sVCAM-1 Levels Research Articles

Nutritional Composition and Anti-Type 2 Diabetes Mellitus Potential of Femur Bone Extracts from Bovine, Chicken, Sheep, and Goat: Phytochemical and In Vivo Studies.

Nutritional deficits in one's diet have been established as the key risk factor for T2DM in recent years. Nutritional therapy has been demonstrated to be useful in treating T2DM. The current study was carried out to assess the nutritional composition of bovine (12 months), chicken (4 months), sheep (13 months), and goat (9 months) femur bone extracts, as well as their potential therapeutic effects on T2DM regression in a Wistar albino rat model (500 mg/kg b.wt.). The proximate composition of the different extracts, their fatty acid composition, their amino acids, and their mineral contents were identified. In vivo data indicated considerably improved T2DM rats, as seen by lower serum levels of TL, TG, TC, ALT, AST, ALP, bilirubin, creatinine, urea, IL-6, TNF-α, sICAM-1, sVCAM-1, and MDA. Low levels of HDL-C, GSH, and total proteins were restored during this study. Histological investigations of liver and pancreatic tissue revealed that the distribution of collagen fibers was nearly normal. The bovine extract, on the other hand, was the most active, followed by the sheep, goat, and finally chicken extract. This research could result in the creation of a simple, noninvasive, low-cost, and reliable method for T2DM control, paving the way for potential early therapeutic applications in T2DM control.

Diabetic Endothelial Cell Glycogen Synthase Kinase 3β Activation Induces VCAM1 Ectodomain Shedding.

Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular disease (CVD) outcomes, supporting VCAM1's role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1's release or its interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane-bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs). Still, the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from an inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β activation in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease, particularly in diabetes, holds significant therapeutic potential.

Correlation between level of vitamin d and svcam-1 towards degree of hypertension in elderly patients

Introduction: At old age, it is often found the condition of vitamin D deficiency associated with decrease of physical performance, increase risk of fall and as the risk of hypertension. sVCAM-1 is a protein expressed on endothelium surface which being activated and also expressed in the initial event of atherosclerosis so that sVCAM-1 can be used as marker to determine the degree of severity of atherosclerosis in human. This study was aimed to evaluate the correlation between vitamin D and sVCAM-1 towards degree of hypertension in elderly patients. Methods: This research was using cross-sectional method conducted at Geriatric Outpatient Clinic, Kidney-Hypertension and Cardiology in Prof. Dr. Ngoerah General Hospital, Denpasar, Bali, Indonesia, starting from April 2022 up to August 2022. Study sample was all of elderly population who came to clinic. Sample was taken using the means of consecutive sampling. Chi-square test was used for bivariate analysis and regression logistical multiple regression test was used for multivariate analysis. Results: Result of bivariate analysis showed that sVCAM-1 was significantly related to the degree of hypertension, in which it obtained the value of p = 0.030, with OR = 3.3. The result was also directly proportional with relation to level of vitamin D towards degree of hypertension, in which it obtained the value of p = 0.031, with OR value = 8.0. In multivariate analysis it obtained that the level of sVCAM-1 was significant statistically towards the degree of hypertension, with p value of 0.032. Conclusion: Based on this study, the results can become reference, in which low level of vitamin D and high level of sVCAM-1, associated with higher blood pressure in elderly patients.

Relationship Between Serum ET-1, HDL-C, and sVCAM-1 and Hearing Loss in Patients with Sudden Deafness.

Vascular causes are most commonly associated with sudden sensorineural hearing loss (SSHL). This study was performed to determine the relationship between serum endothelin-1 (ET-1), high-density lipoprotein cholesterol (HDL-C), soluble vascular cell adhesion molecule-1 (sVCAM-1) levels, and the degree of hearing loss in patients with SSHL. Firstly, 60 SSHL patients were admitted to The First Hospital of Shanxi Medical University. In the same period, 60 healthy subjects matching the age and gender of SSHL patients were selected as the control group. Then, serum levels of ET-1, HDL-C, and sVCAM-1 were measured by enzyme-linked immunosorbent assay (ELISA). Next, the relationship between serum levels of ET-1, HDL-C, and sVCAM-1 with clinicopathological factors and their diagnostic and prognostic values were analyzed and evaluated. Serum ET-1 and sVCAM-1 were increased, and HDL-C was decreased in patients with SSHL. Serum ET-1 and sVCAM-1 were higher and HDL-C was lower in patients aged ≥ 45years, or severe hearing loss patients (P < 0.05). ROC analysis determined that ET-1 (AUC = 0.839), HDL-C (AUC = 0.830), and sVCAM-1 (AUC = 0.865) had excellent diagnostic values. In addition, patients with low levels of ET-1 and sVCAM-1 and high levels of HDL-C had better hearing prognosis (P < 0.05). Abnormal serum ET-1, HDL-C, and sVCAM-1 in patients with SSHL are closely related to age, and degree of hearing loss, and perform diagnostic and prognostic values.

