Publications by authors named "Milan Obradovic"

65 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

Evaluation of immunogenicity and protection mediated by Lawsonia intracellularis subunit vaccines.

Vet Immunol Immunopathol 2021 Jul 7;237:110256. Epub 2021 May 7.

Department of Veterinary Microbiology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, Saskatchewan, Canada. Electronic address:

Lawsonia intracellularis is an economically important bacterium that causes ileitis in pigs. Current vaccines for L. intracellularis do not allow for differentiation between infected and vaccinated animals (DIVA), which is beneficial for disease tracking and surveillance. Previously, we identified five putative surface L. intracellularis proteins that were targeted by antibodies from pigs infected with L. intracellularis which could serve as antigens in a subunit vaccine. We conducted two trials to determine whether these antigens were immunogenic and provided protection against infectious challenge and whether truncated glycoprotein D could be used as a DIVA antigen. For Trial 1, 5 week-old piglets were administered intramuscular monovalent vaccines comprised of a recombinant (r) flagella subunit protein (rFliC,) and DIVA antigen (truncated glycoprotein D (TgD), a herpes virus antigen) both formulated with a combination adjuvant consisting of polyinosinic:polycytidylic acid(poly I:C), host defense peptide 1002 and polyphosphazene, referred to as Triple Adjuvant (TriAdj). Relative to control animals, animals vaccinated with rFliC and rTgD had significantly elevated antigen-specific humoral immunity in sera suggesting that rFliC and TgD are immunogenic. Control animals had negligible anti-TgD titres suggesting that TgD may be a suitable DIVA antigen for pigs. For Trial 2, piglets were immunized with a trivalent vaccine (FOG vaccine consisting of rFLiC, rOppA protein (a ABC Type dipeptide transport system) and rGroEL (a stress response protein)) and a divalent vaccine (CM vaccine consisting of rClpP (an ATP-dependent Clp protease proteolytic subunit) and rMetK (a S-adenosyl methionine synthase)) formulated with Emulsigen®. Relative to the control pigs, pigs immunized with the FOG vaccine produced robust and significantly higher serum IgG antibodies against rFliC and rGroEL, and significantly higher anti-FliC and anti-GroEL IgA antibodies in jejunal (GroEL only) and ileal intestinal mucosa. Pigs immunized with CM vaccine produced significantly higher serum antibodies against rClpP and rMetK and significantly higher anti-rClpP IgA antibodies in the ileum relative to the control pigs. Quantitative polymerase chain reaction (qPCR) analysis showed that 18 days after challenge with infectious L. intracellularis, challenged/control pigs and pigs that received the CM vaccine, but not the pigs vaccinated with the FOG vaccine, shed significantly more bacteria in feces than the unchallenged controls pigs. These data suggest that the FOG vaccinated pigs showed limited protection. While promising, more work is needed to enhance the efficiency of the intramuscular vaccine to show significant disease protection.
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http://dx.doi.org/10.1016/j.vetimm.2021.110256DOI Listing
July 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

Review of the speculative role of co-infections in Streptococcus suis-associated diseases in pigs.

Vet Res 2021 Mar 20;52(1):49. Epub 2021 Mar 20.

Groupe de Recherche Sur Les Maladies Infectieuses en Production Animale (GREMIP), Centre de Recherche en Infectiologie Porcine et Aviaire (CRIPA), Faculty of Veterinary Medicine, University of Montreal, 3200 Sicotte, Saint-Hyacinthe, QC, J2S 2M2, Canada.

Streptococcus suis is one of the most important bacterial swine pathogens affecting post-weaned piglets, causing mainly meningitis, arthritis and sudden death. It not only results in severe economic losses but also raises concerns over animal welfare and antimicrobial resistance and remains an important zoonotic agent in some countries. The definition and diagnosis of S. suis-associated diseases can be complex. Should S. suis be considered a primary or secondary pathogen? The situation is further complicated when referring to respiratory disease, since the pathogen has historically been considered as a secondary pathogen within the porcine respiratory disease complex (PRDC). Is S. suis a respiratory or strictly systemic pathogen? S. suis is a normal inhabitant of the upper respiratory tract, and the presence of potentially virulent strains alone does not guarantee the appearance of clinical signs. Within this unclear context, it has been largely proposed that co-infection with some viral and bacterial pathogens can significantly influence the severity of S. suis-associated diseases and may be the key to understanding how the infection behaves in the field. In this review, we critically addressed studies reporting an epidemiological link (mixed infections or presence of more than one pathogen at the same time), as well as in vitro and in vivo studies of co-infection of S. suis with other pathogens and discussed their limitations and possibilities for improvement and proposed recommendations for future studies.
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http://dx.doi.org/10.1186/s13567-021-00918-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980725PMC
March 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

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency.

