Evaluation of the miRNA-126 and VCAM-1 in scleroderma patients and its association with clinical characteristics.

BACKGROUND: Systemic sclerosis (SSc) has the highest level of mortality and disability among all rheumatological diseases. Being heterogenous leads to no predictable method for clinical courses. The aim of this study was to evaluate the levels of miRNA-126 and soluble VCAM-1 protein markers in patients with SSc, and to examine the assossiation of their levels with the severity of clinical and paraclinical parameters in patients with SSc. METHOD: In current study tweny six patients with SSc along with twenty-three SSc-free controls were recruited. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the VCAM-1 protein. MiRNA-126 amounts in serum were detected by quantitative real-time polymerase chain reaction (PCR). RESULT: SSc patients' average age was 45.42 years and control group 49.85. The mean±SD for circulating miR-126 levels were significantly lower in SSc patients compared with healthy donors (p = 0.02), 0.48 ± 0.72 vs 1.11 ± 0.61 respectively. A significant difference was also observed in the serum level of miRNA-126 in SSc patients who suffer from pulmonary artery hypertension (P = 0.03) and pulmonary fibrosis (P = 0.04). In contrast, analysis of the serum VCAM-1 levels in the study groups uncovered a significant increase in SSc patients (5.92 ± 3.52 µg/ml) compared to control group (2.62 ± 1.2 µg/ml) (P value < 0.001). CONCLUSION: Significant change in circulating levels of miR-126 and VCAM-1 in the SSc patients supporting its role in the pathogenesis of the disease. It could also proposed potential role as a predictor of pulmonary complications for miRNA-126.

Relation of ICAM-1 and VCAM-1 markers in COVID-19 patients in Kirkuk province.

BACKGROUND: The advent of the Coronavirus Disease 2019 (COVID-19) has presented a substantial and urgent global public health issue. Biomarkers have the potential to be utilized for the identification of endothelium and/or alveolar epithelial damage in instances of COVID-19 infection. AIM OF THE STUDY: to evaluate the levels of Intercellular adhesion molecule-1 (ICAM-1) and Vascular cell adhesion molecule (VCAM-1) biomarkers in hospitalized patients who tested positive for COVID-19 infection using Polymerase Chain Reaction (PCR) with the virus specific Immunoglobulins; IgM, and IgG testing. This can help with improved clinical management and treatment programs. METHODS: A case-control study that involved 90 hospitalized patients who tested positive for COVID-19 and 40 apparently healthy control patients, subjects in both groups underwent nasopharyngeal swabs for PCR and blood sample collection for evaluation of serum; IgM, IgG, ICAM-1 and VCAM-1 levels. RESULTS: Males made up the vast majority of the patients (78.9%), with only a minor percentage of females (21.1%) P value 0.1641. Furthermore, every patient in this study had a minimum of one risk factor for COVID-19. The investigator's results show that COVID-19 patients had higher amounts of endothelial cell adhesion indicators (ICAM-1 and VCAM-1) with mean values of 126.27 ± 89.51 ng/mL and 109.74 ± 96.57 ng/mL respectively. While, ICAM-1 and VCAM-1, were present at normal levels in the control group with difference P value 0.0028 and 0.0032 in comparison to the patient's group respectively. CONCLUSIONS: The adhesive markers ICAM and VCAM play a crucial role in the development of COVID-19 and the strong endothelial activation and dysfunction linked to both acute and persistent immunological responses is shown by the substantial correlation found in COVID-19 patients between the presence of IgM and IgG antibodies and higher levels of ICAM-1 and VCAM-1.

Endothelial Dysfunction in Obesity and Therapeutic Targets.

