Publications by authors named "Marija Ilic"

25 Publications

  • Page 1 of 1

Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Mol Psychiatry 2021 Jul 9. Epub 2021 Jul 9.

Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition. We find both a potentiation of neurotransmission and coincident restoration of dendritic spines in the dorsal hippocampus, indicative of reinstatement of dopamine-induced synaptic plasticity in aging rodents. Treatment with (S,S)-CE-158 significantly improved behavioral flexibility in scopolamine-compromised animals and increased the number of spontaneously active prefrontal cortical neurons, both in young and aging rodents. In addition, (S,S)-CE-158 restored learning and memory recall in aging rats comparable to their young performance in a hippocampus-dependent hole board test. In sum, we present a well-tolerated, highly selective DAT inhibitor that normalizes the age-related decline in cognitive function at a synaptic level through increased dopamine signaling.
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http://dx.doi.org/10.1038/s41380-021-01214-xDOI Listing
July 2021

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters.

Biomolecules 2020 08 20;10(9). Epub 2020 Aug 20.

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([HL]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL)Cl]Cl (-) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: > > > > >>[HL]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.
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http://dx.doi.org/10.3390/biom10091213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565988PMC
August 2020

Cell-Based Radiotracer Binding and Uptake Inhibition Assays: A Comparison of Methods to Assess the Potency of Drugs That Target Monoamine Transporters.

Front Pharmacol 2020 19;11:673. Epub 2020 May 19.

Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

High-affinity monoamine transporters are targets for prescribed medications and stimulant drugs of abuse. Therefore, assessing monoamine transporter activity for candidate medications and newly-emerging drugs of abuse provides essential information for industry, academia, and public health. Radiotracer binding and uptake inhibition are the gold standard assays for determining drug-transporter interaction profiles. The combined results from such assays yield a unique biochemical fingerprint for each compound. Over time, different assay methods have been developed to assess transporter activity, and the comparability of data across various assay platforms remains largely unclear. Here, we compare the effects of six well-established stimulants in two different cell-based uptake inhibition assays, one method using adherent cells and the other using suspended cells. Furthermore, we compare the data from transfected cell lines derived from different laboratories and data reported from rat synaptosomes. For transporter inhibitors, IC values obtained by the two experimental methods were comparable, but using different transfected cell lines yielded disparate results. For transporter substrates, differences between the two cell lines were less pronounced but the drugs displayed different inhibition potencies when evaluated by the two methods. Our study illustrates the inherent limitations when comparing transporter inhibition data from different laboratories and stresses the importance of including appropriate control experiments with reference compounds when investigating new drugs of interest.
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http://dx.doi.org/10.3389/fphar.2020.00673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248194PMC
May 2020

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

J Med Chem 2020 01 30;63(1):391-417. Epub 2019 Dec 30.

Neuroscience Laboratory , Paracelsus Medical University , A-5020 Salzburg , Austria.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the -configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by , , and studies that have demonstrated both safety and efficacy profile of this compound class.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01938DOI Listing
January 2020

Operculum shape variation in Theodoxus Montfort, 1810 (Gastropoda: Neritidae).

Zootaxa 2019 Feb 26;4560(3):zootaxa.4560.3.8. Epub 2019 Feb 26.

University of Belgrade, Faculty of Biology, Institute of Zoology, Studentski trg. 16, 11000 Belgrade, Serbia.

The operculum morphology of neritid snails of genus Theodoxus Montfort, 1810 yields important species-specific taxonomic characters. This study is the first attempt to describe morphological differences in snails based on operculum shapes using a geometric morphometric approach. We examined the variability of opercular shapes between sexes and among populations and species based on 91 opercula of adult specimens belonging to six populations of three species of Theodoxus from the central Balkan and the southern border of the Pannonian plain. There are no sex-related differences in operculum shape and size in the studied species. The presence of shape variations influenced by size (allometry) was confirmed for T. danubialis (C. Pfeiffer, 1828) indicating that allometry could be a component of the morphological variation of this species. At the intraspecific level, phenotypic plasticity of operculum shape was found in T. danubialis and T. fluviatilis (Linnaeus, 1758). Of particular interest is the lack of morphological variability in the rare and endangered T. transversalis (C. Pfeiffer, 1828). At the species level a clear morphological distinction of T. fluviatilis from T. danubialis and T. transversalis was detected, confirming that the operculum with a rib could be used as a species-specific morphological character. The main morphological differences between species are an outwardly-stretched opercular/apophysal rib and a shortened tip of the opercular plate in T. fluviatilis, compared to the same structures in T. danubialis and T. transversalis.
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http://dx.doi.org/10.11646/zootaxa.4560.3.8DOI Listing
February 2019