Nat Commun 2020 10 5;11(1):4977. Epub 2020 Oct 5.

Department of Pathology, University of Regensburg, 93053, Regensburg, Germany.

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.
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http://dx.doi.org/10.1038/s41467-020-18701-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536220PMC
October 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

Immune response and protection against Lawsonia intracellularis infections in pigs.

Vet Immunol Immunopathol 2020 Jan 31;219:109959. Epub 2019 Oct 31.

Vaccine and Infectious Disease Organization (VIDO)-International Vaccine Centre (InterVac), University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E3, Canada; School of Public Health, Vaccinology, and Immunotherapeutics, Saskatchewan, Canada. Electronic address:

Lawsonia intracellularis are Gram-negative, obligate intracellular bacteria that cause proliferative enteropathy (PE), an economically important disease for the pig industry. Numerous reviews have been published on the characteristics and pathogenesis of this bacterium since its isolation and taxonomic characterization, with most reviews only partially covering how the host immune response develops during infection and the immune correlates of protection. With the development of increasingly more sophisticated immunological assays and tools for the pig, the immune response against L. intracellularis at distinct stages of pathogenesis has been published. In this review, we discuss current knowledge of the pig immune response against L. intracellularis and strategies to achieve immune protection. The immune response is presented in relation to chronological progression of pathological lesions and clinical symptoms, with emphasis on innate immunity and the adaptive humoral and cell-mediated immune response. The aim is to achieve a comprehensive understanding of the host immune response with respect to the stage-dependent cellular and biochemical processes important during PE development. Also, strategies for development of immune protection and new vaccination technologies are discussed in the light of new discoveries in the field.
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http://dx.doi.org/10.1016/j.vetimm.2019.109959DOI Listing
January 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

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

Immunoproteomic analysis of Lawsonia intracellularis identifies candidate neutralizing antibody targets for use in subunit vaccine development.

Vet Microbiol 2019 Aug 19;235:270-279. Epub 2019 Jul 19.

Vaccine and Infectious Disease Organization (VIDO)-International Vaccine Centre (InterVac), University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E3, Canada; School of Public Health, Vaccinology and Immunotherapeutics, Saskatchewan, Canada. Electronic address:

Lawsonia intracellularis is an obligate intracellular microorganism and the causative agent of porcine proliferative enteropathy. Due to its obligate intracellular nature, characterization of antigens and proteins involved in host-pathogen interaction and immune recognition have been difficult to achieve using conventional microbiological techniques. In this work, we used 2-dimensional gel electrophoresis coupled with Western-immunoblotting, mass spectrometry and bioinformatics to identify bacterial proteins that interact in vitro with pig intestinal cells (IPEC-1), have immunogenic properties and the potential to be used as subunit vaccine antigens. We detected eleven immunogenic bacterial proteins from which fliC (LI0710), LI1153 (annotated by NCBI as Putative protein N), and LI0649 (annotated as autotransporter) were predicted to be expressed on the outer membrane while LI0169 (oppA; annotated as ABC dipeptide transport system) was predicted to be periplasmic with a transmembrane domain forming a central pore through the plasma membrane. Genes coding for these four proteins were cloned and expressed in Escherichia coli and the corresponding recombinant proteins were purified using affinity chromatography. Porcine hyperimmune serum against whole Lawsonia lysate established that all four recombinant proteins were immunogenic. Further, rabbit hyperimmune sera generated against the vaccine strain of L. intracellularis and rabbit serum specific for each recombinant protein showed an inhibitory effect on the attachment and penetration of live, avirulent L. intracellularis, thus indicating that each protein is a potential neutralizing antibody target and a candidate for subunit vaccine formulation.
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http://dx.doi.org/10.1016/j.vetmic.2019.07.014DOI Listing
August 2019

Evoked Compound Action Potentials Reveal Spinal Cord Dorsal Column Neuroanatomy.

Neuromodulation 2020 Jan 19;23(1):82-95. Epub 2019 Jun 19.

Pain Management Research Institute and Kolling Institute, University of Sydney at the Royal North Shore Hospital, St Leonards, NSW, Australia.

