VCAM-1 Research Articles

Vasostatins: new molecular targets for atherosclerosis, post-ischaemic angiogenesis, and arteriogenesis.

The chromogranin-secretogranin secretory proteins-granins-are acidic proteins localized in granules of endocrine cells and neurons. The chromogranin family includes chromogranins A (CgA) and B, as well as secretogranin II (once called chromogranin C). Members of this family undergo catalytic proteolysis to produce active peptides. The CgA-derived peptides vasostatin-1 and vasostatin-2, in particular, appear to protect against atherosclerosis, suppressing the expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, as well as exerting vasodilatory effects by enhancing nitric oxide bioavailability. Vasostatin-1 also suppresses vasoconstriction and abnormal angiogenesis. Vasostatin-1 and vasostatin-2 may be novel therapeutic targets for atherosclerosis and coronary heart disease, also protecting the myocardium against ischaemic damage.

Targeted deletion of NR2F2 and VCAM1 in theca cells impacts ovarian follicular development: insights into polycystic ovary syndrome?†.

Defining features of polycystic ovary syndrome (PCOS) include elevated expression of steroidogenic genes, theca cell androgen biosynthesis, and peripheral levels of androgens. In previous studies, we identified vascular cell adhesion molecule 1 (VCAM1) as a selective androgen target gene in specific NR2F2/SF1 (+/+) theca cells. By deleting NR2F2 and VCAM1 selectively in CYP17A1 theca cells in mice, we documented that NR2F2 and VCAM1 impact distinct and sometimes opposing theca cell functions that alter ovarian follicular development in vivo: including major changes in ovarian morphology, steroidogenesis, gene expression profiles, immunolocalization images (NR5A1, CYP11A1, NOTCH1, CYP17A1, INSL3, VCAM1, NR2F2) as well as granulosa cell functions. We propose that theca cells impact follicle integrity by regulating androgen production and action, as well as granulosa cell differentiation/luteinization in response to androgens and gonadotropins that may underlie PCOS.

Association between Ambient Particulate Air Pollution and Soluble Biomarkers of Endothelial Function: A Meta-Analysis.

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. To summarize the evidence for the potential effects of short-term exposure to ambient particulate air pollution on endothelial function based on existing studies. 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. 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. 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.

Ateroprotective effects of Plinia cauliflora in. New Zealand rabbits: beyond the lipid-lowering effect.

Introduction: Plinia cauliflora [Mart.] Kausel (Myrtaceae), popularly known as "jabuticaba," is a fruit species native to Brazil. Despite extensive widespread usage, its antiatherosclerotic properties' impact remains unknown. Thus, the present study aimed to investigate the cardioprotective effects of a preparation obtained from the fruit peels of P. cauliflora (EEPC). Methods: Male New Zealand rabbits received a 1% cholesterol-supplemented diet for 60days. On the thirtieth day, the animals were divided into five experimental groups and received, once a day, by the oral route, the EEPC (10, 30, and 100mg/kg), simvastatin (2.5mg/kg), or vehicle for 30days. At the end of the experimental period, peripheral blood and arterial branch samples were collected. The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), malondialdehyde (MDA), nitrotyrosine (NT), nitrite, interleukin 1 beta (IL-1b), interleukin 6 (IL-6), soluble inter-cellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were measured. Moreover, the catalase and superoxide dismutase levels were measured on the arterial samples. Histopathological analysis and arterial morphometry were also performed. Results and discussion: The oral administration of ESEG significantly lowered the levels of lipids in rabbits that were fed a CRD diet. This treatment also adjusted the protective system against oxidation in the arteries by decreasing the oxidation of lipids and proteins. Additionally, the levels of IL-1b, IL-6, sICAM-1, and sVCAM-1 in the bloodstream decreased significantly, and this was accompanied by a reduction of atherosclerotic lesions in all branches of the arteries. The findings suggest that EEPC may be a possible option for additional management of atherosclerosis.

Effect of walnut consumption on markers of endothelial function in adults: A systematic review and meta-analysis of randomized controlled trials.