HYPERTENSION-RELATED IMPAIRMENT OF MESENTERIC ENDOTHELIAL FUNCTION CONTRIBUTES INTO GUT-LIVER AXIS VIA INTESTINAL DYSBIOSIS AND HEPATIC STEATOSIS, AND ASSOCIATES WITH GENETIC DYSRE

Objective: Metabolic violations, obesity and other related comorbidities are obvious in arterial hypertension. It is known that Hepatic Steatosis (HS) and Arterial hypertension (AH) has to some extend common pathogenesis realized through metabolic and immune mechanisms involving vascular and digestive system injury, and forming Gut-Liver axis, which remain mostly untouched in recent studies. We aimed on evaluating the endothelial function and mesenteric vessels remodeling depending on I/D polymorphism of angiotensin-converting enzyme (ACE) gene and A1166C polymorphism of angiotensin II type 1 receptor (AGTR1) gene in hypertensive patients with HS. Design and method: Study included 104 AH patients with HS (50 females, 54 males, age 53.2±8.7). Intimae-media thickness (IMT) of abdominal aorta (AO) and other flow mediated parameters of mesenteric vessels state evaluated by sonography. NO (nitrite/nitrate) plasma concentration, vascular adhesive molecule (sVCAM-1) level were defined by IEA. ACE (I/D) and AGTR1 (A1166C) genes polymorphisms assessed with PCR. Results: High risk of endothelial dysfunction (ED) is: D-allele of ACE gene (p&lt;.001); C-allele of AGTR1 gene (p = .02). In DD-genotype were higher flow-mediated parameters of mesenteric vessels. IMT of AO was thicker in CC-genotype of AGTR1 gene (p = .039-.01) and independent on I/D genotypes of ACE gene. sVCAM-1 level was higher (p&lt;.01) in D-allele of ACE gene, than in II-genotype and not depending on A1166C polymorphism of AGTR1 gene. NO plasma level doesn’t depend on ACE (I/D) and AGTR1 (A1166C) genes polymorphisms. Vascular remodeling in HS patients (AO IMT enlargement for more than 0.9 mm) is associated with dysbiosis III-IV grades’ and sVCAM-1 plasma level growth by 1,3-1,6 times (p&lt;.05-.001). AO IMT correlates with dysbiosis severity, presence of HS and sVCAM-1 level and is independent from AH severity. Conclusions: Risk contingents for endothelial dysfunction and mesenteric vessels remodeling in HS patients are: by sVCAM-1 plasma level and diameter of mesenteric vessels increasing – DD-genotype carriers of ACE gene; by IMT of abdominal aorta enlargement – CC-genotype carriers of AGTR1 gene (p&lt;0.02-0.001).

MARKERS OF ENDOTHELIAL DYSFUNCTION IN CORONARY HEART DISEASE PATIENTS DEPENDING ON ARTERIAL HYPERTENSION PRESENCE

Objective: To evaluate the role of arterial hypertension (AH) on endothelial functional state in the coronary heart disease (CHD) patients. Design and method: 173 CHD patients were examined (the average age was 57.24±5.12 years): 92 patients with stable angina (45 with II functional class (FC) (23 without and 22 with AH) and 47 with III FC (26 without and 21 with AH) and 81 patients with acute coronary syndromes (ACS)(43–with unstable angina (UA) (22 without and 21 with AH) and 38–with acute myocardial infarction (MI) (20 without and 18 with AH)). Endothelial dysfunction was assessed by the levels of vasoconstrictor endothelin-1 (ET-1) and the concentration of soluble vascular adhesion molecule (sVCAM), which were determined by ELISA. Results: Both markers of endothelial dysfunction increased with an increase in disease severity. The most severe changes were in patients with ACS, although differences between patients with UA and MI were not significant (p&gt;0.05). Levels of ET-1 were significantly higher (p&lt;0.05) in all clinical variants of CHD in patients with AH regarding patients without it. The same tendance (difference with p&lt;0.01 ) was observed with sVCAM levels, but only in stable CHD patients. sVCAM levels raised significantly in ACS patients not only according to the control group, but also patients with stable CHD (p&lt;0.05), but without difference depending on AH presence in both groups with UA and MI (p&gt;0.05). There were no significant associations between levels of endothelial dysfunction markers and troponin I and T (p&gt;0.05). The significant relationships between levels of sVCAM and ET-1 on one hand and C-reactive protein on other were noted in both groups with stable CHD and with ACS, regardless of the presence of hypertension. Conclusions: Elevated levels of ET-1 and sVCAM in blood of CHD patients are the indicator of atherosclerotic plaque instability and the possibility of ACS development, especially with AH comorbidity.

