Publications by authors named "Esma R Isenovic"

117 Publications

Tryptophan metabolism in atherosclerosis and diabetes.

Curr Med Chem 2021 Jul 14. Epub 2021 Jul 14.

Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

The essential amino acid tryptophan (Trp) undergoes catabolism through several pathways, producing biologically active metabolites that significantly impact physiological processes. The metabolic pathway responsible for the majority of Trp catabolism is the kynurenine synthesis pathway (KP). Serotonin and melatonin are among the most essential Trp pathways degradation products. It has emerged that a strong relationship exists between alterations in Trp metabolism and the onset and progression of atherosclerosis and diabetes. Atherosclerosis is a chronic inflammatory disease of the small and medium arteries wall caused by maladaptive local immune responses, which underpins several cardiovascular diseases (CVD). Systemic low-grade immune-mediated inflammation is implicated in atherosclerosis where pro-inflammatory cytokines, such as interferon-γ (IFN-γ), play a significant role. IFN-γ upregulates the enzyme indoleamine 2,3-dioxygenase (IDO), decreasing serum levels of the Trp and increasing metabolite levels of kynurenine. Increased IDO expression and activity could accelerate the atherosclerosis process. Therefore, activated IDO inhibition could offer possible treatment options regarding atherosclerosis management. Diabetes is a chronic metabolic disease characterized by hyperglycemia that, over time, leads to severe damage to the heart, blood vessels, eyes, kidneys, and peripheral nerves. Trp serum levels and lower activity of IDO were higher in future type 2 diabetes (T2DM) patients. This article reviews recent findings on the link between mammalian Trp metabolism and its role in atherosclerosis and diabetes and outlines the intervention strategies.
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http://dx.doi.org/10.2174/0929867328666210714153649DOI Listing
July 2021

Leptin and Obesity: Role and Clinical Implication.

Front Endocrinol (Lausanne) 2021 18;12:585887. Epub 2021 May 18.

Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

The peptide hormone leptin regulates food intake, body mass, and reproductive function and plays a role in fetal growth, proinflammatory immune responses, angiogenesis and lipolysis. Leptin is a product of the obese () gene and, following synthesis and secretion from fat cells in white adipose tissue, binds to and activates its cognate receptor, the leptin receptor (LEP-R). LEP-R distribution facilitates leptin's pleiotropic effects, playing a crucial role in regulating body mass a negative feedback mechanism between adipose tissue and the hypothalamus. Leptin resistance is characterized by reduced satiety, over-consumption of nutrients, and increased total body mass. Often this leads to obesity, which reduces the effectiveness of using exogenous leptin as a therapeutic agent. Thus, combining leptin therapies with leptin sensitizers may help overcome such resistance and, consequently, obesity. This review examines recent data obtained from human and animal studies related to leptin, its role in obesity, and its usefulness in obesity treatment.
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http://dx.doi.org/10.3389/fendo.2021.585887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167040PMC
May 2021

Could the level of nitrite/nitrate contribute to malignant thyroid nodule diagnostics?

Med Hypotheses 2021 May 23;150:110569. Epub 2021 Mar 23.

Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

Thyroid nodules are among highly prevalent thyroid diseases. To make a distinction between benign and malignant thyroid nodules are of cumbersome significance for each endocrinologist. There is no unique and completely accurate diagnostic test, method, or even biomarker that points to a malignant thyroid nodule. Many studies in modern thyroidology are conducted to determine the usefulness of individual biomarkers, which could help clinicians detect thyroid nodules' potential malignant nature. One interesting biomarker with a promising diagnostic potential for the thyroid gland pathological conditions is nitric oxide (NO). Inducible nitric oxide synthase expression is increased in thyroiditis cases and even more in thyroid carcinoma cases, directly connected with increased NO levels in both pathological conditions. We hypothesize that the basal levels of nitrite/nitrate in serum and biopsy washout could indicate nodules' malignant nature.
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http://dx.doi.org/10.1016/j.mehy.2021.110569DOI Listing
May 2021

Effects of Metformin-Single Therapy on the Level of Inflammatory Markers in Serum of Non-Obese T2DM Patients with NAFLD.

Endocr Metab Immune Disord Drug Targets 2021 Feb 24. Epub 2021 Feb 24.

Department of Radiobiology and Molecular Genetics, VINČA Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade. Serbia.

Background And Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD.

Methods: All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests) and serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide), and FLI/FIB-4 are calculated.

Results: FLI score and ultrasound NAFLD grades correlated (p<0.05). We observed a significant correlation between the levels of ferritin and C-reactive protein (CRP) (p<0.05), and the FLI (p<0.05). Body weight (BW) (p<0.05), waist circumference (WC) (p<0.05), the levels of HbA1c (p<0.05), transferrin (p<0.05), insulin (p<0.05), and FLI score (p<0.05) significantly differed between groups defined by the severity of NAFLD.

Conclusion: This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD.
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http://dx.doi.org/10.2174/1871530321666210225110140DOI Listing
February 2021

Atherosclerosis Linked to Aberrant Amino Acid Metabolism and Immunosuppressive Amino Acid Catabolizing Enzymes.

Front Immunol 2020 28;11:551758. Epub 2020 Sep 28.

Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

Cardiovascular disease is the leading global health concern and responsible for more deaths worldwide than any other type of disorder. Atherosclerosis is a chronic inflammatory disease in the arterial wall, which underpins several types of cardiovascular disease. It has emerged that a strong relationship exists between alterations in amino acid (AA) metabolism and the development of atherosclerosis. Recent studies have reported positive correlations between levels of branched-chain amino acids (BCAAs) such as leucine, valine, and isoleucine in plasma and the occurrence of metabolic disturbances. Elevated serum levels of BCAAs indicate a high cardiometabolic risk. Thus, BCAAs may also impact atherosclerosis prevention and offer a novel therapeutic strategy for specific individuals at risk of coronary events. The metabolism of AAs, such as L-arginine, homoarginine, and L-tryptophan, is recognized as a critical regulator of vascular homeostasis. Dietary intake of homoarginine, taurine, and glycine can improve atherosclerosis by endothelium remodeling. Available data also suggest that the regulation of AA metabolism by indoleamine 2,3-dioxygenase (IDO) and arginases 1 and 2 are mediated through various immunological signals and that immunosuppressive AA metabolizing enzymes are promising therapeutic targets against atherosclerosis. Further clinical studies and basic studies that make use of animal models are required. Here we review recent data examining links between AA metabolism and the development of atherosclerosis.
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http://dx.doi.org/10.3389/fimmu.2020.551758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549398PMC
April 2021

Hyperbaric Oxygen Therapy and Vascular Complications in Diabetes Mellitus.

Angiology 2020 11 8;71(10):876-885. Epub 2020 Jul 8.

Department of Radiobiology and Molecular Genetics, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia.

Vascular complications in patients with diabetes mellitus (DM) are common. Since impaired oxygen balance in plasma plays an important role in the pathogenesis of chronic DM-associated complications, the administration of hyperbaric oxygen therapy (HBOT) has been recommended to influence development of vascular complications. Hyperbaric oxygen therapy involves inhalation of 100% oxygen under elevated pressure from 1.6 to 2.8 absolute atmospheres in hyperbaric chambers. Hyperbaric oxygen therapy increases plasma oxygen solubility, contributing to better oxygen diffusion to distant tissues and preservation of the viability of tissues reversibly damaged by atherosclerosis-induced ischemia, along with microcirculation restoration. Hyperbaric oxygen therapy exerts antiatherogenic, antioxidant, and cardioprotective effects by altering the level and composition of plasma fatty acids and also by promoting signal transduction through membranes, which are impaired by hyperglycemia and hypoxia. In addition, HBOT affects molecules involved in the regulation of nitric oxide synthesis and in that way exerts anti-inflammatory and angiogenic effects in patients with DM. In this review, we explore the recent literature related to the effects of HBOT on DM-related vascular complications.
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http://dx.doi.org/10.1177/0003319720936925DOI Listing
November 2020

Effects of Root on Vascular Diseases.

Curr Vasc Pharmacol 2021 ;19(4):359-369

"VINČA" Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Department of Radiobiology and Molecular Genetics, Belgrade, Serbia.

Background: Gentiana lutea (GL), commonly known as yellow gentian, bitter root, and bitterwort, belongs to family Gentianaceae. GL belongs to genus Gentiana, which is a rich natural source of iridoids, secoiridoids, xantones, flavonoids, triterpenoids, and carbohydrates. Medicinal plants from Gentiana species have anti-oxidant, anti-inflammatory, anti-mitogenic, anti-proliferative, and lipidlowering effects, as well as a cardioprotective, hypotensive, vasodilator and anti-platelet activities.

Objective: We reviewed the recent literature related to the effects of Gentiana species, and their active components on vascular diseases.

Methods: Data used for this review were obtained by searching the electronic database [PUBMED/ MEDLINE 1973 - February 2020]. The primary data search terms of interest were: Gentiana lutea, Gentienacea family, phytochemistry, vascular diseases, treatment of vascular diseases, antioxidant, anti-inflammatory, anti-atherogenic.

Conclusion: Gentiana species and their constituents affect many different factors related to vascular disease development and progression. Therefore, Gentiana-based therapeutics represent potentially useful drugs for the management of vascular diseases.
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http://dx.doi.org/10.2174/1570161118666200529111314DOI Listing
January 2021

Regulation of nitric oxide production in hypothyroidism.

Biomed Pharmacother 2020 Apr 24;124:109881. Epub 2020 Jan 24.

Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia. Electronic address:

Hypothyroidism is a common endocrine disorder that predominantly occurs in females. It is associated with an increased risk of cardiovascular diseases (CVD), but the molecular mechanism is not known. Disturbance in lipid metabolism, the regulation of oxidative stress, and inflammation characterize the progression of subclinical hypothyroidism. The initiation and progression of endothelial dysfunction also exhibit these changes, which is the initial step in developing CVD. Animal and human studies highlight the critical role of nitric oxide (NO) as a reliable biomarker for cardiovascular risk in subclinical and clinical hypothyroidism. In this review, we summarize the recent literature findings associated with NO production by the thyroid hormones in both physiological and pathophysiological conditions. We also discuss the levothyroxine treatment effect on serum NO levels in hypothyroid patients.
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http://dx.doi.org/10.1016/j.biopha.2020.109881DOI Listing
April 2020

HbA1C as a marker of retrograde glycaemic control in diabetes patient with co-existed beta-thalassaemia: A case report and a literature review.