A comparison of the transport kinetics of glycine transporter 1 and glycine transporter 2.

J Gen Physiol 2019 08 3;151(8):1035-1050. Epub 2019 Jul 3.

Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

Transporters of the solute carrier 6 (SLC6) family translocate their cognate substrate together with Na and Cl Detailed kinetic models exist for the transporters of GABA (GAT1/SLC6A1) and the monoamines dopamine (DAT/SLC6A3) and serotonin (SERT/SLC6A4). Here, we posited that the transport cycle of individual SLC6 transporters reflects the physiological requirements they operate under. We tested this hypothesis by analyzing the transport cycle of glycine transporter 1 (GlyT1/SLC6A9) and glycine transporter 2 (GlyT2/SLC6A5). GlyT2 is the only SLC6 family member known to translocate glycine, Na, and Cl in a 1:3:1 stoichiometry. We analyzed partial reactions in real time by electrophysiological recordings. Contrary to monoamine transporters, both GlyTs were found to have a high transport capacity driven by rapid return of the empty transporter after release of Cl on the intracellular side. Rapid cycling of both GlyTs was further supported by highly cooperative binding of cosubstrate ions and substrate such that their forward transport mode was maintained even under conditions of elevated intracellular Na or Cl The most important differences in the transport cycle of GlyT1 and GlyT2 arose from the kinetics of charge movement and the resulting voltage-dependent rate-limiting reactions: the kinetics of GlyT1 were governed by transition of the substrate-bound transporter from outward- to inward-facing conformations, whereas the kinetics of GlyT2 were governed by Na binding (or a related conformational change). Kinetic modeling showed that the kinetics of GlyT1 are ideally suited for supplying the extracellular glycine levels required for NMDA receptor activation.
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http://dx.doi.org/10.1085/jgp.201912318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683666PMC
August 2019

Synthesis of MnCo2O4 nanoparticles as modifiers for simultaneous determination of Pb(II) and Cd(II).

PLoS One 2019 6;14(2):e0210904. Epub 2019 Feb 6.

Department of Analytical Chemistry, University of Belgrade-Faculty of Chemistry, Belgrade, Serbia.

The porous spinel oxide nanoparticles, MnCo2O4, were synthesized by citrate gel combustion technique. Morphology, crystallinity and Co/Mn content of modified electrode was characterized and determined by Fourier transform infra-red spectroscopy (FT-IR), scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), X-ray diffraction pattern analysis (XRD), simultaneous thermogravimetry and differential thermal analysis (TG/DTA). Nanoparticles were used for modification of glassy carbon electrode (GCE) and new sensor was applied for simultaneous determination of Pb(II) and Cd(II) ions in water samples with the linear sweep anodic stripping voltammetry (LSASV).The factors such as pH, deposition potential and deposition time are optimized. Under optimal conditions the wide linear concentration range from 0.05 to 40 μmol/dm3was obtained for Pb(II), with limit of detection (LOD) of 8.06 nmol/dm3 and two linear concentration ranges were obtained for Cd(II), from 0.05 to 1.6 μmol/dm3 and from 1.6 to 40 μmol/dm3, with calculated LOD of 7.02 nmol/dm3. The selectivity of the new sensor was investigated in the presence of interfering ions. The sensor is stable and it gave reproducible results. The new sensor was succesfully applied on determination of heavy metals in natural waters.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210904PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364896PMC
November 2019

Volatiles composition and antioxidant activity L. from Serbia.

Nat Prod Res 2020 Sep 12;34(18):2698-2701. Epub 2019 Jan 12.