SVCAM-1 as a Marker of Endothelial Dysfunction associated with Severe Course of a Novel Coronavirus Infection (COVID-19)

Aim. To study the association of the level of endothelial dysfunction marker sVCAM-1 with the severe course of COVID-19.Material and methods. The study included 100 patients with COVID-19, who were divided into 3 groups depending on the degree of lung damage based on the results of computed tomography (CT): group CT 1 – 29 patients, group CT 2 – 61 patients and the group CT 3 – 10 patients. In addition to the standard examination performed for coronavirus infection, all patients underwent carotid Doppler ultrasound, analysis of arterial stiffness indices (CAVI, ABI) using the VaSera device, and evaluation of the plasma sVCAM-1 concentration by ELISA.Results. The plasma sVCAM-1 concentration was significantly higher in the groups of patients with moderately severe (CT 2) and severe (CT 3) lung lesions than in patients with mild lesions (CT 1). In the general group of patients significant correlations were found between the plasma sVCAM-1 concentration and the level of oxygen saturation (r=-0.39, p=0.032), hospital length of stay (r=0.24, p=0.026), values of C-reactive protein (r=0.25, p=0.042), ferritin (r=0.38, p=0.021), LDH (r=0.52, p=0.015) , as well as the percentage of pulmonary involvement according to CT data at admission (r=0.41, p=0.019) and on the day of discharge (r=0.35, p=0.022). According to multivariate regression analysis, sVCAM-1 does not depend upon gender, age, body mass index (BMI), the presence of type 2 diabetes mellitus (T2DM) and hypertension, and is a marker associated with cytokine storm progression, intermediate negative dynamics according to CT data, and need for respiratory support. The presence of type 2 diabetes, as well as elevated sVCAM-1 concentrations, is associated with an increased risk of high-dose glucocorticosteroid therapy. The threshold levels of this marker were calculated for each of the above events. We revealed a correlation between the sVCAM-1 concentration and the carotid intimal medial thickness in the general group of patients (r=0.25, p=0.036).Conclusion. An increase in the plasma sVCAM-1 concentration reflects the progression of endothelial dysfunction, one of the key factors in the pathogenesis of COVID-19. The latter necessitates the need for endothelium protective therapy for these patients. The evaluation of sVCAM-1 in blood plasma is a promising diagnostic technique aimed at predicting the risk of a severe course of COVID-19 and its long-term health hazards.

Characterization of the endotheliopathy, innate-immune activation and hemostatic imbalance underlying CAR-T cell toxicities: laboratory tools for an early and differential diagnosis

BackgroundChimeric antigen receptor (CAR)-T cell-based immunotherapy constitutes a revolutionary advance for treatment of relapsed/refractory hematological malignancies. Nevertheless, cytokine release and immune effector cell-associated neurotoxicity syndromes are life-threatening toxicities in which...

Vascular cell adhesion molecule‑1 levels in patients with coronary artery disease with type 2 diabetes mellitus

Chronic systemic inflammation is a key component of the pathogenesis of both type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD). Soluble vascular cell adhesion molecule‑1 (sVCAM‑1) is considered as the indicator of vascular inflammation and endothelial activation. The aim of our study was to investigate sVCAM‑1 levels in patients with CAD with T2DM and to determine their dependence on a previous history of myocardial infarction (MI). The study included 52 patients with stable CAD with T2DM, 20 CAD patients without diabetes and 14 control group persons. sVCAM-1 levels were measured in serum by the enzyme-linked immunosorbent assay. sVCAM‑1 levels in patients with CAD with T2DM and patients with CAD without diabetes were higher than in the control group (p&lt;0,001 and p&lt;0,001, respectively). The difference in sVCAM‑1 levels between CAD patients with T2DM and without diabetes was not significant (p=0,355). There were no significant correlations of sVCAM‑1 levels with glucometabolic indices in any group. Only in patients with CAD with T2DM sVCAM‑1 level negatively correlated with high-density lipoprotein cholesterol. CAD patients with and without T2DM with a history of myocardial infarction (MI) had higher sVCAM‑1 levels than patients without previous MI (p=0,038, р=0,043, respectively). Only in diabetic CAD patients sVCAM‑1 levels were increased in those without a history of MI (р=0,036, in comparison with the controls). There were no correlations between sVCAM‑1 levels and left ventricular remodeling indices in patients either with or without MI. Conclusions. In patients with CAD with T2DM and patients with CAD without T2DM, sVCAM‑1 levels increased in comparison with the controls. However, in patients without diabetes sVCAM‑1 level was increased only in those with previous MI. In patients with T2DM, sVCAM‑1 level increased in the absence of previous MI and there was the further significant increase of its level in postinfarction cardiosclerosis.