J Clin Pharm Ther 2020 Apr 17;45(2):379-383. Epub 2019 Nov 17.

Laboratory for Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.

What Is Known And Objective: The HbA1C marker used in assessing diabetes control quality is not sufficient in diabetes patients with thalassaemia.

Case Description: A male diabetic patient with thalassaemia was hospitalized due to distal neuropathic pain, right toe trophic ulcer, unacceptable five-point glycaemic profile and recommended HbA1C value. After simultaneously initiated insulin therapy and management of ulcer by hyperbaric oxygen, the patient showed improved glycaemic control and ulcer healing, which led to the patient's discharge.

What Is New And Conclusion: In thalassaemia and haemoglobinopathies, due to discrepancies in the five-point glycaemic profile and HbA1C values, it is necessary to measure HbA1C with a different method or to determine HbA1C and fructosamine simultaneously.
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http://dx.doi.org/10.1111/jcpt.13073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384187PMC
April 2020

Effects of IGF-1 on the Cardiovascular System.

Curr Pharm Des 2019 ;25(35):3715-3725

Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

Cardiovascular (CV) diseases are the most common health problems worldwide, with a permanent increase in incidence. Growing evidence underlines that insulin-like growth factor 1 (IGF-1) is a very important hormone responsible for normal CV system physiology. IGF-1 is an anabolic growth hormone, responsible for cell growth, differentiation, proliferation, and survival. Despite systemic effects, IGF-1 exerts a wide array of influences in the CV system affecting metabolic homeostasis, vasorelaxation, cardiac contractility and hypertrophy, autophagy, apoptosis, and antioxidative processes. The vasodilatory effect of IGF-1, is achieved through the regulation of the activity of endothelial nitric oxide synthase (eNOS) and, at least partly, through enhancing inducible NOS (iNOS) activity. Also, IGF-1 stimulates vascular relaxation through regulation of sodium/potassiumadenosine- triphosphatase. Numerous animal studies provided evidence of diverse influences of IGF-1 in the CV system such as vasorelaxation, anti-apoptotic and prosurvival effects. Human studies indicate that low serum levels of free or total IGF-1 contribute to an increased risk of CV and cerebrovascular disease. Large human trials aiming at finding clinical efficacy and outcome of IGF-1-related therapy are of great interest. We look forward to the development of new IGF 1 therapies with minor side effects. In this review, we discuss the latest literature data regarding the function of IGF-1 in the CV system in the physiological and pathophysiological conditions.
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http://dx.doi.org/10.2174/1381612825666191106091507DOI Listing
June 2020

Proton Pump Inhibitors and Radiofrequency Ablation for Treatment of Barrett's Esophagus.

Mini Rev Med Chem 2020 ;20(11):975-987

Department of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Belgrade, Serbia.

Gastroesophageal Reflux Disease (GERD) is characterized by acid and bile reflux in the distal oesophagus, and this may cause the development of reflux esophagitis and Barrett's oesophagus (BE). The natural histological course of untreated BE is non-dysplastic or benign BE (ND), then lowgrade (LGD) and High-Grade Dysplastic (HGD) BE, with the expected increase in malignancy transfer to oesophagal adenocarcinoma (EAC). The gold standard for BE diagnostics involves high-resolution white-light endoscopy, followed by uniform endoscopy findings description (Prague classification) with biopsy performance according to Seattle protocol. The medical treatment of GERD and BE includes the use of proton pump inhibitors (PPIs) regarding symptoms control. It is noteworthy that long-term use of PPIs increases gastrin level, which can contribute to transfer from BE to EAC, as a result of its effects on the proliferation of BE epithelium. Endoscopy treatment includes a wide range of resection and ablative techniques, such as radio-frequency ablation (RFA), often concomitantly used in everyday endoscopy practice (multimodal therapy). RFA promotes mucosal necrosis of treated oesophagal region via high-frequency energy. Laparoscopic surgery, partial or total fundoplication, is reserved for PPIs and endoscopy indolent patients or in those with progressive disease. This review aims to explain distinct effects of PPIs and RFA modalities, illuminate certain aspects of molecular mechanisms involved, as well as the effects of their concomitant use regarding the treatment of BE and prevention of its transfer to EAC.
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http://dx.doi.org/10.2174/1389557519666191015203636DOI Listing
February 2021

Antioxidant enzymes expression in lymphocytes of patients undergoing carotid endarterectomy.

Med Hypotheses 2020 Jan 3;134:109419. Epub 2019 Oct 3.

Vinca Institute of Nuclear Sciences, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

To remedy carotid artery stenosis and prevent stroke surgical intervention is commonly used, and the gold standard being carotid endarterectomy (CEA). During CEA cerebrovascular hemoglobin oxygen saturation decreases and when this decrease reaches critical levels it leads to cerebral hypoxia that causes neuronal damage. One of the proposed mechanism that affects changes during CEA and contribute to acute brain ischemia (ABI) is oxidative stress. The increased production of reactive oxygen species and reactive nitrogen species during ABI may cause an unregulated inflammatory response and further lead to structural and functional injury of neurons. Antioxidant activity are involved in the protection against neuronal damage after cerebral ischemia. We hypothesized that neuronal injury and poor outcomes in patients undergoing CEA may be results of oxidative stress that disturbed function of antioxidant enzymes and contributed to the DNA damage in lymphocytes.
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http://dx.doi.org/10.1016/j.mehy.2019.109419DOI Listing
January 2020

Clinical Approach for the Treatment of Obesity-associated Diseases.