Findings on the effect of walnut consumption on endothelial function are conflicting. Therefore, the present systematic review and meta-analysis summarized available trials in this regard. A systematic search was performed in online databases including PubMed-Medline, Scopus, and ISI Web of Science up to October 2023. Articles that reported the effect of walnut intake on flow-mediated dilation (FMD), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and stimulus-adjusted response measure (SARM) were included. Random effects models for a weighted mean difference (WMD) or standardized mean difference (SMD) were used to test for the overall effect. Six eligible trials were analyzed (250 participants). Walnut intake significantly increased FMD (WMD: 0.94%, 95% CI: 0.12 to 1.75; p = 0.02). However, meta-analysis could not show any beneficial effect of walnut intake on ICAM-1 (SMD: -0.23, 95% CI: -0.68 to 0.22; p = 0.31), VCAM-1 (SMD: -0.02, 95% CI: -1.38 to 1.34; p = 0.97), and SARM (WMD: 0.01%, 95% CI: -0.01 to 0.04; p = 0.28). In conclusion, the present meta-analysis suggests that walnuts may reduce cardiovascular disease risk by improving FMD. However, further studies should be performed on adults to determine the effect of walnut intake on endothelial function.

Mesenchymal stem cells (MSCs) from the mouse bone marrow show differential expression of interferon regulatory factors IRF-1 and IRF-2.

Interferon regulatory factors (IRF-1 and IRF-2) are transcription factors widely implicated in various cellular processes, including regulation of inflammatory responses to pathogens, cell proliferation, oncogenesis, differentiation, autophagy, and apoptosis. We have studied the expression of IRF-1, IRF-2 mRNAs by RT-PCR, cellular localization of the proteins by immunofluorescence, and expression of mRNAs of genes regulated by IRF-1, IRF-2 by RT-PCR in mouse bone marrow cells (BMCs) and mesenchymal stem cells (MSCs). Higher level of IRF-1 mRNA was observed in BMCs and MSCs compared to that of IRF-2. Similarly, differential expression of IRF-1 and IRF-2 proteins was observed in BMCs and MSCs. IRF-1 was predominantly localized in the cytoplasm, whereas IRF-2 was localized in the nuclei of BMCs. MSCs showed nucleo-cytoplasmic distribution of IRF-1 and nuclear localization of IRF-2. Constitutive expression of IRF-1 and IRF-2 target genes: monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and caspase-1was observed in both BMCs and MSCs. MSCs showed constitutive expression of the pluripotency-associated factors, Oct3/4 and Sox-2. Lipopolysaccharide (LPS)-treatment of MSCs induced prominent cellular localization of IRF-1 and IRF-2. Our results suggest that IRF-1 and IRF-2 exhibit differential expression of their mRNAs and subcellular localization of the proteins in BMCs and MSCs. These cells also show differential levels of constitutive expression of IRF-1 and IRF-2 target genes. This may regulate immune-responsive properties of BMCs and MSCs through IRF-1, IRF-2-dependent gene expression and protein-protein interaction. Regulating IRF-1 and IRF-2 may be helpful for immunomodulatory functions of MSCs for cell therapy and regenerative medicine.

Identification of common and specific fibrosis-related genes in three common chronic kidney diseases

Background Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD. Methods Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes. Results Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis. Conclusions There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

FUNCTIONAL ACTIVITY OF MONOMERIC C-REACTIVE PROTEIN IN INTERVERTEBRAL DISC

Monomeric C reactive protein (mCRP) presents important proinflammatory effects in endothelial cells, leukocytes, or chondrocytes. However, CRP in its pentameric form exhibits weak anti-inflammatory activity. It is used as a biomarker to follow severity and progression in infectious or inflammatory diseases, such as intervertebral disc degeneration (IVDD). This work assesses for the first time the mCRP effects in human intervertebral disc cells, trying to verify the pathophysiological relevance and mechanism of action of mCRP in the etiology and progression of IVD degeneration.We demonstrated that mCRP induces the expression of multiple proinflammatory and catabolic factors, like nitric oxide synthase 2 (NOS2), cyclooxygenase 2 (COX2), matrix metalloproteinase 13 (MMP13), vascular cell adhesion molecule 1 (VCAM1), interleukin (IL)-6, IL-8, and lipocalin 2 (LCN2), in human annulus fibrosus (AF) and nucleus pulposus (NP) cells. We also showed that nuclear factor-κβ (NF-κβ), extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphoinositide 3-kinase (PI3K) are at play in the intracellular signaling of mCRP.Our results indicate that the effect of mCRP is persistent and sustained, regardless of the proinflammatory environment, as it was similar in healthy and degenerative human primary AF cells. This is the first article that demonstrates the localization of mCRP in intravertebral disc cells of the AF and NP and that provides evidence for the functional activity of mCRP in healthy and degenerative human AF and NP disc cells.

