Browsing by Author "Rakocevic, Jelena (55251810400)"

Inflammation plays an important role in all stages of atherosclerosis — from endothelial dysfunction, to formation of fatty streaks and atherosclerotic plaque, and its progression to serious complications, such as atherosclerotic plaque rupture. Although dyslipidemia is a key driver of atherosclerosis, pathogenesis of atherosclerosis is now considered interplay between cholesterol and inflammation, with the significant role of the immune system and immune cells. Despite modern therapeutic approaches in primary and secondary cardiovascular prevention, cardiovascular diseases remain the leading cause of mortality worldwide. In order to reduce residual cardiovascular risk, despite the guidelines-guided optimal medical therapy, novel therapeutic strategies are needed for prevention and management of coronary artery disease. One of the innovative and promising approaches in atherosclerotic cardiovascular disease might be inflammation-targeted therapy. Numerous experimental and clinical studies are seeking into metabolic pathways underlying atherosclerosis, in order to find the most suitable pathway and inflammatory marker/s that should be the target for anti-inflammatory therapy. Many anti-inflammatory drugs have been tested, from the well-known broad range anti-inflammatory agents, such as colchicine, allopurinol and methotrexate, to targeted monoclonal antibodies specifically inhibiting a molecule included in inflammatory pathway, such as canakinumab and tocilizumab. To date, there are no approved anti-inflammatory agents specifically indicated for silencing inflammation in patients with coronary artery disease. The most promising results came from the studies which tested colchicine, and studies where the inflammatory-target was NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/interleukin-1 beta (IL-1β)/interleukin-6 (IL-6)/C-reactive protein (CRP) pathway. A growing body of evidence, along with the ongoing clinical studies, suggest that the anti-inflammatory therapy might become an additional strategy in treating atherosclerotic cardiovascular disease. Herein we present an overview of the role of inflammation in atherosclerosis, the most important inflammatory markers chosen as targets of anti-inflammatory therapy, along with the critical review of the major clinical trials which tested non-targeted and targeted anti-inflammatory drugs in patients with atherosclerotic cardiovascular disease. © 2023 The Author(s). Published by IMR Press.

Introduction: Angiogenesis is the growth of both new vascular and lymphatic blood vessels from the existing vasculature. During this process, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs) express specific markers, which help their discrimination and easier identification. Since the coronary thrombi material aspirated from patients with ST-elevation myocardial infarction (STEMI) proved as good angiogenesis model, we investigated the expression of CD34 and CD31 as BECs markers, and D2-40, LYVE-1 and VEGFR3 as LEC markers in this material. Materials and methods: Aspirated thrombi were stained immunohistochemically for CD34, CD31, D2-40, LYVE-1 and VEGFR3. Organizational patterns of immunopositive cells were graded as single cells, clusters or microvessels. Double immunofluorescence for CD31, D2-40, LYVE-1 and VEGRF3 was done. Thrombi were also graded as fresh (< 1 day old), lytic (1-5 days old) and organized (> 5 days old). Results: Serial sections of aspirated thrombi showed concordant BEC and LEC markers immunopositivity. Double immunoflorescence proved co-expression of CD31 and LEC markers on the same cells. Cells expressing LEC markers organized in clusters and microvessels were mainly present in lytic and organized thrombi. Conclusion: Co-expression of BEC and LEC markers on the same non-tumorous cell during thrombus neovascularization indicates existing in vivo plasticity of endothelial cells under non-tumorous pathological conditions. It also points that CD34 and CD31 on one hand, and D2-40, LYVE-1 and VEGFR3 immunostaining on the other hand, cannot solely be a reliable indicators whether vessel is lymphatic or not. © 2015 Elsevier Inc.