Authors:
Esma R Isenovic

Curr Pharm Des 2019 ;25(18):2017-2018

InstituteVinca, University of Belgrade Mike Alasa 12-14 110001 Belgrade, Serbia.

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http://dx.doi.org/10.2174/138161282518190822153931DOI Listing
March 2020

Redox control of vascular biology.

Biofactors 2020 Mar 4;46(2):246-262. Epub 2019 Sep 4.

Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.

Redox control is lost when the antioxidant defense system cannot remove abnormally high concentrations of signaling molecules, such as reactive oxygen species (ROS). Chronically elevated levels of ROS cause oxidative stress that may eventually lead to cancer and cardiovascular and neurodegenerative diseases. In this review, we focus on redox effects in the vascular system. We pay close attention to the subcompartments of the vascular system (endothelium, smooth muscle cell layer) and give an overview of how redox changes influence those different compartments. We also review the core aspects of redox biology, cardiovascular physiology, and pathophysiology. Moreover, the topic-specific knowledgebase DES-RedoxVasc was used to develop two case studies, one focused on endothelial cells and the other on the vascular smooth muscle cells, as a starting point to possibly extend our knowledge of redox control in vascular biology.
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http://dx.doi.org/10.1002/biof.1559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187163PMC
March 2020

Endothelial Dysfunction in Dyslipidaemia: Molecular Mechanisms and Clinical Implications.

Curr Med Chem 2020 ;27(7):1021-1040

Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

The endothelium consists of a monolayer of Endothelial Cells (ECs) which form the inner cellular lining of veins, arteries, capillaries and lymphatic vessels. ECs interact with the blood and lymph. The endothelium fulfils functions such as vasodilatation, regulation of adhesion, infiltration of leukocytes, inhibition of platelet adhesion, vessel remodeling and lipoprotein metabolism. ECs synthesize and release compounds such as Nitric Oxide (NO), metabolites of arachidonic acid, Reactive Oxygen Species (ROS) and enzymes that degrade the extracellular matrix. Endothelial dysfunction represents a phenotype prone to atherogenesis and may be used as a marker of atherosclerotic risk. Such dysfunction includes impaired synthesis and availability of NO and an imbalance in the relative contribution of endothelialderived relaxing factors and contracting factors such as endothelin-1 and angiotensin. This dysfunction appears before the earliest anatomic evidence of atherosclerosis and could be an important initial step in further development of atherosclerosis. Endothelial dysfunction was historically treated with vitamin C supplementation and L-arginine supplementation. Short term improvement of the expression of adhesion molecule and endothelial function during antioxidant therapy has been observed. Statins are used in the treatment of hyperlipidaemia, a risk factor for cardiovascular disease. Future studies should focus on identifying the mechanisms involved in the beneficial effects of statins on the endothelium. This may help develop drugs specifically aimed at endothelial dysfunction.
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http://dx.doi.org/10.2174/0929867326666190903112146DOI Listing
April 2020

Serum nitric oxide levels correlate with quality of life questionnaires scores of hypothyroid females.

Med Hypotheses 2019 Oct 2;131:109299. Epub 2019 Jul 2.

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia; Faculty of Stomatology in Pancevo, University Business Academy in Novi Sad, Pancevo, Serbia.

Primary hypothyroidism can affect lipid metabolism, cardiovascular (CV) function, and overall patients' quality of life (QoL). Decrease in serum nitric oxide (NO) levels could promote the atherosclerosis acceleration in hypothyroid patients. Our hypothesis is that serum NO level is altered in hypothyroidism; more specifically, we hypothesize that the early vascular changes that can be observed in hypothyroidism could be due to these alterations and that serum NO levels are associated with lipid levels in female patients diagnosed with subclinical hypothyroidism (SCH) or clinical hypothyroidism (CH). Furthermore, since serum NO level is an early marker of atherosclerosis and related CV disorders, which are commonly present and follow hypothyreosis and greatly contribute to overall QoL, we further hypothesized that NO level would correlate with Thyroid Symptom Questionnaire (TSQ) and General Health Questionnaire 12 (GHQ12) scores in hypothyroid patients. A collaterally of our hypothesis was that levothyroxine (LT4) treatment would affect serum NO levels as well as TSQ and GHQ12 scores. Therefore, we have analyzed lipid profile, the level of NO and QoL scores in female patients diagnosed with SCH and CH in order to determine the correlation between NO and generic and thyroid disease symptoms in treatment naïve SCH and CH patients and after LT4 treatment and laboratory euthyroidism achievement. As a consequence of our hypothesis is that measurement of serum NO level in SCH and CH patients may be an innovative way to improve LT4 treatment efficacy. This assumption could have a practical significance for future investigations regarding the management of hypothyroidism treatment protocols in current guidelines.
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http://dx.doi.org/10.1016/j.mehy.2019.109299DOI Listing
October 2019

Effect of Hyperbaric Oxygen Therapy on Fatty Acid Composition and Insulin-like Growth Factor Binding Protein 1 in Adult Type 1 Diabetes Mellitus Patients: A Pilot Study.