The crosstalk between neuropilin-1 and tumor necrosis factor-α in endothelial cells.

Tumor necrosis factor-α (TNFα) is a master cytokine which induces expression of chemokines and adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), in endothelial cells to initiate the vascular inflammatory response. In this study, we identified neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, as a modulator of TNFα-induced inflammatory response of endothelial cells. NRP1 shRNA expression suppressed TNFα-stimulated leukocyte adhesion and expression of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells (HUVECs). Likewise, it reduced TNFα-induced phosphorylation of MAPK p38 but did not significantly affect other TNF-induced signaling pathways, such as the classical NFκB and the AKT pathway. Immunofluorescent staining demonstrated co-localization of NRP1 with the two receptors of TNF, TNFR1 and TNFR2. Co-immunoprecipitation further confirmed that NRP1 was in the same protein complex or membrane compartment as TNFR1 and TNFR2, respectively. Modulation of NRP1 expression, however, neither affected TNFR levels in the cell membrane nor the receptor binding affinities of TNFα. Although a direct interface between NRP1 and TNFα/TNFR1 appeared possible from a protein docking model, a direct interaction was not supported by binding assays in cell-free microplates and cultured cells. Furthermore, TNFα was shown to downregulate NRP1 in a time-dependent manner through TNFR1-NFκB pathway in HUVECs. Taken together, our study reveals a novel reciprocal crosstalk between NRP1 and TNFα in vascular endothelial cells.

Levels of VCAM-1 and ICAM-1 in serum of active and inactive Systemic Lupus Erythematosus patients as biochemical markers for risk of cardiovascular disease

Background: Cardiovascular complications represent one of the consequences of chronic autoimmune diseases such as Systemic Lupus Erythematosus (SLE), which has significant rates of morbidity and mortality. Dyslipidemia can be brought on by steroid medications, which are frequently given to SLE patients and are considered to be one of the major risk factors for cardiovascular diseases. Objectives: This study attempted to investigate a potential association between circulating vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) as risk factors for atherosclerosis and their relationship to cardiovascular risk. Patients and methods: A total of 100 patients and 50 apparently healthy controls were included in the study. All patients were from the Department of Rheumatology, Baghdad Hospital / Medical City during the period from 1 December 2021 to 1 March 2022 who were all treated with antimalarial drugs as immunosuppressants such as chloroquine (CQ) or hydroxychloroquine HCQ). They were divided according to the SLE disease activity index 2000 (SLEDAI-2K) into the active group (SLEDAI ≥ 10) and the inactive group (SLEDAI). Results: Serum VCAM and ICAM were significantly high in all study groups of SLE patients. The VCAM mean ± SD were (271.9±63.90), (247.9±82.92) and (97.7±24.69) in the active, inactive controls respectively. The ICAM mean ± SD were (3.1±0.91), (2.7±0.79) and (1.8±0.22) in the active, inactive and controls respectively. The values have increased gradually with increasing disease activity. The area under curve (AUC) of ICAM and VCAM were (0.802), (0.776) in active SLE patients and (0.858), (0.674) in inactive SLE patients. However, the AUC of VCAM and ICAM in active group were the highest. Conclusion: In SLE patients, VCAM-1 and ICAM-1 serum levels may operate as disease detection and severity differentiation indicators, and they may be linked to the number of coronary lesions in people at risk of developing CVD. Received: Aug.,2022 Accepted: Sept., 2022 Published: April 2023

Effect of Yoga-Based Cardiac Rehabilitation Program on Endothelial Function, Oxidative Stress, and Inflammatory Markers in Acute Myocardial Infarction: A Randomized Controlled Trial.