Introduction: Angiogenesis is the growth of both new vascular and lymphatic blood vessels from the existing vasculature. During this process, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs) express specific markers, which help their discrimination and easier identification. Since the coronary thrombi material aspirated from patients with ST-elevation myocardial infarction (STEMI) proved as good angiogenesis model, we investigated the expression of CD34 and CD31 as BECs markers, and D2-40, LYVE-1 and VEGFR3 as LEC markers in this material. Materials and methods: Aspirated thrombi were stained immunohistochemically for CD34, CD31, D2-40, LYVE-1 and VEGFR3. Organizational patterns of immunopositive cells were graded as single cells, clusters or microvessels. Double immunofluorescence for CD31, D2-40, LYVE-1 and VEGRF3 was done. Thrombi were also graded as fresh (< 1 day old), lytic (1-5 days old) and organized (> 5 days old). Results: Serial sections of aspirated thrombi showed concordant BEC and LEC markers immunopositivity. Double immunoflorescence proved co-expression of CD31 and LEC markers on the same cells. Cells expressing LEC markers organized in clusters and microvessels were mainly present in lytic and organized thrombi. Conclusion: Co-expression of BEC and LEC markers on the same non-tumorous cell during thrombus neovascularization indicates existing in vivo plasticity of endothelial cells under non-tumorous pathological conditions. It also points that CD34 and CD31 on one hand, and D2-40, LYVE-1 and VEGFR3 immunostaining on the other hand, cannot solely be a reliable indicators whether vessel is lymphatic or not. © 2015 Elsevier Inc.

Gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) can jeopardize mother and/or fetus. Vascular ATP-sensitive potassium (KATP) channels most likely participate in the processes of diabetes and hypertension. The aim of this research was to examine whether GDM and PIH cause changes in the expression and function of KATP channels in vascular smooth muscle of human umbilical vein (HUV). Western blot and immunohistochemistry detected significantly decreased expression of Kir6.1 subunit of KATP channels in GDM and PIH, while the expression of SUR2B was unchanged. In GDM, a K+ channel opener, pinacidil caused reduced relaxation of the endothelium-denuded HUVs compared to normal pregnancy. However, its effects in HUVs from PIH subjects were similar to normal pregnancy. In all groups KATP channel blocker glibenclamide antagonized the relaxation of HUV induced by pinacidil without change in the maximal relaxations indicating additional KATP channel-independent mechanisms of pinacidil action. Iberiotoxin, a selective antagonist of large-conductance calcium-activated potassium channels, inhibited the relaxant effect of pinacidil in PIH, but not in normal pregnancy and GDM. Experiments performed in K+-rich solution confirmed the existence of K+-independent effects of pinacidil, which also appear to be impaired in GDM and PIH. Thus, the expression of KATP channels is decreased in GDM and PIH. In GDM, vasorelaxant response of HUV to pinacidil is reduced, while in PIH it remains unchanged. It is very likely that KATP channels modulation and more detailed insight in KATP channel-independent actions of pinacidil may be precious in the therapy of pathological pregnancies. © 2019 Elsevier Inc.

Gestational diabetes mellitus (GDM) and pregnancy-induced hypertension (PIH) can jeopardize mother and/or fetus. Vascular ATP-sensitive potassium (KATP) channels most likely participate in the processes of diabetes and hypertension. The aim of this research was to examine whether GDM and PIH cause changes in the expression and function of KATP channels in vascular smooth muscle of human umbilical vein (HUV). Western blot and immunohistochemistry detected significantly decreased expression of Kir6.1 subunit of KATP channels in GDM and PIH, while the expression of SUR2B was unchanged. In GDM, a K+ channel opener, pinacidil caused reduced relaxation of the endothelium-denuded HUVs compared to normal pregnancy. However, its effects in HUVs from PIH subjects were similar to normal pregnancy. In all groups KATP channel blocker glibenclamide antagonized the relaxation of HUV induced by pinacidil without change in the maximal relaxations indicating additional KATP channel-independent mechanisms of pinacidil action. Iberiotoxin, a selective antagonist of large-conductance calcium-activated potassium channels, inhibited the relaxant effect of pinacidil in PIH, but not in normal pregnancy and GDM. Experiments performed in K+-rich solution confirmed the existence of K+-independent effects of pinacidil, which also appear to be impaired in GDM and PIH. Thus, the expression of KATP channels is decreased in GDM and PIH. In GDM, vasorelaxant response of HUV to pinacidil is reduced, while in PIH it remains unchanged. It is very likely that KATP channels modulation and more detailed insight in KATP channel-independent actions of pinacidil may be precious in the therapy of pathological pregnancies. © 2019 Elsevier Inc.