Can J Diabetes 2020 Feb 8;44(1):22-29. Epub 2019 May 8.

Institute of Nuclear Sciences Vinča, Laboratory of Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia; Faculty of Stomatology, Pančevo, University Business Academy, Novi Sad, Serbia. Electronic address:

Objective: Metabolic changes in type 1 diabetes mellitus (T1DM) impair vasodilation, and this leads to tissue hypoxia and microvascular pathology. Hyperbaric oxygen therapy (HBOT) can significantly improve the outcome of ischemic conditions in T1DM patients and reduce vascular complications. The aim of our study was to assess the effects of HBOT on plasma fatty acid (FA) composition, and expression of insulin-like growth factor binding protein 1 (IGFBP-1) in T1DM patients.

Methods: Our study included 24 adult T1DM patients diagnosed with peripheral vascular complications. The patients were exposed to 10 sessions of 100% oxygen inhalation at 2.4 atmosphere absolute for 1 hour. Blood samples were collected at admission and after HBOT for measurement of metabolic parameters, FA composition and IGFBP-1. Measurement of plasma FA composition was determined by gas chromatography. Expression of IGFBP-1 in the serum was estimated by Western blot analysis.

Results: HBOT decreased blood levels of total cholesterol (p<0.05), triglycerides (p<0.05) and low-density lipoprotein (p<0.05). HBOT increased plasma levels of individual FAs: palmitic acid (p<0.05), palmitoleic acid (p<0.05), docosapentaenoic acid (p<0.05) and docosahexaenoic acid (p<0.01), and decreased levels of stearic acid (p<0.05), alpha linolenic acid (p<0.05) and linoleic acid (p<0.01). Expression of IGFBP-1 (p<0.01) was increased, whereas the level of insulin (p<0.001) was decreased in the serum after HBOT.

Conclusions: Our results indicate that HBOT exerts beneficial effects in T1DM patients by improving the lipid profile and altering FA composition.
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http://dx.doi.org/10.1016/j.jcjd.2019.04.018DOI Listing
February 2020

Literature-Based Enrichment Insights into Redox Control of Vascular Biology.

Oxid Med Cell Longev 2019 16;2019:1769437. Epub 2019 May 16.

Vinca Institute, University of Belgrade, Laboratory for Molecular Endocrinology and Radiobiology, Belgrade, Serbia.

In cellular physiology and signaling, reactive oxygen species (ROS) play one of the most critical roles. ROS overproduction leads to cellular oxidative stress. This may lead to an irrecoverable imbalance of redox (oxidation-reduction reaction) function that deregulates redox homeostasis, which itself could lead to several diseases including neurodegenerative disease, cardiovascular disease, and cancers. In this study, we focus on the redox effects related to vascular systems in mammals. To support research in this domain, we developed an online knowledge base, DES-RedoxVasc, which enables exploration of information contained in the biomedical scientific literature. The DES-RedoxVasc system analyzed 233399 documents consisting of PubMed abstracts and PubMed Central full-text articles related to different aspects of redox biology in vascular systems. It allows researchers to explore enriched concepts from 28 curated thematic dictionaries, as well as literature-derived potential associations of pairs of such enriched concepts, where associations themselves are statistically enriched. For example, the system allows exploration of associations of pathways, diseases, mutations, genes/proteins, miRNAs, long ncRNAs, toxins, drugs, biological processes, molecular functions, etc. that allow for insights about different aspects of redox effects and control of processes related to the vascular system. Moreover, we deliver case studies about some existing or possibly novel knowledge regarding redox of vascular biology demonstrating the usefulness of DES-RedoxVasc. DES-RedoxVasc is the first compiled knowledge base using text mining for the exploration of this topic.
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http://dx.doi.org/10.1155/2019/1769437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542245PMC
December 2019

Glutathione "Redox Homeostasis" and Its Relation to Cardiovascular Disease.

Oxid Med Cell Longev 2019 9;2019:5028181. Epub 2019 May 9.

Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

More people die from cardiovascular diseases (CVD) than from any other cause. Cardiovascular complications are thought to arise from enhanced levels of free radicals causing impaired "redox homeostasis," which represents the interplay between oxidative stress (OS) and reductive stress (RS). In this review, we compile several experimental research findings that show sustained shifts towards OS will alter the homeostatic redox mechanism to cause cardiovascular complications, as well as findings that show a prolonged antioxidant state or RS can similarly lead to such cardiovascular complications. This experimental evidence is specifically focused on the role of glutathione, the most abundant antioxidant in the heart, in a redox homeostatic mechanism that has been shifted towards OS or RS. This may lead to impairment of cellular signaling mechanisms and elevated pools of proteotoxicity associated with cardiac dysfunction.
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http://dx.doi.org/10.1155/2019/5028181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532282PMC
December 2019

Drug Delivery Systems for Diabetes Treatment.

Curr Pharm Des 2019 ;25(2):166-173

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia.

Background: Insulin is essential for the treatment of Type 1 diabetes mellitus (T1DM) and is necessary in numerous cases of Type 2 diabetes mellitus (T2DM). Prolonged administration of anti-diabetic therapy is necessary for the maintenance of the normal glucose levels and thereby preventing vascular complications. A better understanding of the disease per se and the technological progress contribute to the development of new approaches with the aim to achieve better glycemic control.