The aim of this study was to evaluate the effects of yoga-based cardiac rehabilitation (Yoga-CaRe) on the endothelial system, oxidative stress, and inflammatory markers in patients with acute myocardial infarction (MI). A sub-study was conducted in two clinical sites of the Yoga-CaRe trial (a multicenter randomized controlled trial). Participants with acute MI were randomized and allocated to either the Yoga-CaRe program (13 sessions with encouragement to home practice) or enhanced standard care (three educational sessions). Endothelial function, oxidative stress, and inflammatory biomarkers were assessed using biomarkers such as asymmetric dimethylarginine (ADMA), endothelial nitric oxide synthase (eNOS), endothelin-1 (ET-1), E-selectin, P-selectin, vascular cell adhesion molecule (VCAM), intercellular cell-adhesion molecule-1, total nitric oxide concentration (NOx), oxidized low-density lipoprotein (Oxd-LDL), superoxide dismutase, total antioxidant capacity (TAOC), tumor necrosis factor-alpha (TNFα), and C-reactive protein (CRP) at baseline and 12 weeks. Laboratory and statistical analysis were done by staff blinded to group allocation. Eighty-two patients (of the 110 patients recruited) completed the study. The mean age was 53.1 ± 10.6 and 51.9 ± 10.7 years in enhanced standard care and Yoga-CaRe group, respectively. At 12 weeks, Yoga-CaRe significantly reduced ADMA, ET-1, and ICMA-1 than the enhanced standard care group. Although E-selectin and VCAM at 12 weeks were reduced in both groups, enhanced standard care had a significantly higher reduction than the Yoga-CaRe group. Among markers of oxidative stress, TAOC increased in the Yoga-CaRe group. We found no difference in eNOS, NOx, P-selectin, TNFα, CRP, and Oxd-LDL between the two groups. Yoga-CaRe improved the endothelial function (through a reduction in ET-1 and modulating adhesion molecules) and enhanced antioxidant capacity.

Effects of Semaglutide in Doxorubicin-Induced Cardiac Toxicity in Wistar Albino Rats.

Doxorubicin (DOX) is used to treat various types of cancers. However, its use is restricted by cardiotoxicity, a leading cause of morbidity and mortality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) may be associated with cardioprotective properties. This study aims to determine the protective effects of different semaglutide (SEM) doses on DOX-induced cardiotoxicity in a rat model. Thirty-five female Wistar rats were divided into five groups. The first group received distilled water as a negative control (NC); the positive control (PC) group received distilled water plus DOX; the third group (SL) received a low dose of SEM (0.06 mg/kg) plus DOX; the fourth group (SM) received a moderate dose of SEM (0.12 mg/kg) plus DOX; and the fifth group (SH) received a high dose of SEM (0.24 mg/kg) plus DOX. Blood samples were collected on day 8 to assess serum troponin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total lipid profile, and vascular cell adhesion molecule 1 (VCAM-1). Cardiac tissue was sent for histopathological analysis. DOX increased the total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), LDH, and CKP levels. Moderate and high doses of semaglutide significantly reduced serum cholesterol levels (*p = 0.0199), (**p = 0.0077), respectively. A significant reduction (***p = 0.0013) in total body weight after treatment with SEM was observed in the SL group and a highly significant reduction (****p < 0.0001) was observed in the SM and SH groups. SEM at all doses reduced CPK levels. The SL group showed a significant reduction in troponin level (*p=0.0344). Serum LDH levels were reduced by all three SEM doses. The histopathological findings support the biochemical results. Semaglutide may possess cardioprotective properties against DOX-induced cardiotoxicity in a rat model by decreasing serum biochemical markers of cardiotoxicity.

Correlation of oxidative stress and vascular endothelial dysfunction with hippocampal perfusion in atrial fibrillation patients with cognitive impairment.