Subclinical Carotid Atherosclerosis in Patients with Rheumatoid Arthritis at Low Cardiovascular Risk.

To evaluate the rate of subclinical carotid atherosclerosis and clinical significance of immunoinflammatory markers in patients with rheumatoid arthritis (RA) at low cardiovascular risk. The study included 275 RA patients and a control group of 100 participants without autoimmune diseases. All study participants were at low cardiovascular risk, calculated by the QRISK3 scale (<20%), and free of cardiovascular disease. Ultrasound examination of carotid arteries was performed to measure cIMT and to detect atherosclerotic plaques (ASP) in carotid arteries. sIСАМ-1, sVСАМ, and sCD40L levels were determined by enzyme immunoassay. Carotid ASP was observed more frequently in RA patients (27%) than in the control group (17%), p = 0.03. The frequency of ASP in RA patients did not depend on the disease's stage or activity. There was a significant correlation between cIMT and age, cardiovascular risk determined by QRISK3, level of total cholesterol, LDL, and blood pressure in RA patients, p < 0.05 in all cases. No correlation between cIMT and blood levels of sCD40L, sVCAM, and sICAM was found. In RA patients, a higher concentration of sVCAM was detected in the carotid ASP group compared to the non-atherosclerotic group. sCD40L was associated with cIMT and total cholesterol in the ASP group and with total cholesterol and blood pressure in non-atherosclerotic patients. Subclinical atherosclerotic lesions of the carotid arteries were observed significantly more frequently in RA patients with low cardiovascular risk than in the control group. The results of the study demonstrate the association between cIMT, traditional cardiovascular risk factors, and immunoinflammatory markers in RA patients.

Bacterial gut microbiome differences in adults with ADHD and in children with ADHD on psychostimulant medication

Recent evidence suggests that there is a link between neurodevelopmental disorders, such as attention-deficit hyperactivity disorder (ADHD), and the gut microbiome. However, most studies to date have had low sample sizes, have not investigated the impact of psychostimulant medication, and have not adjusted for potential confounders, including body mass index, stool consistency and diet. To this end, we conducted the largest, to our knowledge, fecal shotgun metagenomic sequencing study in ADHD, with 147 well-characterized adult and child patients. For a subset of individuals, plasma levels of inflammatory markers and short-chain fatty acids were also measured. In adult ADHD patients (n = 84), compared to controls (n = 52), we found a significant difference in beta diversity both regarding bacterial strains (taxonomic) and bacterial genes (functional). In children with ADHD (n = 63), we found that those on psychostimulant medication (n = 33 on medication vs. n = 30 not on medication) had (i) significantly different taxonomic beta diversity, (ii) lower functional and taxonomic evenness, (iii) lower abundance of the strain Bacteroides stercoris CL09T03C01 and bacterial genes encoding an enzyme in vitamin B12 synthesis, and (iv) higher plasma levels of vascular inflammatory markers sICAM-1 and sVCAM-1. Our study continues to support a role for the gut microbiome in neurodevelopmental disorders and provides additional insights into the effects of psychostimulant medication. However, additional studies are needed to replicate these findings and examine causal relationships with the disorder.

Clinical and biochemical short-term effects of hyperbaric oxygen therapy on SARS-Cov-2+ hospitalized patients with hypoxemic respiratory failure