Objective: Current therapies for DM are faced with some challenges. The purpose of this review is to analyze in detail the current trends for insulin delivery systems for diabetes treatment.

Results: Contemporary ways have been proposed for the management of both types of diabetes by adequate application of drug via subcutaneous, buccal, oral, ocular, nasal, rectal and pulmonary ways. Development of improved oral administration of insulin is beneficial regarding mimicking physiological pathway of insulin and minimizing the discomfort of the patient. Various nanoparticle carriers for oral and other ways of insulin delivery are currently being developed. Engineered specific properties of nanoparticles (NP): controlling toxicity of NP, stability and drug release, can allow delivery of higher concentration of the drug to the desired location.

Conclusions: The successful development of any drug delivery system relies on solving three important issues: toxicity of nanoparticles, stability of nanoparticles, and desired drug release rate at targeted sites. The main goals of future investigations are to improve the existing therapies by pharmacokinetic modifications, development of a fully automatized system to mimic insulin delivery by the pancreas and reduce invasiveness during admission.
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http://dx.doi.org/10.2174/1381612825666190306153838DOI Listing
February 2020

Early Effects of Hyperbaric Oxygen on Inducible Nitric Oxide Synthase Activity/Expression in Lymphocytes of Type 1 Diabetes Patients: A Prospective Pilot Study.

Int J Endocrinol 2019 10;2019:2328505. Epub 2019 Jan 10.

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia.

This study aimed at examining the early effects of hyperbaric oxygen therapy (HBOT) on inducible nitric oxide synthase (iNOS) activity/expression in lymphocytes of type 1 diabetes mellitus (T1DM) patients. A group of 19 patients (mean age: 63 ± 2.1) with T1DM and with the peripheral arterial disease were included in this study. Patients were exposed to 10 sessions of HBOT in the duration of 1 h to 100% oxygen inhalation at 2.4 ATA. Blood samples were collected for the plasma C-reactive protein (CRP), plasma free fatty acid (FFA), serum nitrite/nitrate, and serum arginase activity measurements. Expression of iNOS and phosphorylation of p65 subunit of nuclear factor-B (NFB-p65), extracellular-regulated kinases 1/2 (ERK1/2), and protein kinase B (Akt) were examined in lymphocyte lysates by Western blot. After exposure to HBOT, plasma CRP and FFA were significantly decreased ( < 0.001). Protein expression of iNOS and serum nitrite/nitrate levels were decreased ( < 0.01), while serum arginase activity was increased ( < 0.05) versus before exposure to HBOT. Increased phosphorylation of NFB-p65 at Ser ( < 0.05) and decreased level of NFB-p65 protein ( < 0.001) in lymphocytes of T1DM patients were observed after HBOT. Decreased phosphorylation of ERK1/2 ( < 0.05) and Akt ( < 0.05) was detected after HBOT. Our results indicate that exposure to HBO decreased iNOS activity/expression via decreasing phosphorylation of ERK1/2 and Akt followed by decreased activity of NFB.
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http://dx.doi.org/10.1155/2019/2328505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348926PMC
January 2019

Hypothesis regarding the effects of gonadotropins on the level of free fatty acids and phospholipids in serum and follicular fluid during controlled ovarian stimulation.

Med Hypotheses 2019 Feb 18;123:30-34. Epub 2018 Dec 18.

Institute Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Mike Petrovica Alasa 12-14, 11000 Belgrade, Serbia.

Controlled ovarian stimulation (COS) is used to augment the number of retrieved oocytes in in vitro fertilization (IVF). Follicular fluid (FF) contributes significantly to oocyte quality. Since the FF is composed of follicular secretions and plasma exudation, it reflects alterations in granulosa and thecal cells secretion as well as changes in the level of plasma constituents. Phospholipids (PL) and free fatty acids (FFA) are important constituents of both, FF and serum. Our hypothesis is that COS affects the level of PL and FFA in serum. Furthermore, since the level of PL and FFA in FF partially depends on their levels in serum, as a collaterally of our hypothesis is that the existing level of PL and FFA in serum correlates with the levels of PL and FFA in FF, and that the dose of applied gonadotropins during COS will correlate with the levels of PL and FFA in serum and FF. In addition, we assume that the level of PL and FFA in serum and in FF after COS will correlate with the retrieved number of GQ oocytes, one of the most important outcomes of COS. .
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http://dx.doi.org/10.1016/j.mehy.2018.11.021DOI Listing
February 2019

Genetic Markers for Coronary Artery Disease.

Medicina (Kaunas) 2018 May 28;54(3). Epub 2018 May 28.

Laboratory of Radiobiology and Molecular Genetics, Institute of Nuclear Science Vinca, University of Belgrade, 11000 Belgrade, Serbia.

Coronary artery disease (CAD) and myocardial infarction (MI) are recognized as leading causes of mortality in developed countries. Although typically associated with behavioral risk factors, such as smoking, sedentary lifestyle, and poor dietary habits, such vascular phenotypes have also long been recognized as being related to genetic background. We review the currently available data concerning genetic markers for CAD in English and non-English articles with English abstracts published between 2003 and 2018. As genetic testing is increasingly available, it may be possible to identify adequate genetic markers representing the risk profile and to use them in a clinical setting.
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http://dx.doi.org/10.3390/medicina54030036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6122104PMC
May 2018

Estradiol-mediated regulation of hepatic iNOS in obese rats: Impact of Src, ERK1/2, AMPKα, and miR-221.