Endothelial cell markers are membrane-bound or cytoplasmic molecules expressed by endothelial cells, which help their easier identification and discrimination from other cell types. During vasculogenesis, endothelial cells differentiate from hemangioblasts to form new blood vessels. With the discovery of endothelial progenitor cells (EPC) and their ability to form new blood vessels, the term vasculogenesis is not only reserved for the embryonic development. Possibility of de novo blood vessel formation from EPC is now widely explored in different ischemic conditions, especially in cardiovascular medicine. Numerous clinical trials have tested enhancing tissue vascularization by delivering hematopoietic cells that expressed endothelial markers. This therapeutic approach proved to be challenging and promising, particularly for patients who have exhausted all conventional therapeutic modalities. Angiogenesis, which refers to the formation of new blood vessels from existing vasculature, is indispensable process during tumor progression and metastasis. Blockage of tumor angiogenesis by targeting and inhibiting endothelial cell has emerged as novel safe and efficacious method to control many advanced malignant diseases. Numerous clinical studies are currently testing new antiangiogenic drugs which target and inhibit endothelial cell markers, receptors or molecules which transmit receptor-mediated signals, therefore inhibiting endothelial cell proliferation, migration and vascular tube formation. Many of these drugs are now widely used in clinical settings as first- or second-line chemotherapy in advanced malignant conditions. So far, these therapeutic approaches gave modest, yet encouraging clinical improvements, prolonging survival and improving functional capacity and quality of life for many terminally ill patients. Here we present the most commonly used endothelial cell markers along with their applicability in contemporary clinical practice. © 2017 Elsevier Inc.

Endothelial cell markers are membrane-bound or cytoplasmic molecules expressed by endothelial cells, which help their easier identification and discrimination from other cell types. During vasculogenesis, endothelial cells differentiate from hemangioblasts to form new blood vessels. With the discovery of endothelial progenitor cells (EPC) and their ability to form new blood vessels, the term vasculogenesis is not only reserved for the embryonic development. Possibility of de novo blood vessel formation from EPC is now widely explored in different ischemic conditions, especially in cardiovascular medicine. Numerous clinical trials have tested enhancing tissue vascularization by delivering hematopoietic cells that expressed endothelial markers. This therapeutic approach proved to be challenging and promising, particularly for patients who have exhausted all conventional therapeutic modalities. Angiogenesis, which refers to the formation of new blood vessels from existing vasculature, is indispensable process during tumor progression and metastasis. Blockage of tumor angiogenesis by targeting and inhibiting endothelial cell has emerged as novel safe and efficacious method to control many advanced malignant diseases. Numerous clinical studies are currently testing new antiangiogenic drugs which target and inhibit endothelial cell markers, receptors or molecules which transmit receptor-mediated signals, therefore inhibiting endothelial cell proliferation, migration and vascular tube formation. Many of these drugs are now widely used in clinical settings as first- or second-line chemotherapy in advanced malignant conditions. So far, these therapeutic approaches gave modest, yet encouraging clinical improvements, prolonging survival and improving functional capacity and quality of life for many terminally ill patients. Here we present the most commonly used endothelial cell markers along with their applicability in contemporary clinical practice. © 2017 Elsevier Inc.