Parallel to the increasing prevalence of obesity in the world, the mortality from cardiovascular disease has also increased. Low-grade chronic inflammation in obesity disrupts vascular homeostasis, and the dysregulation of adipocyte-derived endocrine and paracrine effects contributes to endothelial dysfunction. Besides the adipose tissue inflammation, decreased nitric oxide (NO)-bioavailability, insulin resistance (IR), and oxidized low-density lipoproteins (oxLDLs) are the main factors contributing to endothelial dysfunction in obesity and the development of cardiorenal metabolic syndrome. While normal healthy perivascular adipose tissue (PVAT) ensures the dilation of blood vessels, obesity-associated PVAT leads to a change in the profile of the released adipo-cytokines, resulting in a decreased vasorelaxing effect. Higher stiffness parameter ß, increased oxidative stress, upregulation of pro-inflammatory cytokines, and nicotinamide adenine dinucleotide phosphate (NADP) oxidase in PVAT turn the macrophages into pro-atherogenic phenotypes by oxLDL-induced adipocyte-derived exosome-macrophage crosstalk and contribute to the endothelial dysfunction. In clinical practice, carotid ultrasound, higher leptin levels correlate with irisin over-secretion by human visceral and subcutaneous adipose tissues, and remnant cholesterol (RC) levels predict atherosclerotic disease in obesity. As a novel therapeutic strategy for cardiovascular protection, liraglutide improves vascular dysfunction by modulating a cyclic adenosine monophosphate (cAMP)-independent protein kinase A (PKA)-AMP-activated protein kinase (AMPK) pathway in PVAT in obese individuals. Because the renin-angiotensin-aldosterone system (RAAS) activity, hyperinsulinemia, and the resultant IR play key roles in the progression of cardiovascular disease in obesity, RAAS-targeted therapies contribute to improving endothelial dysfunction. By contrast, arginase reciprocally inhibits NO formation and promotes oxidative stress. Thus, targeting arginase activity as a key mediator in endothelial dysfunction has therapeutic potential in obesity-related vascular comorbidities. Obesity-related endothelial dysfunction plays a pivotal role in the progression of type 2 diabetes (T2D). The peroxisome proliferator-activated receptor gamma (PPARγ) agonist, rosiglitazone (thiazolidinedione), is a popular drug for treating diabetes; however, it leads to increased cardiovascular risk. Selective sodium-glucose co-transporter-2 (SGLT-2) inhibitor empagliflozin (EMPA) significantly improves endothelial dysfunction and mortality occurring through redox-dependent mechanisms. Although endothelial dysfunction and oxidative stress are alleviated by either metformin or EMPA, currently used drugs to treat obesity-related diabetes neither possess the same anti-inflammatory potential nor simultaneously target endothelial cell dysfunction and obesity equally. While therapeutic interventions with glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide or bariatric surgery reverse regenerative cell exhaustion, support vascular repair mechanisms, and improve cardiometabolic risk in individuals with T2D and obesity, the GLP-1 analog exendin-4 attenuates endothelial endoplasmic reticulum stress.

Extensive study of CCN4, VCAM-1, MMP-3, and GM-CSF as reliable markers for disease activity in rheumatoid arthritis.

Background: The involvement of Wnt-1-induced secreted protein-1 (WISP1/CCN4) in several inflammatory reaction has recently been proposed. Nevertheless, this protein's involvement in rheumatoid arthritis (RA) remains debated. Associations between poorly diagnosed RA and several classical markers derived from demography and biochemistry have been reported. Aim: We sought to investigate the reliability and effectiveness of serum concentrations of CCN4, vascular cell adhesion molecule-1 (VCAM-1), matrix melloprotenase-3 (MMP-3), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in monitoring and predicting RA and bone damage, and their correlation with RA disease course. Methods: The study analyzed 128 patients with RA, comprising 68 newly diagnosed and 60 previously diagnosed patients, as well as 60 controls. Biomarker levels were measured with enzyme linked immuno-sorbent assays. Routine laboratory parameters such as serological, clinical, biochemical, and hematological parameters were additionally measured. Demography, anthropometry, and clinical symptom data were collected through interviews and a questionnaire. The joint disease activity score 28 (DAS28) was used to determine disease activity. Results: Concentrations of four biomarkers were significantly higher in the RA group than the healthy controls. Elevated biomarker concentrations were also observed in patients with high, rather than moderate or low, DAS28-ESR activity status, except for monocyte count, hematocrit (%), and urea level. Furthermore, CCN4 level positively correlated with VCAM-1, MMP-3, and GM-CSF levels, DA-S28-CRP and DAS28-ESR. The levels of three predictive markers, CCN4, VCAM-1, and MMP-3, were elevated in non-treated patients, whereas GM-CSF level showed no difference. The highest area under the curve was 73.3% for CCN4, with 93.3% sensitivity and 64.7% specificity. Conclusion: Our data suggest that CCN4 can be reliably used to indicate activity and therapeutic response associated with RA, thus facilitating earlier RA diagnosis.

Sustainability of shear stress conditioning in endothelial colony-forming cells compared to human aortic endothelial cells to underline suitability for tissue-engineered vascular grafts.