Biotechnol Appl Biochem 2018 Nov 6;65(6):797-806. Epub 2018 Aug 6.

Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.

Purpose: This study aimed to investigate in vivo effects of estradiol on the regulation of hepatic inducible nitric oxide synthase (iNOS) expression in the high fat (HF) diet-induced obesity. Also, we aimed to investigate whether activation of the extracellular signal-regulated kinase (ERK1/2), adenosine monophosphate-activated protein kinase (AMPK), Src kinase, and miR-221 is involved in estradiol-mediated regulation of iNOS in the liver of obese male Wistar rats. Male Wistar rats were fed a standard laboratory diet or a HF diet for 10 weeks. Half of HF rats were treated with estradiol intraperitoneally (40 μg/kg), whereas the other half were placebo-treated 24 H before euthanasia. Results show that estradiol treatment of HF rats decreased hepatic iNOS mRNA (P < 0.05) and protein expression (P < 0.01), the protein levels of p65 subunit of nuclear factor κB (P < 0.05) and ERα (P < 0.05), ERK1/2 phosphorylation (P < 0.001), and ERα/Src kinase association (P < 0.05). By contrast, hepatic Src protein level (P < 0.05), AMPKα phosphorylation (P < 0.05), and miR-221 expression (P < 0.05) were increased in HF rats after estradiol treatment. Our results indicate that estradiol in vivo regulates hepatic iNOS expression in obese rats via molecular mechanisms involving ERK1/2, AMPK, Src, and miR-221 signaling.
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http://dx.doi.org/10.1002/bab.1680DOI Listing
November 2018

Homocysteine and Hyperhomocysteinaemia.

Curr Med Chem 2019 ;26(16):2948-2961

Institute of nuclear science Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia.

Homocysteine (Hcy) is a thiol group containing the amino acid, which naturally occurs in all humans. Hcy is degraded in the body through two metabolic pathways, while a minor part is excreted through kidneys. The chemical reactions that are necessary for degradation of Hcy require the presence of folic acid, vitamins B6 and B12. Consequently, the level of the total Hcy in the serum is influenced by the presence or absence of these vitamins. An elevated level of the Hcy, hyperhomocysteinemia (HHcy) and homocystinuria is connected with occlusive artery disease, especially in the brain, the heart, and the kidney, in addition to venous thrombosis, chronic renal failure, megaloblastic anemia, osteoporosis, depression, Alzheimer's disease, pregnancy problems, and others. Elevated Hcy levels are connected with various pathologies both in adult and child population. Causes of HHcy include genetic mutations and enzyme deficiencies in 5, 10-methylenetetrahydrofolate reductase (MTHFR) methionine synthase (MS), and cystathionine β-synthase (CβS). HHcy can be caused by deficiencies in the folate, vitamin B12 and to a lesser extent, deficiency in B6 vitamin what influences methionine metabolism. Additionally, HHcy can be caused by the rich diet and renal impairment. This review presents literature data from recent research related to Hcy metabolism and the etiology of the Hcy blood level disorder. In addition, we also described various pathological mechanisms induced by hereditary disturbances or nutritional influences and their association with HHcy induced pathology in adults and children and treatment of these metabolic disorders.
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http://dx.doi.org/10.2174/0929867325666180313105949DOI Listing
October 2019

Involvement of PI3K, Akt and RhoA in Oestradiol Regulation of Cardiac iNOS Expression.

Curr Vasc Pharmacol 2019 ;17(3):307-318

Institute of Nuclear Sciences "Vinca", Department of Radiobiology and Molecular Genetics, University of Belgrade, Belgrade, Serbia.

Background: Oestradiol is an important regulatory factor with several positive effects on the cardiovascular (CV) system. We evaluated the molecular mechanism of the in vivo effects of oestradiol on the regulation of cardiac inducible nitric oxide (NO) synthase (iNOS) expression and activity.

Methods: Male Wistar rats were treated with oestradiol (40 mg/kg, intraperitoneally) and after 24 h the animals were sacrificed. The concentrations of NO and L-Arginine (L-Arg) were determined spectrophotometrically. For protein expressions of iNOS, p65 subunit of nuclear factor-κB (NFκB-p65), Ras homolog gene family-member A (RhoA), angiotensin II receptor type 1 (AT1R), insulin receptor substrate 1 (IRS-1), p85, p110 and protein kinase B (Akt), Western blot method was used. Coimmunoprecipitation was used for measuring the association of IRS-1 with the p85 subunit of phosphatidylinositol- 3-kinase (PI3K). The expression of iNOS messenger ribonucleic acid (mRNA) was measured with the quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis of the tissue was used to detect localization and expression of iNOS in heart tissue.

Results: Oestradiol treatment reduced L-Arg concentration (p<0.01), iNOS mRNA (p<0.01) and protein (p<0.001) expression, level of RhoA (p<0.05) and AT1R (p<0.001) protein. In contrast, plasma NO (p<0.05), Akt phosphorylation at Thr308 (p<0.05) and protein level of p85 (p<0.001) increased after oestradiol treatment.