Introduction: The electrically evoked compound action potential (ECAP) is a measure of the response from a population of fibers to an electrical stimulus. ECAPs can be assessed during spinal cord stimulation (SCS) to elucidate the relationship between stimulation, electrophysiological response, and neuromodulation. This has consequences for the design and programming of SCS devices.

Methods: Sheep were implanted with linear epidural SCS leads. After a stimulating pulse, electrodes recorded ECAPs sequentially as they propagated orthodromically or antidromically. After filtering, amplification, and signal processing, ECAP amplitude and dispersion (width) was measured, and conduction velocity was calculated. Similar clinical data was also collected. A single-neuron computer model that simulated large-diameter sensory axons was used to explore and explain the observations.

Results: ECAPs, both animal and human, have a triphasic structure, with P1, N1, and P2 peaks. Conduction velocity in sheep was 109 ms , which indicates that the underlying neural population includes fibers of up to 20 μm in diameter. For travel in both directions, propagation distance was associated with decrease in amplitude and increase in dispersion. Importantly, characteristics of these changes shifted abruptly at various positions along the cord.

Discussion: ECAP dispersion increases with propagation distance due to the contribution of slow-conducting small-diameter fibers as the signal propagates away from the source. An analysis of the discontinuities in ECAP dispersion changes with propagation revealed that these are due to the termination of smaller-diameter, slower-conducting fibers at corresponding segmental levels. The implications regarding SCS lead placement, toward the goal of maximizing clinical benefit while minimizing side-effects, are discussed.

Conflict Of Interest: John Parker is the founder and CEO of Saluda Medical and holds stock options. Milan Obradovic, Nastaran Hesam Shariati, Dean M. Karantonis, Peter Single, James Laird-Wah, Robert Gorman and Mark Bickerstaff are employees of Saluda Medical with stock options. At the time the data was collected for the study, Prof. Cousins was a paid consultant for Saluda Medical. John Parker, Milan Obradovic, Dean Karantonis, James Laird-Wah, Robert Gorman and Peter Single are co-inventors in one or more patents related to the topics discussed in this work.
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http://dx.doi.org/10.1111/ner.12968DOI Listing
January 2020

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

Development of flow cytometry based adherence assay for Neisseria gonorrhoeae using 5'-carboxyfluorosceinsuccidyl ester.

BMC Microbiol 2019 03 25;19(1):67. Epub 2019 Mar 25.

Vaccine and Infectious Disease Organization - International Vaccine Centre (VIDO-InterVac), University of Saskatchewan, Saskatoon, Saskatchewan, S7N 5E3, Canada.

Background: Neisseria gonorrhoeae is an obligate human pathogen and its adherence to host cells is essential for its pathogenesis. Gonococcal adherence assays are based on the enumeration of bacteria attached to human cells on solid media. Because conventional adherence assays are based on bacterial counts, they are often time consuming to perform and prone to observer bias. A flow cytometry based method, using the cell-permeable fluorescent dye 5'-carboxyfluoroscein succidyl ester (CFSE), was developed to dramatically increase the number of adherent N. gonorrhoeae quantified per assay while improving repeatability and removing observer bias. Piliated N. gonorrhoeae F62 were stained with CFSE then the staining reaction was quenched with foetal bovine serum. Human cervical ME-180 cells were infected with CFSE-stained N. gonorrhoeae (multiplicity of the infection 100:1) for 2 h. Infected cells were washed to remove loosely adhered bacteria. Flow cytometry was used to quantify the percentage of ME-180 cells associated with CFSE-stained N. gonorrhoeae and a minimum of 30,000 events were recorded. Real time-PCR analysis targeting opa gene (encoding N. gonorrhoeae opacity associated gonococcal outer membrane protein) was performed on infected ME-180 cells to confirm the flow cytometric adherence assay results. A rabbit was immunized with heat-killed N. gonorrhoeaeF62 to generate hyperimmune serum. The functional compatibility of the assay was confirmed by studying the effect of N. gonorrhoeae F62 antiserum on blocking adherence/invasion of CFSE-stained bacteria to ME-180 cells.

Results: We observed that 20.3% (+/- 1.0) ME-180 cells were associated with CFSE-stained N. gonorrhoeae. Heat-inactivated hyperimmune serum, at 1:10 to 1:80 dilutions, significantly inhibited gonococcal adherence by 6 and 3 fold, respectively. Real time-PCR analysis targeting opa gene confirmed that hyperimmune serum blocked adherence/invasion of N. gonorrhoeae to the ME-180 cells in a dilution-dependent manner.