The endothelialization of cardiovascular implants is supposed to improve the long-term patency of these implants. In addition, in previous studies, it has been shown, that the conditioning of endothelial cells by dynamic cultivation leads to the expression of an anti-thrombogenic phenotype. For the creation of a tissue-engineered vascular graft (TEVG), these two strategies were combined to achieve optimal hemocompatibility. In a clinical setup, this would require the transfer of the already endothelialized construct from the conditioning bioreactor to the patient. Therefore, the reversibility of the dynamic conditioning of the endothelial cells with arterial-like high shear stress (20 dyn/cm2) was investigated to define the timeframe (tested in a range of up to 24 h) for the perseverance of dynamically induced phenotypical changes. Two types of endothelial cells were compared: endothelial colony-forming cells (ECFCs) and human aortic endothelial cells (HAECs). The results showed that ECFCs respond far more sensitively and rapidly to flow than HAECs. The resulting cell alignment and increased protein expression of KLF-2, Notch-4, Thrombomodulin, Tie2 and eNOS monomer was paralleled by increased eNOS and unaltered KLF-2 mRNA levels even under stopped-flow conditions. VCAM-1 mRNA and protein expression was downregulated under flow and did not recover under stopped flow. From these time kinetic results, we concluded, that the maximum time gap between the TEVG cultivated with autologous ECFCs in future reactor cultivations and the transfer to the potential TEVG recipient should be limited to ∼6 h.

Association of Endothelial Cell Activation with Acute Kidney Injury during Coronary Angiography and the Influence of Recombinant Human C1 Inhibitor-A Secondary Analysis of a Randomized, Placebo-Controlled, Double-Blind Trial.

BACKGROUND: Acute kidney injury (AKI) as a result of iodinated contrast media (CM) has been linked to CM-induced renal ischemia and toxic effects on endothelial cells (EC). The recombinant human C1 inhibitor (rhC1INH) has been shown to influence EC activation. METHODS: Secondary analysis of 74/77 (96%) participants of a double-blind, randomized, and placebo-controlled study that assessed the effect of rhC1INH on AKI. E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), and CC-chemokin-ligand-5 (CCL5) were determined in frozen blood samples over 48 h and analyzed according to the treatment group and renal outcomes. RESULTS: The mean age was 76.7 years, and 37 patients each received rhC1INH and placebo, respectively. In the entire study population, minor differences in median EC activation markers/CCL5 concentrations during the first 48 h compared to baseline were observed (e.g., E-selectin 27.5 ng/mL at baseline vs. 29.7 ng/mL on day 1, CCL5: 17.7 ng/mL at baseline vs. 32.2 ng/mL on day 2). Absolute changes in ICAM-1/E-selectin concentrations correlated with a higher peak change in urinary NGAL concentrations. However, AKI was not associated with significant changes in EC markers/CCL5. Last, no significant differences in serum concentrations of EC activation markers/CCL5 were evident between the placebo and the rhC1INH group. CONCLUSIONS: CM administration during coronary angiography only mildly activated ECs within the first 48 h, which does not explain subsequent AKI. The administration of rhC1INH was not associated with a reduction of EC activation or CCL5.

Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.

Endothelial dysfunction is common in Systemic Lupus Erythematosus (SLE), even in the absence of cardiovascular disease. Evidence suggests that impaired mitophagy contributes to SLE. Mitochondrial dysfunction is also associated with impaired endothelial function. Spermidine, a natural polyamine, stimulates mitophagy by the PINK1-parkin pathway and counters age-associated endothelial dysfunction. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned to spermidine treatment (lpr_Spermidine and MpJ_Spermidine) for 8 weeks or as control (lpr_Control and MpJ_Control). lpr_Control mice exhibited impaired endothelial function (e.g., decreased relaxation to acetylcholine), increased markers of inflammation, and lower protein content of parkin, a mitophagy marker, in the thoracic aorta. Spermidine treatment prevented endothelial dysfunction in MRL-lpr mice. Furthermore, aortas from lpr_Spermidine mice had lower levels of inflammatory markers and higher levels of parkin. Lupus phenotypes were not affected by spermidine. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function, inflammation, and mitophagy in SLE mice. These results support future studies of the beneficial effects of spermidine on endothelial dysfunction and cardiovascular disease risk in SLE.

Characterization of ibrutinib's effects on the morphology, proliferation, phenotype, viability, and anti-inflammatory potential of adipose-derived mesenchymal stromal cells.

Ibrutinib (IB) is a tyrosine kinase inhibitor (TKI) that has immunomodulatory action and can be used as second-line therapy for steroid-refractory or steroid-resistant chronic Graft versus Host Disease (cGVHD). Mesenchymal stromal cells (MSCs) are distributed throughout the body and their infusion has also been explored as a second-line therapeutic alternative for the treatment of cGVHD. Considering the currently unknown effects of IB on endogenous MSCs, as well as the possible combined use of IB and MSCs for cGVHD, we investigated whether adipose tissue-derived MSCs present IB-targets, as well as the consequences of treating MSCs with this drug, regarding cell viability, proliferation, phenotype, and anti-inflammatory potential. Interestingly, we show for the first time that MSCs express several IB target genes. Also of note, the treatment of such cells with this TKI elevated the levels of CD90 and CD105 surface proteins, as well as VCAM-1. Furthermore, IB-treated MSCs presented increased mRNA expression of the anti-inflammatory genes PD-L1, TSG-6, and IL-10. However, continued exposure to IB, even at low doses, compromised the viability of MSCs. These data indicate that the use of IB can stimulate an anti-inflammatory profile in MSCs, but also that a continued exposure to IB can compromise MSC viability over time.