To evaluate the correlation of oxidative stress and vascular endothelial dysfunction with hippocampal perfusion in patients with atrial fibrillation and cognitive impairment. In total, 41 atrial fibrillation patients with cognitive impairment were compared to 45 atrial fibrillation patients without cognitive impairment. Oxidative stress, vascular endothelial dysfunction, hippocampal perfusion, and cognitive function were measured. Serum level of oxidized low-density lipoprotein was significantly higher in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. Serum levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were significantly higher, and nitric oxide was lower, in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. The regional cerebral blood volume, mean transit time, and time to peak were significantly higher in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. Moreover, regional cerebral blood flow was significantly lower in the atrial fibrillation + cognitive impairment group than in the atrial fibrillation group. Age, left atrial diameter, and regional cerebral blood volume were negatively correlated with the cognitive function score in the atrial fibrillation + cognitive impairment group. Serum levels of oxidized low-density lipoprotein, regional cerebral blood volume, regional cerebral blood flow, mean transit time, and time to peak were significantly correlated with cognitive impairment in atrial fibrillation patients after multivariate logistic regression analysis. Hippocampal perfusion and oxidative stress were significantly correlated with cognitive impairment in atrial fibrillation patients.

Astragaloside IV Mediates the PI3K/Akt/mTOR Pathway to Alleviate Injury and Modulate the Composition of Intestinal Flora in ApoE-/- Atherosclerosis Model Rats.

Atherosclerosis (AS) is a chronic inflammatory vascular disease with a complex pathogenesis. Astragaloside IV (AST IV), the primary active component of Astragalus, possesses anti-inflammatory, antioxidant, and immunomodulatory properties. This research aims to investigate the outcome of AST IV on AS and its potential molecular mechanism. A high-fat diet (21% fat, 50% carbohydrate, 20% protein, 0.15% cholesterol, and 34% sucrose) was utilized to feed Apolipoprotein E deficient (ApoE-/-) SD rats for 8 weeks, followed by continuous intragastric administration of AST IV for 8 weeks. Biochemical detection was conducted for serum lipid levels and changes in vasoactive substances. After Masson staining, aortic root oil red O staining, and Hematoxylin Eosin (HE) staining, the efficacy of AST IV was verified using quantitative reverse transcription polymerase chain reaction (qRT-PCR). The mRNA expression levels of inflammatory factors and endothelial dysfunction-related biomarkers in rat aortic root tissues were appraised. The changes in the composition of intestinal flora in rats after AST IV treatment were appraised using Image J (Multi-point Tool). Western blot was used to evaluate phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway-related protein levels in rat aortic root tissues. AST IV administration alleviated the pathological symptoms of AS rats. AST IV administration reduced serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), endothelin-1 (ET-1) and angiotensin (Ang)-II (Ang-II) levels, and augmented serum high-density lipoprotein cholesterol (HDL-C) and nitric oxide (NO) levels. At the same time, AST IV administration inhibited the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-2 (MMP-2), macrophage inflammatory protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in the aortic root tissue of AS rats. In addition, the intestinal flora changed significantly after AST IV administration. The number of Bifidobacterium, Lactobacillus, and Bacteroides augmented significantly, and Enterobacter, Enterococcus, Fusobacterium, and Clostridium significantly decreased. Mechanistically, AST IV administration inhibited the phosphorylation of PI3K, Akt, and mTOR in AS rats. When combined with Dactolisib (BEZ235) (a PI3K/Akt/mTOR pathway inhibitor), AST IV could further inhibit phosphorylation and reduce inflammation. AST IV has a potential anti-AS effect, which can improve the pathological changes of the aorta in ApoE-/- rats fed with a high-fat diet, reduce the level of inflammatory factors, and modulate the composition of intestinal flora via the PI3K/Akt/mTOR pathway.

Metallic Copper-Based Dual-Enzyme Biomimetic Nanoplatform for Mild Photothermal Enhancement of Anticancer Catalytic Activity.