Background/Aim. Thyroid nodules are usually asymptomatic and may occur in 68% of the general population. In most cases, they are discovered incidentally. As malignancy is proven in 10-15% of cases, a rational diagnostic approach is necessary. The aim of this retrospective study was to examine and grade different characteristics of patients with nodular and multinodular atoxic goiter in order to identify the potential predictors for the assessment of thyroid cancer risk. Methods. The study included 275 patients with nodular and multinodular atoxic goiter hospitalized at the Clinic for Endocrinology of the Military Medical Academy, Belgrade, Serbia, from January 1, 2017, to October 1, 2022, for preoperative preparation. The most relevant clinical, biohumoral, and pathomorphological characteristics were analyzed. Results. Patients with multiple thyroid nodules were older (57.21 ± 13.16 vs. 49.36 ± 15.83 years, p < 0.001) and had higher body mass index (29.12 kg/m2 vs. 26.50 kg/m2, p = 0.004) compared to patients with one nodule. On the other hand, patients with one thyroid nodule had a higher level of the thyroid-stimulating hormone than patients with multiple nodules (1.73 mIU/L vs. 1.21 mIU/L, p < 0.0001). Comparison of patients with and without proven thyroid cancer has shown a highly significant association between the higher categories of Bethesda classification and the presence of cancer (Bethesda IV-VI vs. Bethesda II-III, 52.2% vs. 22.3%, respectively, p = 0.002). Conclusion. Considering all the observed parameters, the cytological finding of fine needle aspiration biopsy emerged as the only one with predictive relevance for assessing thyroid cancer risk. © 2024 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Background: Coronary chronic total occlusion (CTO) is characterized by the presence of collateral blood vessels which can provide additional blood supply to CTO-artery dependent myocardium. Successful CTO recanalization is followed by significant decrease in collateral donor artery blood flow and collateral derecruitment, but data on coronary hemodynamic changes in relation to myocardial function are limited. We assessed changes in coronary flow velocity reserve (CFVR) by echocardiography in collateral donor and recanalized artery following successful opening of coronary CTO. Methods: Our study enrolled 31 patients (60 ± 9 years; 22 male) with CTO and viable myocardium by SPECT scheduled for percutaneous coronary intervention (PCI). Non-invasive CFVR was measured in collateral donor artery before PCI, 24 h and 6 months post-PCI, and 24 h and 6 months in recanalized artery following successful PCI of CTO. Results: Collateral donor artery showed significant increase in CFVR 24 h after CTO recanalization compared to pre-PCI values (2.30 ± 0.49 vs. 2.71 ± 0.45, p = 0.005), which remained unchanged after 6-months (2.68 ± 0.24). Baseline blood flow velocity of the collateral donor artery significantly decreased 24 h post-PCI compared to pre-PCI (0.28 ± 0.06 vs. 0.24 ± 0.04 m/s), and remained similar after 6 months, with no significant difference in maximum hyperemic blood flow velocity pre-PCI, 24 h and 6 months post-PCI. CFVR of the recanalized coronary artery 24 h post-PCI was 2.55 ± 0.35, and remained similar 6 months later (2.62 ± 0.26, p = NS). Conclusions: In patients with viable myocardium, prompt and significant CFVR increase in both recanalized and collateral donor artery, was observed within 24 h after successful recanalization of CTO artery, which maintained constant during the 6 months. © 2020 The Author(s).

Background/Objectives: Composite hemangioendothelioma (CHE) is a rare vascular endothelial tumor with borderline malignancy. This study presents a case of CHE and an updated systematic review of previously reported cases, providing insights into recurrence patterns and survival outcomes. Methods: A comprehensive electronic search was conducted across PubMed, Scopus, the Cochrane Library, and Web of Science up to 31 December 2024, to identify eligible case reports. Kaplan–Meier curves were used to estimate event-free survival. Results: We report a 61-year-old man with a splenic lesion associated with weight loss and abdominal pain persisting for 1 year. Intraoperative findings revealed an enlarged spleen and multiple hepatic deposits. Splenectomy and liver biopsy revealed a well-demarcated, nodular tumor measuring 160 × 145 × 100 mm, with histological and immunohistochemical findings consistent with CHE, complicated by hepatic metastasis. Of 405 potentially eligible studies, 59 were included in the review, covering cases from 2000 to 2024, with a peak in 2020 and 2023. The median age of patients was 42 years, with the most common tumor sites being the lower extremities (30.48%), followed by the face, head, and neck (20.95%), and upper extremities (18.1%). Surgical intervention was the most common treatment (60.95%). Recurrence-free survival was observed in 42.86% of cases, while 15.24% experienced recurrence with or without metastasis. Two patients (1.90%) died from the disease. The median recurrence-free survival was 48 months (95% CI: 7.3–88.7). Conclusions: CHE exhibits significant morphological variation and can mimic other vascular tumors. Accurate diagnosis is crucial for proper prognosis and avoiding overtreatment due to misdiagnosis as more aggressive neoplasms. Patients with high-risk CHE should undergo closer surveillance to ensure timely detection of progression. © 2025 by the authors.