VCAM-1 mediates proximal tubule-immune cell cross talk in failed tubule recovery during AKI-to-CKD transition.

Studies in animal models have suggested a linkage between the inflammatory response to injury and subsequent nephron loss during the acute kidney injury (AKI) to chronic kidney disease (CKD) transition. Failure of normal repair during the CKD transition correlates with de novo expression of vascular cell adhesion protein-1 (VCAM-1) by a subset of injured proximal tubule cells. This study identified the role of VCAM-1 expression in promoting the failed repair state. Single-cell transcriptome analysis of patients with AKI and CKD and whole kidney RNA and protein analyses of mouse models of CKD confirmed a marked increase of VCAM-1 expression in the proximal tubules of injured kidneys. In immortalized mouse proximal tubular cells and primary cultured renal cells (PCRCs), VCAM-1 expression was induced by proinflammatory cytokines including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. Analyses of bulk RNA sequencing of TNF-α-treated primary cultured renal cells or pseudo-bulk RNA sequencing of biopsies from Kidney Precision Medicine Project datasets indicated activation of NF-κB and an enrichment of inflammatory response and cell adhesion pathways in VCAM-1-positive cells. Pharmacological inhibition of NF-κB signaling or genetic deletion of myeloid differentiation factor 88 and TIR domain-containing adapter-inducing interferon-ß suppressed TNF-α- and IL-1ß-induced VCAM-1 expression in vitro. TNF-α stimulation or overexpression of VCAM-1 significantly increased splenocyte adhesion to the mouse proximal tubular monolayer in culture. These results demonstrate that persistence of proinflammatory cytokines after AKI can induce NF-κB-dependent VCAM-1 expression by proximal tubule cells, mediating increased immune cell adhesion to the tubule and thus promoting further tubule injury and greater risk of progression from AKI to CKD.NEW & NOTEWORTHY We demonstrated the induction of VCAM-1 and its biological function in proximal tubules. We found that proinflammatory cytokines (TNF-α and IL-1ß) significantly induced VCAM-1 expression via NF-κB signaling pathway. TNF-α treatment or overexpression of VCAM-1 in immortalized MPT cells increased CD45+ splenocyte adhesion. Pharmacological inhibition of NF-κB or genetic deletion of Vcam1 suppressed TNF-α-induced splenocyte adhesion in vitro, suggesting that VCAM-1 mediates proximal tubular-immune cell cross talk in failed tubule recovery during AKI-to-CKD transition.

Acute kidney injury is associated with soluble vascular cell adhesion molecule 1 levels and short-term mortality in patients with ischemic stroke.

BACKGROUND: The mechanisms that modulate the onset of acute kidney inlury (AKI) after ischemic stroke (IS) and valuable biomarkers to predict the occurrence and prognosis of AKI among patients with IS are missing. OBJECTIVE: To evaluate the frequency of AKI and the prognostic validity of clinical and laboratory biomarkers in predicting AKI and short-term mortality after the IS. METHODS: Ninety-five patients with IS were enrolled. Baseline IS severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and disability was determined after three-month follow-up using the modified Rankin Scale. Patients with IS were also categorized as survivors and non-survivors after the follow-up. Baseline data and laboratory biomarkers were obtained up to 24 h of the admission. RESULTS: Fifteen (15.7 %) patients with IS presented AKI. The proportion of patients with vitamin D deficiency and the mortality were higher among those with AKI than those without AKI (p=0.011 and p-0.009, respectively). Patients with AKI showed higher disability and higher increased soluble vascular cellular adhesion molecule-1 (sVCAM-1) than those without AKI (p=0.029 and p=0.023, respectively). Logistic regression analysis showed that only sVCAM-1 was associated with the occurrence of AKI after IS [odds ratio (OR): 2.715, 95 % confidence intereval (CI): 1.12-6.67, p=0.027]. When both AKI and NIHSS were evaluated as explanatory variables, this panel showed an OR of 5.782 (95 % CI: 1.09-30.43, p<0.001) and correctly classified 83.6 % of cases. CONCLUSION: In conclusion, sVCAM-1 levels showed a potential useful for prediction of AKI after IS.