Conclusion: Our results suggest that oestradiol in vivo regulates cardiac iNOS expression via the PI3K/Akt signaling pathway, through attenuation of RhoA and AT1R.
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http://dx.doi.org/10.2174/1570161116666180212142414DOI Listing
May 2020

PCSK9 and Hypercholesterolemia: Therapeutic Approach.

Curr Drug Targets 2018 ;19(9):1058-1067

Institute of nuclear sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia.

Despite the intensive research and progress in modern pharmacotherapy, hypercholesterolemia and related cardiovascular complications remain one of the leading causes of mortality and disability in the modern world. A significant contribution to the treatment of hypercholesterolemia was made by the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9). This enzyme is responsible for the degradation of the low-density lipoprotein (LDL) receptor (LDLR) found at the surface of the plasma membrane in the liver and directly associated with serum LDL level. Limitations in standard therapy used in the treatment of lipid disorders have led to the development of new drugs, such as an inhibitor of PCSK9. Over the past years, the greatest achievement in discovering the PCSK9 inhibitor was made by designing monoclonal antibodies that disable PCSK9 to bind LDLR and RNA interference to reduce PCSK9 production, but one of the main disadvantages is costeffectiveness. In this review, we will summarize the most recent findings of basic and clinical studies which focus on PCSK9 function, regulation and therapeutic target for the treatment of hypercholesterolemia and associated cardiovascular diseases.
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http://dx.doi.org/10.2174/1389450119666171205101401DOI Listing
October 2019

Renal Dysfunction Following Elective Endovascular Aortic Aneurysm Repair.

Curr Vasc Pharmacol 2019 ;17(2):133-140

Laboratory of Radiobiology and Molecular Genetics, Institute of Nuclear Sciences Vinca, University of Belgrade, Mike Petrovica Alasa 12-14, Belgrade 11000, Serbia.

Abdominal aortic aneurysm (AAA) is a degenerative disease of the aortic wall with potentially fatal complications. Open repair (OR) was considered the gold standard, until the emergence of endovascular aneurysm repair (EVAR), which is less invasive and equally (if not more) effective. As the popularity of endovascular procedures grows, related complications become more evident, with kidney damage being one of them. Although acute kidney injury (AKI) following EVAR is relatively common, its true incidence is still uncertain. Also, there is insufficient data concerning long-term renal outcomes after EVAR, especially with repeated contrast agent exposure. Despite the lack of firm evidence on the effectiveness of individual strategies, it is evident that prevention of AKI following EVAR requires a multifactorial approach. This review focuses on recent findings based on human studies regarding the current evidence of renal impairment after EVAR, its quantification and strategies for its prevention.
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http://dx.doi.org/10.2174/1570161115666171116163203DOI Listing
May 2020

Editorial: Relationship between Vitamin D and Metalloproteinases (MMPs) in Acute Myocardial Infarction (AMI).

Curr Vasc Pharmacol 2018 ;16(4):361-362

Institute of Nuclear Sciences Vinca, University of Belgrade, Laboratory of Radiobiology and Molecular Genetics, Belgrade, Serbia.

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http://dx.doi.org/10.2174/1570161115999171004111230DOI Listing
August 2019

Chronic Latent Magnesium Deficiency in Obesity Decreases Positive Effects of Vitamin D on Cardiometabolic Risk Indicators.

Curr Vasc Pharmacol 2018 ;16(6):610-617

Laboratory for Molecular Genetics and Radiobiology, Institute Vinca, University of Belgrade, Belgrade, Serbia.

Background: Obesity and micronutrient deficiencies contribute to the risk of cardiometabolic diseases such are type 2 diabetes mellitus and Cardiovascular Disease (CVD).

Objective: We examined the frequency of concomitant deficit of Magnesium (Mg) and vitamin D in obese patients and evaluated the connection of these combined deficiencies with indicators of cardiometabolic risk in non-diabetic subjects.

Methods: Non-diabetic middle aged adults (n = 80; mean age 36 ± 4 years, 52% women) were recruited based on weight/adiposity parameters [i.e. Body Mass Index (BMI) and body fat percentage (FAT%)]. Cardiometabolic risk indicators [insulin resistance (Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)) and CVD risk (Framingham risk score for predicting 10-year CVD)], Mg status (i.e. total serum Mg concentration (TMg), Chronic Latent Mg Deficiency (CLMD) - 0.75-0.85 mmol/L), vitamin D status (i.e. serum concentration of 25-hydroxyvitamin D (25(OH)D), vitamin D deficiency <50 nmol/l) were assessed.

Results: Among obese subjects 36% presented a combination of vitamin D deficiency and CLMD. In all studied patients, 25(OH)D and TMg levels both, individually and combined, showed a negative linear correlation with HOMA-IR and CVD risk. In subjects with CLMD (TMg <0.85 mmol/L), a negative linear coefficient was found between 25(OH)D and, HOMA-IR and CVD risk, compared with subjects with normal TMg status (TMg ≥0.85 mmol/L).

Conclusion: CLMD and vitamin D deficiency may commonly be present in obese non-diabetic subjects. Individually and combined, both deficiencies predispose non-diabetic patients to increased risk of cardiometabolic diseases. Maintaining normal Mg status may improve the beneficial effects of vitamin D on cardiometabolic risk indicators.
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http://dx.doi.org/10.2174/1570161115666170821154841DOI Listing
June 2019
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