BackgroundHyperbaric oxygen therapy (HBOT) has been proposed to address COVID-19- associated respiratory failure. However, its biochemical effects are poorly known. Method50 patients with hypoxemic COVID-19 pneumonia were divided into C group (standard care) and H group (standard care plus HBOT). Blood was obtained at t = 0 and t = 5 days. Oxygen saturation (O2 Sat) was followed up. White blood cell (WC) count, lymphocytes (L) and platelets(P) and serum analysis (glucose, urea, creatinine, sodium, potassium, ferritin, D dimer, LDH and CRP) were carried out. Plasma levels of sVCAM, sICAM, sPselectin, SAA and MPO, and of cytokines (IL-1β, IL-1RA, IL-6, TNFα, IFNα, IFNγ, IL-15, VEGF, MIP1α, IL-12p70, IL-2 and IP-10) were measured by multiplex assays. Angiotensin Converting Enzyme 2 (ACE-2) levels were determined by ELISA. ResultsThe average basal O2 Sat was 85 ± 3%. The days needed to reach O2 Sat >90% were: H: 3 ± 1 and C: 5 ± 1 (P < 0,01). At term, H increased WC, L and P counts (all, H vs C: P < 0,01). Also, H diminished D dimer levels (H vs C, P < 0,001) and LDH concentration (H vs C, P < 0.01]. At term, H showed lower levels of sVCAM, sPselectin and SAA than C with respect to basal values (H vs C: ΔsVCAM: P < 0,01; ΔsPselectin: P < 0,05; ΔSAA: P < 0,01). Similarly, H showed diminished levels of TNFα (ΔTNFα: P < 0,05) and increased levels of IL-1RA and VEGF than C respect to basal values (H vs C: ΔIL-1RA and ΔVEGF: P < 0,05). ConclusionPatients underwent HBOT improved O2 Sat with lower levels of severity markers (WC and platelets count, D dimer, LDH, SAA). Moreover, HBOT reduced proinflammatory agents (sVCAM, sPselectin, TNFα) and increased anti-inflammatory and pro-angiogenic ones (IL-1RA and VEGF).

Soluble Vascular Cell Adhesion Molecule-1 as an Inflammation-Related Biomarker of Coronary Slow Flow.

Background: Coronary slow flow (CSF) is an angiographic entity characterized by delayed coronary opacification with no evident obstructive lesion in the epicardial coronary artery. Several studies have shown that the occurrence and development of CSF may be closely related to inflammation. Soluble vascular cell adhesion molecule-1 (sVCAM-1) is a biomarker related to inflammation. The aim of this study was to evaluate the correlation between plasma soluble VCAM-1 level and CSF occurrence and thus the predictive value of VCAM-1 for CSF. Methods: Forty-six CSF patients and thirty control subjects were enrolled. Corrected thrombolysis in myocardial infarction frame count (cTFC) was used to diagnose CSF. Functional status and quality of life were determined by the Seattle Angina Questionnaire (SAQ). Echocardiography was used to evaluate the systolic and diastolic function of the left ventricle (LV) and right ventricle (RV). The plasma levels of sVCAM-1, IL-6, and TNF-α were quantified by enzyme-linked immunosorbent assay. Results: Compared with the control group, the physical limitation score by the SAQ, the LV global longitudinal strain (GLS), mitral E, and mitral E/A decreased in patients with CSF, while the plasma IL-6 and TNF-α levels increased. The plasma sVCAM-1 level in the CSF group was significantly higher than that in the control group (186.03 ± 83.21 vs. 82.43 ± 42.12 ng/mL, p < 0.001), positively correlated with mean cTFC (r = 0.57, p < 0.001), and negatively correlated with the physical limitation score (r = −0.32, p = 0.004). Logistic regression analyses confirmed that plasma sVCAM-1 level (OR = 1.07, 95%CI: 1.03−1.11) is an independent predictor of CSF, and the receiver operating characteristic curve analysis showed that plasma sVCAM-1 levels had statistical significance in predicting CSF (area under curve = 0.88, p < 0.001). When the sVCAM-1 level was higher than 111.57 ng/mL, the sensitivity for predicting CSF was 87% and the specificity was 73%. Conclusions: Plasma sVCAM-1 level can be used to predict CSF and was associated with the clinical symptoms of patients. It may serve as a potential biomarker for CSF in the future.

Biomarkers for Premature Coronary Artery Disease (PCAD): A Case Control Study.

Coronary artery disease (CAD) is often associated with the older generation. However, in recent years, there is an increasing trend in the prevalence of CAD among the younger population; this is known as premature CAD. Although biomarkers for CAD have been established, there are limited studies focusing on premature CAD especially among the Malay male population. Thus, the aim of this research was to compare the biomarkers between premature CAD (PCAD) and older CAD (OCAD) among Malay males. Subjects, recruited from the Universiti Kebangsaan Malaysia Medical Centre and National Heart Institution, were divided into four groups: healthy control < 45 years old; premature CAD (PCAD) < 45 years old; healthy control > 60 years old; and older CAD (OCAD) > 60 years old, with n = 30 for each group. Ten potential markers for CAD including soluble sVCAM-1, sICAM-1, interleukin-2, interleukin-6, interleukin-10, Apo-E and Apo-A1, homocysteine, CRP, and vitamin D levels were examined. Our results revealed premature CAD patients had significantly higher values (p < 0.05) of sVCAM-1, CRP, interleukin-6, and vitamin D when compared to the age-matched controls. Similarly, older CAD patients showed higher levels of sVCAM-1, CRP, and interleukin-2 when compared to their age-matched controls. After adjusting for multiple parameters, only CRP remained significant for PCAD and interleukin-2 remained significant for CAD. This indicates that premature CAD and older CAD patients showed different profiles of protein biomarkers. CRP has the potential to become a biomarker for premature CAD while interleukin-2 is a better biomarker for older CAD together with other typical panels of protein biomarkers.

