinogenesis. Among those, NF-κB signaling plays a pivotal role during infection and malignant transformation of the gastric epithelium. However, deficiency of the adaptor molecule myeloid differentiation primary response 88 (MyD88), which signals through NF-κB, led to an accelerated development of gastric pathology upon H. felis infection, but the mechanisms leading to this phenotype remained elusive. Non-canonical NF-κB signaling was shown to aggravate H. pylori-induced gastric inflammation via activation of the lymphotoxin β receptor (LTβR). In the present study, we explored whether the exacerbated pathology observed in MyD88-deficient (Myd88-/-) mice was associated with aberrant activation of non-canonical NF-κB. Our results indicate that, in the absence of MyD88, H. felis infection enhances the activation of non-canonical NF-κB that is associated with increase in Cxcl9 and Icam1 gene expression and CD3+ lymphocyte recruitment. In addition, activation of signal transducer and activator of transcription 3 (STAT3) signaling was higher in Myd88-/- compared to wild type (WT) mice, indicating a link between MyD88 deficiency and STAT3 activation in response to H. felis infection. Thereby, MyD88 deficiency results in accelerated and aggravated gastric pathology induced by Helicobacter through activation of non-canonical NF-κB.

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