Background: Chemodynamic therapy (CDT) is recognized as a promising cancer treatment. Recently, copper sulfide nanostructures have been extensively employed as Fenton-like reagents that catalyze the formation of acutely toxic hydroxyl radicals (·OH) from hydrogen peroxide (H2O2). However, CDT therapeutic potency is restricted by the tumor microenvironment (TME), such as insufficient amounts of hydrogen peroxide, excessive glutathione levels, etc. To address these disadvantages, glucose oxidase (GOx) or catalase (CAT) can be utilized to enhance CDT, while low therapeutic efficacy still inhibits their future applications. Our previous study revealed that mild photothermal effect could boost the CDT catalytic effectiveness as well as GOx enzyme activity over a range. Results: We engineered and constructed a hollow CuS nanoplatform loaded with GOx and CAT, coating with macrophage membranes (M@GOx-CAT@CuS NPs). The nanoplatforms allowed enhancement of the reactive oxygen species creation rate and GOx catalytic activeness of CDT through mild phototherapy directed by photoacoustic imaging. After actively targeting vascular cell adhesion molecule-1 (VCAM-1) in cancer cells mediated by macrophage membrane coating, M@GOx-CAT@CuS NPs released GOx and CAT under near-infrared irradiation. GOx catalyzed the formation of H2O2 and gluconic acid with glucose, creating a better catalytic environment for CDT. Meanwhile, CAT-catalyzed H2O2 decomposition to generate sufficient oxygen, appropriately alleviating the oxygen shortage in the TME. In addition, starvation effects decreased adenosine triphosphate levels and further underregulated heat shock protein expression to reduce the heat resistance of tumor cells, resulting in a better mild phototherapy outcome. Both invitro and invivo experiments demonstrated that the newly developed M@GOx-CAT@CuS nanoplatform has remarkable synergistic anticancer therapeutic effects. Conclusion: The cascade reaction-enhanced biomimetic nanoplatform opens up a new avenue for precision tumor diagnostic and therapeutic research.

Endothelial Mitochondria-Associated Membranes (MAMs) Isolation by Percoll Step Gradients.

Mitochondria-associated membranes (MAMs) are regions where the endoplasmic reticulum (ER) interacts with mitochondria and regulate lipid trafficking, calcium signaling, ER stress, and inflammation activation. Isolation of MAMs from endothelial cells is vital for studying insight into the immune regulation of many inflammatory diseases. Endothelial cells (ECs) are critical innate immune cells due to their paracrine function of secreting interleukins, chemokines, cytokines, and growth factors, as well as expressing levels of pattern recognition receptors including toll-like receptors (TLRs). Furthermore, ECs regulate and recruit monocytes by expressing adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin, to facilitate monocyte diapedesis in areas of damage and inflammation. This protocol consists of step-by-step instructions on isolating pure MAMs and other subcellular fractions from endothelial cells, which is critical to understanding ER and mitochondria crosstalks in endothelial functions in health and disease.

Soluble Vascular Cell Adhesion Molecule-1 as an Atherogenic Biomarker in Coronary Artery Disease: A Cross-sectional Study

Soluble Vascular Cell Adhesion Molecule-1 as an Atherogenic Biomarker in Coronary Artery Disease: A Cross-sectional Study

Are soluble E-selectin, ICAM-1, and VCAM-1 potential predictors for the development of diabetic retinopathy in young adults, 15-34 years of age? A Swedish prospective cohort study.

The aim of this study was to determine plasma levels of three adhesion molecules that may contribute to the development of diabetic retinopathy; soluble endothelial selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1), in young adults, aged 15-34 years at diagnosis of diabetes, to find potential predictors for development of retinopathy, and to evaluate their relation to diabetes associated autoantibodies. Participants with type 1 (n = 169) and type 2 diabetes (n = 83) were selected from the complications trial of the Diabetes Incidence Study in Sweden and classified in two subgroups according to presence (n = 80) or absence (n = 172) of retinopathy as determined by retinal photography at follow-up 8-10 years after diagnosis of diabetes. Blood samples were collected at diagnosis in 1987-88. The levels of sE-selectin, sICAM-1, and sVCAM-1 were analysed by enzyme-linked immunosorbent assay and islet cell antibodies by a prolonged two-colour immunofluorescent assay. Mean HbA1c (p<0.001) and clinical characteristics: mean body mass index (p = 0.019), systolic blood pressure (p = 0.002), diastolic blood pressure (p = 0.003), male gender (p = 0.026), and young age at diagnosis of diabetes (p = 0.015) remained associated with development of retinopathy in type 1 diabetes. However, in a multivariate analysis only HbA1c remained as a risk factor. sE-selectin was significantly higher in the group with type 2 diabetes and retinopathy, compared to the group with type 2 diabetes without retinopathy (p = 0.04). Regarding sE-selectin, sICAM-1, and sVCAM-1 in participants with type 1 diabetes, no differences were observed between the groups with or without retinopathy. This trial confirmed the role of HbA1c and clinical characteristics as predictors for development of retinopathy in type 1 diabetes. sE-selectin stands out as a potential predictor for development of retinopathy in type 2 diabetes, whereas a predictive role for sICAM-1 and sVCAM-1 could not be identified neither for type 1 nor type 2 diabetes.

