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Institute: Institute of Experimental Pharmacology & Toxicology

Aldo-keto reductases in chronic diseases – in silico modeling of significant enzymes and their complexes with indole derivatives
Aldoketoreduktázy v chronických ochoreniach – in silico modelovanie významných enzýmov a ich komplexov s indolovými derivátmi
Program: VEGA
Project leader: RNDr. Májeková Magdaléna PhD.
Annotation:The aldo-keto reductases belong into a family of enzymes characterized as monomeric NADPH-dependent oxidoreductases. Till now the number of more than 100 enzymes from this family is known. They are divided according to their substrate specificity to individual subgroups. Apart from their beneficial physiological functions hold by biosynthesis, metabolism and detoxication, they can play also a negative role by various pathologic processes as chronic diabetic complications, inflammation, carcinogenesis, asthma etc. The aim of this work is to elaborate and test the specific models of significant subgroups of aldoketoreductases by means of in silico methods. The individual models are to be used for considering the inhibition properties of indole compounds with measured or perspective biological activity.
Duration: 1.1.2014 - 31.12.2017

Indole-1-acetic acid derivatives as aldose reductase inhibitors: design, synthesis and biological activity
Deriváty kyseliny 1-indoloctovej ako inhibítory aldózareduktázy: dizajn, syntéza a biologická aktivita
Program: VEGA
Project leader: Ing. Štefek Milan CSc.
Duration: 1.1.2015 - 31.12.2017

Pharmacological intervention in glucose-toxicity in type 2 diabetes
Farmakologické ovplyvnenie glukózovej toxicity pri diabete typu 2
Program: SRDA
Project leader: RNDr. Májeková Magdaléna PhD.
Annotation:Glucose toxicity plays important role not only in a development of chronic diabetic complications but also in an induction of insulin secretion disorder, decrease of beta cell mass and development of insulin resistance. The aim of this project is to design and test novel compounds with indolyl acetic acid scaffold, multi-target-directed ligands, which should slow down the onset of diabetes mellitus type 2 and reduce progression of diabetic complications.
Duration: 1.7.2016 - 30.6.2020

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Inhibícia proliferácie a indukcia apoptózy v rakovinových bunkách ovplyvnením ich metabolického profilu
Program: VEGA
Project leader: RNDr. Blaškovič Dušan PhD.
Duration: 1.1.2015 - 31.12.2018

Mechanisms, early detection and therapy of asphyxial injury in perinatal period - comparison of experimental data with clinical observation of asphyxial newborns
Mechanizmy, skorá detekcia a terapia asfyktického poškodenia v perinatálnom období – porovnanie experimentálnych údajov s klinickým obrazom asfyktického novorodenca
Program: VEGA
Project leader: Doc. RNDr. Ujházy Eduard CSc.
Annotation:The results from our studies concerning uncovering the mechanisms and possibilities of early detection of embryo-fetal damage confirmed that our proposed model of subchronic perinatal asphyxia using rat model is suitable for next studies. We will use this model for further expansion of knowledge about the mechanisms of actions of asphyxia in the process of late organogenesis and perinatal period. It is important to detect suitable biochemical and morphological markers to reduce the risk of complications due to asphyxia during development, as well as the possibility of its early therapy via antioxidant active ingredients of natural and synthetic origin. The ability of these compounds to bind to transport blood components (albumin, hemoglobin) will be monitored and a method for testing the effects on neuronal cell cultures will be developed. Integral part of this project will be correlations of given data from experimental studies with clinical observations in full-term asphyxiated newborns.
Duration: 1.1.2015 - 31.12.2018