The aim of this study was to test the hypothesis that subchronic co-application of vitamins B6 and folic acid (FA) could affect heart failure (HF) induced by monocrotaline (MCT), with the modulation of oxidative stress parameters and cardiometabolic biomarkers. Biochemical and histomorphometric analyses were assessed in blank solution-exposed controls (C1 physiological saline 1 mL/kg, 1 day, n = 8; C2 physiological saline 1 mL/kg, 28 days, n = 8), MCT-induced HF (MCT 50 mg/kg, n = 8), B6+FA (vitamin B6 7 mg·kg–1·day –1, FA 5 mg·kg–1·day –1; n = 8), and MCT+B6+FA (MCT 50 mg/kg, vitamin B6 7 mg·kg–1·day –1, FA 5 mg·kg–1·day –1; n = 8) in male Wistar albino rats (body mass 160 g at the start). Superoxide dismutase and glutathione peroxidase activities, thiol-, carbonyl groups, and nitrotyrosine were determined in cardiac tissue. Echocardiography was performed to confirm MCT-induced HF. The right ventricular wall hypertrophy, accompanied with significant increase of troponin T and preserved renal and liver function, has been shown in MCT-induced HF. However, these effects were not related to antioxidant effects of vitamin B6 and FA, since several parameters of oxidative stress were more pronounced after treatment. In this study, co-application of vitamins B6 and FA did not attenuate hypertrophy of the right ventricle wall but aggravated oxidative stress, which is involved in HF pathogenesis. © 2020, Canadian Science Publishing. All rights reserved.

The aim of this study was to test the hypothesis that subchronic co-application of vitamins B6 and folic acid (FA) could affect heart failure (HF) induced by monocrotaline (MCT), with the modulation of oxidative stress parameters and cardiometabolic biomarkers. Biochemical and histomorphometric analyses were assessed in blank solution-exposed controls (C1 physiological saline 1 mL/kg, 1 day, n = 8; C2 physiological saline 1 mL/kg, 28 days, n = 8), MCT-induced HF (MCT 50 mg/kg, n = 8), B6+FA (vitamin B6 7 mg·kg–1·day –1, FA 5 mg·kg–1·day –1; n = 8), and MCT+B6+FA (MCT 50 mg/kg, vitamin B6 7 mg·kg–1·day –1, FA 5 mg·kg–1·day –1; n = 8) in male Wistar albino rats (body mass 160 g at the start). Superoxide dismutase and glutathione peroxidase activities, thiol-, carbonyl groups, and nitrotyrosine were determined in cardiac tissue. Echocardiography was performed to confirm MCT-induced HF. The right ventricular wall hypertrophy, accompanied with significant increase of troponin T and preserved renal and liver function, has been shown in MCT-induced HF. However, these effects were not related to antioxidant effects of vitamin B6 and FA, since several parameters of oxidative stress were more pronounced after treatment. In this study, co-application of vitamins B6 and FA did not attenuate hypertrophy of the right ventricle wall but aggravated oxidative stress, which is involved in HF pathogenesis. © 2020, Canadian Science Publishing. All rights reserved.