Dietary ellagic acid blocks inflammation-associated atherosclerotic plaque formation in cholesterol-fed apoE-deficient mice.

Atherosclerosis particularly due to high circulating level of low-density lipoprotein is a major cause of cardiovascular diseases. Ellagic acid is a natural polyphenolic compound rich in pomegranates and berries. Our previous study showed that ellagic acid improved functionality of reverse cholesterol transport in murine model of atherosclerosis. The aim of this study is to investigate whether ellagic acid inhibited inflammation-associated atherosclerotic plaque formation in cholesterol-fed apolipoprotein E (apoE)-knockout (KO) mice. Wild type mice and apoE-KO mice were fed a cholesterol-rich Paigen diet for 10 weeks to induce severe atherosclerosis. Concurrently, 10 mg/kg ellagic acid was orally administered to the apoE-KO mice. Plaque lesion formation and lipid deposition were examined by staining with hematoxylin and eosin, Sudan IV and oil red O. The plasma leukocyte profile of cholesterol-fed mice was not altered by apoE deficiency. Oral administration of ellagic acid attenuated plaque lesion formation and lipid deposition in the aorta tree of apoE-KO mice. Ellagic acid substantially reduced plasma levels of soluble vascular cell adhesion molecule and interferon-γ in Paigen diet-fed apoE-KO mice. When 10 mg/kg ellagic acid was administered to cholesterol-fed apoE-KO mice, the levels of CD68 and MCP-1 were strongly reduced in aorta vessels. The protein expression level of nitric oxide synthase-2 (NOS2) in the aorta was highly enhanced by supplementation of ellagic acid to apoE-KO mice, but the expression level of heme oxygenase-1 (HO-1) in the aorta was reduced. Furthermore, ellagic acid diminished the increased aorta expression of the inflammatory adhesion molecules in cholesterol-fed apoE-KO mice. The treatment of ellagic acid inhibited the scavenger receptor-B1 expression in the aorta of apoE-KO mice, while the cholesterol efflux-related transporters were not significantly changed. These results suggest that ellagic acid may be an atheroprotective compound by attenuating apoE deficiency-induced vascular inflammation and reducing atherosclerotic plaque lesion formation.

Keypoints in Cells and Atherogenesis

Endothelial dysfunction is the initial event in the atherogenic process, resulting from several events, such as expression of leukocyte binding sites, production of growth factors, chemotactic and vasoreactive molecules, ability to oxidize low-density lipoprotein (LDL) and respond to oxidized lipoproteins, ability to express procoagulant activity, and modulation of vascular permeability. Thus, the endothelium, when subjected to different conditions and factors, plays an active role in the development of atherosclerotic plaque. The expression of several adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), P-selectin in atherosclerotic plaques, mediating the interaction between endothelial cells and leukocytes, has been described. The modification of LDLs, in conjunction with other chemotactic factors produced by injured endothelial cells, recruit circulating monocytes into the subendothelial space, where they become macrophages. The proliferation of smooth muscle cells is an important event in the progression of arterial injury, occurring in 3 stages: smooth muscle cell replication still within the media layer; migration from the middle layer to the intima and proliferation within the intima. Apoptotic cells were evidenced in the atherosclerotic lesion, suggesting that apoptosis is part of the normal vascular healing process. The final stage of atherosclerotic lesion development is conversion of the fibrotic lesion to an advanced lesion, a lesion in which a thrombus forms as a result of plaque ulceration or intraplaque hemorrhage.