ФУНКЦИОНАЛЬНАЯ АКТИВНОСТЬ ЭНДОТЕЛИЯ В СИСТЕМНОМ И МЕСТНОМ КРОВОТОКЕ У ПАЦИЕНТОВ ОБЛИТЕРИРУЮЩИМ АТЕРОСКЛЕРОЗОМ И РАЗВИТИЕ РЕСТЕНОЗА ПОСЛЕ ОПЕРАЦИИ БЕДРЕННО-ПОДКОЛЕННОГО ШУНТИРОВАНИЯ

Objective: To analyze the role of markers of the endothelial dysfunction in the vessels of the systemic and local blood flow before and after femoropopliteal bypass surgery (FPBS) in the development of restenosis at obliterating lesions of the femoropopliteal arterial segment (FPAS). Methods: The results of the examination and treatment of 82 patients with obliterating atherosclerosis who underwent FPBS were analyzed. Before and after surgery they underwent testing for serum homocysteine, oxidized low-density lipoprotein, soluble vascular cell adhesion molecule-1 (sVCAM-1), plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), and annexin V in the systemic and local blood flow. Based on the condition of the reconstruction zone after 12 months, all patients were divided into two groups. Group 1 included patients without restenosis (n=21), and Group 2 – with restenosis (n=61). Results: Before surgery Group 2 patients showed significant differences in the severity of adhesive and hemostatic forms of endothelial dysfunction, as well as apoptosis in comparison with Group 1. It was found that before surgery, Group 2 patients had a significantly higher level of sVCAM-1 in the local bloodstream (by 37.5%, p=0.014), PAI-1 in the systemic and local bloodstream (by 15.6%, p=0.010, and by 16.4%, p=0.008 respectively) and annexin V in the systemic and local bloodstream (by 48.9%, p=0.012 and by 60.2%, p=0.002 respectively). After surgery Group 2 patients had significantly higher levels of PAI-1 in the systemic (by 18.9%, p=0.004) and local (by 11.1%, p=0.049) blood flow, and annexin V in the systemic circulation (by 28.4%, p=0.011) compared with Group 1. Thus increased levels of sVCAM-1 in the local bloodstream, PAI-1, and annexin V – in the systemic and local bloodstream before surgery were associated with postoperative development of restenosis, while higher values of PAI-1 in the systemic and local bloodstream and annexin V in the systemic circulation after surgery were related to subsequent restenosis development. Conclusion: The results of the study indicate impairment of the adhesive and hemostatic function of the endothelium, and increased level of apoptosis in the blood vessels of systemic and local blood flow in patients with restenosis, which can be used to develop personalized approach to management of this disorder and improve the results of revascularization interventions on FPAS. Keywords: Obliterating atherosclerosis of the lower extremities, femoropopliteal bypass surgery, functional activity of the endothelium, restenosis.

Vascular Cell Adhesion Molecule 1 and Adiponectin Receptor 1 in Plasma-Derived Extracellular Vesicles of Type 2 Diabetes Patients

Background: Patients with diabetes are susceptible to accelerated vascular damage associated with increased circulating extracellular vesicles (EVs) from endothelial tissue. Adiponectin is a cytokine with anti-inflammatory and insulin-sensitivity properties decreased in the plasma of patients with type 2 diabetes (T2D). This study aimed to assess the content of receptor 1 for adiponectin (AdipoR1) in both total and endothelial EVs from plasma samples of T2D patients and normoglycemic subjects. Methods: Insulin and soluble vascular endothelial molecule-1 (sVCAM-1) in plasma were measured by ELISA, and we used flow cytometry to determine the content of AdipoR1, CD106, and CD144 in plasma-derived EVs from 14 patients with diabetes and 34 normoglycemic subjects. Results: Compared to normoglycemic subjects, the percentage of vesicles CD144+ (p = 0.0041) and CD106+ (p = 0.0011) were higher in patients with diabetes. Compared to T2D patients, the percentage and medium fluorescence intensity from the total EVs/AdipoR1+ (p = 0.041 and p = 0.0220) were higher in normoglycemic subjects. Plasmatic sVCAM-1 was negatively correlated with plasma adiponectin (b = - 14.415, p &lt; 0.0001), along with the percentage of EVs/AdipoR1+ (b = - 8.209, p = 0.001); and correlated positively with the percentage of EVs/CD144+ (b = 6.768, p &lt; 0.0001) and HOMA-IR (b = 67.919, p &lt; 0.0001). Conclusions: Our results show that the content of AdipoR1 in plasma-derived VEs is lower in patients with T2D than in subjects with normoglycemic. AdipoR1 content in EVs is negatively associated with the endothelial damage marker sVCAM-1 level in plasma and with the HOMA-IR value.