Modulation of calcium homeostasis in pancreatic beta-cells by flavonoids under conditions of endoplasmic reticulum stress
Modulácia vápnikovej homeostázy flavonoidmi v pankreatických beta-bunkách za podmienok stresu endoplazmatického retikula
Program: VEGA
Project leader: RNDr. Lomenová Jana PhD.
Annotation:The project is aimed at the evaluation of protective effect of selected flavonoids and their derivatives upon injury to the pancreatic INS-1E ß-cells under conditions of ER stress in terms of reduction of apoptosis, regulation of intracellular calcium, decrease of intracellular ROS/RNS, increase of insulin secretion and regulation of the expression of the Ca2+ regulating proteins. Flavonoids will be selected based on molecular modeling (interaction SERCA - flavonoid) in silico and based on effects on SR/ER Ca2+-ATPase (SERCA) activity in vitro. Endoplasmic reticulum (ER) stress in pancreatic ß-cells will be induced by: i) free fatty acids, ii) cytokines iii) specific SERCA inhibitors such thapsigargin, iv) high glucose/methylglyoxal, v) reactive oxygen/nitrogen species (eg. peroxynitrite). Effect of flavonoids on ER stress will contribute to the understanding of the mechanism of action of these substances potentially useful in the prevention/treatment of type 2 diabetes and its complications.
Duration: 1.1.2016 - 31.12.2019

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Molekulárno-farmakologické prístupy k inovatívnej terapii reumatoidnej artritídy hodnotenej v experimentálnych podmienkach in vivo a in vitro
Program: SRDA
Project leader: PharmDr. Bauerová Katarína PhD., DrSc.
Duration: 1.7.2016 - 30.6.2020

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MVTS: Podnetné organické syntézy inšpirované prírodou – od chémie prírodných produktov po objav liečiv
Program: Other projects
Project leader: RNDr. Horáková Ľubica PhD.
Duration: 1.3.2015 - 31.3.2019

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Názov projektu: Výskum ovplyvnenia zápalu, chronickej autoimunitnej reakcie a redoxnej regulácie organizmu v experimentálnej artritíde použitím nových látok pre adjuvantnú terapiu reumatoidnej artritídy
Program: VEGA
Project leader: PharmDr. Bauerová Katarína PhD., DrSc.
Duration: 1.1.2015 - 31.12.2018

Prenatal and postnatal effects of δ and µ opioid receptor ligands on the hippocampal development and function
Prenatálne a postnatálne účinky ligandov δ a µ opioidných receptorov na vývoj a funkciu hipokampu
Program: SRDA
Project leader: RNDr. Dubovický Michal CSc.
Annotation:Ligands of opioid receptors δ (DOR) and µ opioid receptors (MOR) are commonly used in treatment of severe acute and chronic pain. DORs are involved also in mood disorders like depression and anxiety, which are related to the hippocampal function. Treatment with DOR ligands does not result in adverse effects including addiction, which are common with MOR ligands. However, much less is known about DOR – activated signaling pathways than about MOR – activated pathways. We will analyze the effect of acute (seconds to minutes) and chronic (hours to days) in in vitro and in vivo (prenatal and postnatal) administration of DOR ligands on the morphological and electrophysiological properties of rat hippocampal neurons and compare them with effects of MOR ligands and with effects of ligands specific for MOR-DOR heteromers. Further, involvement of calcium transporting proteins in signal transduction pathways activated by DORs and MORs ligands will be addressed by molecular biology methods. Possible remodeling of the dendritic spines will be investigated using transmission electron microscopy. Effect of DOR ligands on hippocampal plasticity in control and stressed rats will be examined using behavioral tests and molecular neuroscience techniques. Excitability will be investigated in primary culture of hippocampal neurons by patch clamp and in situ by in vivo electrophysiology. Both models enable to follow effects of acute and chronic drug application as well as possible receptor desensitization and offer complementary advantages. Primary neuronal culture is the possibility to visually identify neurons, characterize in details both action potentials and underlying ionic currents and to correlate electrophysiology and molecular biology on the same batch of neurons. In vivo electrophysiology offers the possibility to measure neuronal activity within its normal environment including all interactions with other brain parts.
Duration: 1.7.2016 - 30.6.2020