Conclusions: Flow cytometric analysis was amenable to quick, easy and high-throughput quantification of the association of N. gonorrhoeae with ME-180 cells and was functionally confirmed using PCR analysis. These approaches may be adapted for in vitro and in vivo adherence studies related to gonococcal pathogenesis.
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http://dx.doi.org/10.1186/s12866-019-1438-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434840PMC
March 2019

Glucocorticoids promote breast cancer metastasis.

Nature 2019 03 13;567(7749):540-544. Epub 2019 Mar 13.

Department of Biomedicine, Department of Surgery, University Hospital Basel, University of Basel, Basel, Switzerland.

Diversity within or between tumours and metastases (known as intra-patient tumour heterogeneity) that develops during disease progression is a serious hurdle for therapy. Metastasis is the fatal hallmark of cancer and the mechanisms of colonization, the most complex step in the metastatic cascade, remain poorly defined. A clearer understanding of the cellular and molecular processes that underlie both intra-patient tumour heterogeneity and metastasis is crucial for the success of personalized cancer therapy. Here, using transcriptional profiling of tumours and matched metastases in patient-derived xenograft models in mice, we show cancer-site-specific phenotypes and increased glucocorticoid receptor activity in distant metastases. The glucocorticoid receptor mediates the effects of stress hormones, and of synthetic derivatives of these hormones that are used widely in the clinic as anti-inflammatory and immunosuppressive agents. We show that the increase in stress hormones during breast cancer progression results in the activation of the glucocorticoid receptor at distant metastatic sites, increased colonization and reduced survival. Our transcriptomics, proteomics and phospho-proteomics studies implicate the glucocorticoid receptor in the activation of multiple processes in metastasis and in the increased expression of kinase ROR1, both of which correlate with reduced survival. The ablation of ROR1 reduced metastatic outgrowth and prolonged survival in preclinical models. Our results indicate that the activation of the glucocorticoid receptor increases heterogeneity and metastasis, which suggests that caution is needed when using glucocorticoids to treat patients with breast cancer who have developed cancer-related complications.
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http://dx.doi.org/10.1038/s41586-019-1019-4DOI Listing
March 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

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

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

Regulation of hepatic Na/K-ATPase in obese female and male rats: involvement of ERK1/2, AMPK, and Rho/ROCK.

Mol Cell Biochem 2018 Mar 17;440(1-2):77-88. Epub 2017 Aug 17.

Laboratory of Radiobiology and Molecular Genetics, Vinca Institute of Nuclear Sciences, University of Belgrade, Mike Petrovica Alasa 12-14, P.O.Box 522, 11000, Belgrade, Serbia.

In this study, we assessed whether the disturbed regulation of sodium/potassium-adenosine-triphosphatase (Na/K-ATPase) occurs as a consequence of obesity-induced IR in sex-specific manner. We also assessed whether alterations of IRS/PI3K/Akt, ERK1/2, AMPKα, and RhoA/ROCK signaling cascades have an important role in this pathology. Female and male Wistar rats (150-200 g, 8 weeks old) were fed a standard laboratory diet or a high-fat (HF) diet (42% fat) for 10 weeks. The activity of hepatic Na/K-ATPase and Rho, and the association of IRS-1/p85 were assessed in liver. Furthermore, the protein level of α Na/K-ATPase in plasma membrane fractions, and protein levels of IRS-1, PI3K-p85, -p110, RhoA, ROCK1, ROCK2, ERK1/2, AMPKα, ERα, and ERβ in liver lysates were assessed. The expression of hepatic α Na/K-ATPase mRNA was also analyzed by qRT-PCR. The results show that HF-fed female rats exhibited an increase in hepatic ERK1/2 (p < 0.05) and AMPKα (p < 0.05) phosphorylation levels, unchanged level of Na/K-ATPase α mRNA, decreased level of Na/K-ATPase activity (p < 0.05), and decreased α Na/K-ATPase protein expression (p < 0.01). In liver of HF-fed male rats, results show decreased levels of Na/K-ATPase activity (p < 0.01), both protein and mRNA of α subunit (p < 0.05), but significant increase in Rho activity (p < 0.05). Our results indicate significant sex differences in α Na/K-ATPase mRNA expression and activation of ERK1/2, AMPKα, and Rho in the liver. Exploring the sex-specific factors and pathways that promote obesity-related diseases may lead to a better understanding of pathogenesis and discovering new therapeutic targets.
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http://dx.doi.org/10.1007/s11010-017-3157-zDOI Listing
March 2018