The Effects of Indoxyl Sulfate and Oxidative Stress on the Severity of Peripheral Nerve Dysfunction in Patients with Chronic Kidney Diseases.

Pieces of evidence support the view that the accumulation of uremic toxins enhances oxidative stress and downstream regulation of signaling pathways, contributing to both endothelial microangiography and cell dysfunction. This study is to address the impact of protein-binding uremic toxins on the severity of peripheral nerve function in patients with chronic kidney disease (CKD). Fifty-four patients with CKD were included in the Toronto Clinical Neuropathy Score (TCNS), nerve conduction study (NCS), and laboratory studies including protein-binding uremic toxin (indoxyl sulfate [IS] and p-cresyl sulfate [PCS]), oxidative stress (Thiol and thiobarbituric acid reacting substances [TBARS]), and endothelial dysfunction (serum intercellular adhesion molecule 1 [sICAM-1] and serum vascular adhesion molecule 1 [sVCAM-1]) at enrollment. We used composite amplitude scores (CAS) to analyze the severity of nerve conductions on peripheral nerve function. TCNS and CAS were higher in the diabetic CKD group (p = 0.02 and 0.01, respectively). The NCS revealed the compound muscle action potential of ulnar and peroneal nerves and the sensory nerve action potential of ulnar and sural nerves (p = 0.004, p = 0.004, p = 0.004, and p = 0.001, respectively), which was found to be significantly low in the diabetic group. CAS was significantly correlated with age (r = 0.27, p = 0.04), urine albumin-creatinine ratio (UACR) (r = 0.29, p = 0.046), free-form IS (r = 0.39, p = 0.009), sICAM-1 (r = 0.31, p = 0.02), sVCAM-1 (r = 0.44, p &lt; 0.0001), TBARS (r = 0.35, p = 0.002), and thiols (r = -0.28, p = 0.045). Linear regression revealed that only TBARS and free-form IS were strongly associated with CAS. The mediation analysis shows that the sVCAM-1 level serves as the mediator between higher IS and higher CAS. IS and oxidative stress contribute to the severity of peripheral nerve dysfunction in patients with CKD, and chronic glycemic impairment can worsen the conditions.

Influence factors of deep venous thromboembolism after knee arthroplasty and significance of changes of serum nets and sVCAM-1 levels

To investigate the relationship between the changes of serum neutrophil extracellular traps (NETs), soluble vascular cell adhesion molecule-1(sVCAM-1) and deep venous thromboembolism after knee arthroplasty. From May 2017 to April 2020, 30 patients with deep venous thromboembolism after knee arthroplasty were retrospectively selected as the observation group, and 60 patients without deep venous thromboembolism after knee arthroplasty in the same period were randomly selected as the control group. The clinical data, serum levels of nets and sVCAM-1 before and 1, 3 and 5 days after operation were compared between the two groups. Logistic regression model was used to analyze the influencing factors of deep venous thromboembolism after knee arthroplasty; Pearson correlation was used to analyze the relationship between serum nets and sVCAM-1 levels;Draw the receiver operating characteristic curve(ROC) to obtain the area under the curve(AUC), and analyze the diagnostic value of serum nets and sVCAM-1 levels for deep vein thromboembolism after knee arthroplasty. There were statistically significant differences between two groups in age, body mass index, and postoperative knee elevation and flexion ratio(P<0.05). The level of serum NETs and sVCAM-1 on the 1st and 3rd day after surgery of the observation group were higher than the control group(P<0.05). Logistic regression analysis showed that age, body mass index, knee flexion position, serum nets and sVCAM-1 levels at 1 and 3 days after operation were all the influencing factors of DVT after knee arthroplasty (P<0.05);Pearson correlation analysis showed that there was a positive correlation between the levels of serum NETs and sVCAM-1 in patients with deep venous thromboembolism after knee arthroplasty 1 and 3 days after operation(P<0.05). The ROC curve of predicting deep venous thromboembolism after knee arthroplasty by serum nets and sVCAM-1 levels at 1 and 3 days after operation was drawn, the results showed that the AUC of serum nets and sVCAM-1 levels at 1 day after operation was higher than that at 3 days after operation, which had a good predictive effect. The influencing factors of deep vein thromboembolism after knee arthroplasty are age, body mass index, postoperative knee elevation and flexion, postoperative serum NETs and sVCAM-1 levels, especially postoperative serum NETs and sVCAM-1 levels. Changes can be used as potential biomarkers for predicting postoperative deep vein thromboembolism, and clinical attention should be paid to it.