Prenatal programming of psychiatric diseases: experimental approaches for evaluation of causes and mechanisms of their origin
Prenatálne programovanie chorôb v dospelosti: subchronická prenatálna asfyxia u potkanov ako vhodný model na štúdium mechanizmov embryo-fetálneho programovania neurobehaviorálnych zmien v dospelosti
Program: VEGA
Project leader: RNDr. Mach Mojmír PhD.
Annotation:Incidence of mental diseases in the developed countries has an increasing trend. At least one mental disease occurred per year approximately in 27% of EU inhabitants (more than 82 mil. people). It is estimated that till 2020, depression will be the main cause of morbidity in the developed countries. There are many evidences on neurodevelopmental origin of mental diseases. Various environmental and maternal factors acting during prenatal period and early childhood can increase sensitivity of the individual to anxiety, depression or other mental disorders in later postnatal life. Insufficient oxygen and nutrition supply of tissues, excessive stress or chemical substances and drugs can adversely affect the development of the brain. Objective of the project proposal will be the evaluation of key epigenetic factors which may play an important role in development of mental diseases. Up-to-date molecular biology as well as non-invasive methods of ethological analyses of appropriate animal models will be utilized.
Duration: 1.1.2016 - 31.12.2019

Prevention of hypoxic-ischemic damage of the neonatal rat brain: testing of novel approaches involving pharmacological and non-pharmacological intervention
Prevencia hypoxicko-ischemického poškodenia neonatálneho mozgu potkana: testovanie nových spôsobov farmakologickej a nefarmakologickej intervencie
Program: VEGA
Project leader: RNDr. Juránek Ivo PhD., DrSc.
Annotation:The proposed project is focused on testing novel ways, suggested by our group, to prevent neonatal brain damage resulting from perinatal hypoxic-ischemic (HI) insult, which is one of the most frequent causes of newborn mortality and morbidity. So far, there is no effective therapy for neonatal HI encephalopathy. In the present project, newborn rats will be exposed to cerebral HI insult, and brain damage will be followed noninvasively by magnetic-resonance imaging (MRI) and spectroscopy (MRS) in vivo, and neurological deficit by standard neurobehavioral tests. Originality lies in using combination of antiinflammatory omega-3 fatty acids (DHA+EPA) and excitotoxicity inhibitor (MgSO4) against HI damage. Originality is also a in non-pharmacological approach that include combination of mild hypothermia (34°C) and graded reoxygenation (8-12-16-21% O2). Expected results will contribute to better understanding of mechanisms of HI brain damage and to a proposal of effective management of neonates with HI brain insult.
Duration: 1.1.2016 - 31.12.2019

Protective effects of natural and synthetic substances against oxidative damage of high-molar-mass hyaluronan, isolated mammal cells and their mitochondria
Protektívne účinky prírodných a syntetických látok pred oxidačným poškodením vysokomolekulového hyalurónanu, izolovaných živočíšnych buniek a ich mitochondrií
Program: VEGA
Project leader: RNDr. Valachová Katarína PhD.
Annotation:Hyaluronan (HA) is a polysaccharide of molar mass several megaDaltons present in tissues of vertebrates. In inflammatory diseases the average molar mass of HA decreases by action of oxidants. A significant decrease of synovial fluid (SF) viscoelasticity was detected, thereby its lubricating properties are worsened. High-molar-mass HA solutions are relevantly used for in vitro studies of free radicals and oxidants performance and also for a study of protective effects of antioxidants/drugs in a role of prevention or chain-breaking degradation of HA macromolecules. Substances of synthetic origin such as antiinflammatory drugs, mitochondria targeted antioxidants and natural substances with demonstrated antioxidative effects against HA degradation will be tested as protectors of oxidative degradation of cell lines of fibroblasts NIH-3T3, B-HNF-1, VH10 and cell organels, especially mitochondria.
Duration: 1.1.2015 - 31.12.2018

Redox control of the professional phagocytes in blood and in the central nervous system: Molecular mechanisms and functional significance.
Redoxná regulácia profesionálnych fagocytov v krvi a v centrálnom nervovom systéme: Molekulárne mechanizmy a funkčný význam.
Program: VEGA
Project leader: PharmDr. Jančinová Viera PhD.
Annotation:The submitted project is a continuation of our previous research in the pharmacological regulation of inflammatory processes. The focus is on neutrophils and microglial cells (resident brain macrophages) which are considered active participants in the initiation and progression of pathological states connected with chronic inflammation such as arthritis or neurodegenerative diseases. The aim of the project is to explain cellular and molecular mechanisms involved in the pharmacological modulation of these cells. Attention will be paid to drugs and derivatives of natural substances which are able to influence the production of reactive oxygen and nitrogen species. The coordinated research of two types of phagocytes creates an opportunity for the sharing of modern instruments and excellent methods as immunofluorescence microscopy or flow cytometry. Cooperation between basic research and clinical practice will allow the use of these methods in the analysis of phagocytes from patients with rheumatoid arthritis.
Duration: 1.1.2016 - 31.12.2018

Risk factors of cardiovascular and cerebrovascular diseases and pharmacological possibilities of their influence
Rizikové faktory kardiovaskulárnych a cerebrovaskulárnych ochorení a farmakologické možnosti ich ovplyvnenia
Program: VEGA
Project leader: RNDr. Gáspárová Zdenka PhD.
Annotation:The project is aimed at the study of mechanisms of etiopathogenesis of metabolic syndrome (MS) and metabolic cognitive syndrome (MSC). The goal is to design new effective therapy affecting the origin and development of risk factors of cardiovascular and cerebrovascular diseases. Experiments will be performed on a genetic model of rats with hereditary hypertriglyceridemia, fed with hyperlipidemic diet. The induced metabolic disorders will become manifest by hypertension, hypercholesterolemia, hyperglycemia, hypertriglyceridemia, inflammatory reactions and increased markers of oxidative stress. Effect on the risk factors of MS and MCS, lipidic profile, on markers of damage at cellular and molecular level, function, behavioral and histopathological changes will be studied after repeated administration of the new pyridoindole SMe1EC2, flavonoid rutin, and atorvastatin as a standard. Action on several risk factors of cardiovascular and cerebrovascular diseases simultaneously is expected.
Duration: 1.1.2015 - 31.12.2018

Investigation of anatomical-functional differences between the effects of aripiprazole and quetiapine, atypical antipsychotics with similar therapeutic indications, but different impact on brain dopaminergic receptors, in experimental animals
Štúdium anatomicko-funkčných rozdielov v účinkoch aripiprazolu a kvetiapínu, atypických antipsychotík s podobnými terapeutickými vlastnosťami, ale rozdielnym vplyvom na dopaminergické receptory v mozgu, u experimentálnych zvierat
Program: SRDA
Project leader: RNDr. Mach Mojmír PhD.
Annotation:Antipsychotics (APs) represent a group of drugs used in the treatment of spectrum of psychotic and depressive disorders. However, frequency of ATs treatment is rather increasing than decreasing and growing number of atypical AP drugs have also been emerged over the last few years. In addition, APs treatment is connected with a number of unwanted side effects, such as extrapyramidal syndrome, akathisia, body mass increase, agranulocytosis, tardive dyskinesia, somnolencia, etc. Anatomical-functional investigations are incessantly bringing information about the effects of APs on the activity of neurons and their spatial distribution in the brain, which allows more precisely to define and predict the consequences of the APs treatment. The aim of the present study is to reveal the effect of acute and repeated treatment of two, relatively new atypical APs, aripiprazole (ARI) and quetiapine (QUE), on the activity of neurons in the forebrain and extra forebrain areas of the brain, to identify the phenotype (chemical) character of the targeted neurons, to investigate their impact on the behavior and to compare their impact on the activity of signaling pathways, expression of signaling molecules, and secretion of selected neuropeptides in anatomically precisely defined brain structures. The data of the present project will be new and will serve for the deeper understanding of the biology of serious mental disorders. They also may bring new impulses to the drug developing processing to prepare drugs with more directed and beneficial therapeutic features.
Duration: 1.7.2016 - 30.6.2020

Study of consequences of maternal depression and antidepressant venlafaxine treatment on functional development of the brain and behavior of rat offspring
Štúdium dôsledkov materskej depresie a podávania antidepresíva venlafaxínu na funkčný vývin mozgu a správanie potomstva potkanov
Program: VEGA
Project leader: RNDr. Dubovický Michal CSc.
Duration: 1.1.2015 - 31.12.2018

The total number of projects: 17