Baseline severity and soluble vascular cell adhesion molecule 1 (sVCAM-1) as biomarker predictors of short-term mortality in acute ischemic stroke.

The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5-14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795-0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.

Parmodulin, an Allosteric Inhibitor of Protease Activated Receptor 1 (PAR1) Protects Sickle Cell Mice from Thromboinflammation and Endothelial Dysfunction

Protease activated receptor 1 (PAR1) couples the coagulation cascade to endothelial inflammation in many diseases, including sickle cell disease (SCD). PAR1 is a GPCR activated by proteolytic cleavage of an extracellular N-terminus, and demonstrates biased signaling. Activation of PAR1 by thrombin stimulates prothrombotic and proinflammatory signaling, whereas activation by activated protein C (APC) stimulates cytoprotective and anti-inflammatory pathways. The ideal PAR-1 targeted therapy would inhibit detrimental signaling while preserving beneficial signaling. 3K3A-APC is a signaling selective variant of APC that activates cytoprotective PAR1 signaling with minimal anticoagulant effects, demonstrated to have a beneficial role in stroke models. Parmodulin 2 (PM2) is a small molecule allosteric inhibitor of PAR1 that simultaneously blocks detrimental signaling and activate beneficial cytoprotective signaling similar to that induced by APC. We previously demonstrated that endogenous APC-PAR1 signaling contributes to thrombin generation and inflammation in a mouse model of SCD, whereas thrombin-PAR signaling enhances these pathways. We hypothesize that inducing cytoprotective PAR1 signaling with either 3K3A-APC and PM2 will reduce thrombo-inflammation in sickle cell mice at steady state. Townes wild type (HbAA) and sickle (HbSS) mice (male and female, 4 months old) were used in the studies. In the first experiment, HbAA and HbSS (n=4-5 per group) mice were treated daily with either saline (SAL) or 3K3A-APC (0.2mg/kg, BW) for 4 days. Samples were collected 1 hour after final dose. As previously demonstrated, plasma levels of thrombin-anti thrombin (TAT) complexes, the proinflammatory cytokine IL-6, high mobility group box 1 (HMGB1), and, soluble vascular cell adhesion molecule (sVCAM), were increased in HbSS mice compared to HbAA controls. Surprisingly 3K3A-APC treatment did reduce any of these parameters in HbSS mice. APC and its variant 3K3A-APC require binding to the endothelial protein C receptor (EPCR) to activate PAR1; it is known that SCD causes increased EPCR shedding. Indeed, we found that both SAL- and 3K3A-APC treated HbSS mice had elevated sEPCR levels compared to HbAA controls. Together, these data indicate that 3K3A-APC does not affect thrombo-inflammation in HbSS mice at steady state most likely due to by reduced ECPR expression on the endothelium. In the second experiment, HbAA and HbSS (male and female, 4 months old) mice (n=8-11 per group) were treated with vehicle (20% DMSO, 20% PEG800, 60% PBS) or PM2 (10 mg/kg, BW) every other day for 1 week. The last dose was administered on the 8th day 1 hour prior to collecting plasma samples. As expected, HbSS mice had elevated plasma TAT levels compared to HbAA mice (11.04 ± 1.4 vs 45.19 ± 6.3, p<0.05) which was significantly attenuated by PM2 treatment in SS mice (16.17 ± 2, p<0.05). Similar results were observed for IL-6 (AA: 2.06 ± 0.7 vs SS: 29.12 ± 9.6 vs SS+PM2: 5.83 ± 2.9; p<0.05); sVCAM (AA: 330.6 ± 31.5 vs SS: 571.4 ± 50.4 vs SS+PM2: 403.3 ± 41.22; p<0.05) and HMGB1 (AA: 11.46 ± 1.1 vs SS: 25.37 ± 1.5 vs SS+PM2: 19.12 ± 1.7; p<0.05). PM2 had no effect on markers of anemia in HbSS mice including RBC, hematocrit, and reticulocyte counts. In the present study ,3K3A-APC did not attenuate thrombin generation and cytokine production in HbSS mice; this might be due to the shedding of EPCR which is important co-receptor for the protective APC-PAR1 signaling. In contrast, PM2-mediated allosteric inhibition of thrombin/PAR1 and simultaneous induction of APC-like cytoprotective signaling attenuated levels of TAT, IL-6, HMGB1, and sVCAM in HbSS mice. Future studies towards evaluating the effect of PM2 on downstream targets of PAR1 signaling in sickle mice will provide more insight into the mechanism of this protective effect.