Department of Chemistry, Faculty of Science and Mathematics University of Niš, Niš, Serbia.

The chemical composition of the essential oil and the volatiles obtained by static headspace (HS) of L. is presented. The GC-MS analysis of the hydrodistilled oil resulted in the identification of 90 components, representing 92.7% of the oil. The most abundant compounds were: caryophyllene oxide (9.8%), -longipinocarveol (9.2%), eucalyptol (7.3%) and intermedeol (6.2%). The major constituent of L. HS volatiles was eucalyptol (87.4%). The antioxidant activity was evaluated by four different methods: 2,2-diphenyl-1-picryl-hydrazylhydrate free radical assay (DPPH), 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) method, total reducing power (TRP), ferric reducing antioxidant power (FRAP), and cupric reducing antioxidant capacity (CUPRAC). Total phenolic content in (TPC) examined oil was 177.95 µg GAE/mg oil. Radical scavenging potential of the oil was promising RSC-DPPH was 57.4% and RSC-ABTS was 82.7%.[Formula: see text].
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http://dx.doi.org/10.1080/14786419.2018.1550767DOI Listing
September 2020

Dispersive micro-solid phase extraction of 16 priority polycyclic aromatic hydrocarbons from water by using thermally treated clinoptilolite, and their quantification by GC-MS.

Mikrochim Acta 2018 11 21;185(12):556. Epub 2018 Nov 21.

Faculty of Science and Mathematics, University of Nis, Visegradska 33, Nis, 18000, Serbia.

The authors report on a novel sorbent (thermally treated natural zeolite; clinoptilolite) for use in dispersive micro-solid phase extraction (D-μ-SPE) of polycyclic aromatic hydrocarbons (PAHs) from water samples. The method was applied to the D-μ-SPE of 16 priority PAHs which then were quantified by gas chromatography with mass spectrometric detection (GC-MS). The method was validated in terms of specificity and selectivity, linearity and linear range, accuracy, precision, uncertainty, limits of detection and quantification. Figures of merit include (a) linear analytical ranges between 2.08 and 208 ppb, and (b) detection limits in the range from 0.01 to 0.92 ppb. The method was successfully applied to the determination of PAHs in river waters. Graphical abstract Schematic representation of dispersive micro-solid phase extraction (D-μ-SPE) of trace levels of PAHs in water samples by using thermally treated clinoptilolite as sorbent prior to gas chromatography-mass spectrometry analysis (GC-MS).
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http://dx.doi.org/10.1007/s00604-018-3091-0DOI Listing
November 2018

A daily single dose of a novel modafinil analogue CE-123 improves memory acquisition and memory retrieval.

Behav Brain Res 2018 05 1;343:83-94. Epub 2018 Feb 1.

Department of Neuroproteomics, Paracelsus Medical University, Salzburg, Austria. Electronic address:

Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 μM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions.
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http://dx.doi.org/10.1016/j.bbr.2018.01.032DOI Listing
May 2018

A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats.

Front Behav Neurosci 2017 27;11:222. Epub 2017 Nov 27.

Paracelsus Medical University, Salzburg, Austria.

Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT) are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123) with higher specificity for DAT in male rats in an attentional set-shifting task (ASST), that proves for cognitive flexibility and a 5-choice serial-reaction time task (5-CSRTT) assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R-Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity.
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http://dx.doi.org/10.3389/fnbeh.2017.00222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711856PMC
November 2017

Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

J Med Chem 2017 11 9;60(22):9330-9348. Epub 2017 Nov 9.

Neuroscience Laboratory, Paracelsus Medical University , 5020 Salzburg, Austria.

Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01313DOI Listing
November 2017

Phytochemical analysis of Saponaria officinalis L. shoots and flowers essential oils.

Nat Prod Res 2018 Feb 12;32(3):331-334. Epub 2017 Jul 12.

a Laboratories for Organic Chemistry and Biochemistry, Faculty of Science and Mathematics, Department of Chemistry , University of Niš , Niš , Serbia.

Phytochemical analysis by GC and GC/MS of the essential oil samples obtained from fresh shoots and flowers of Saponaria officinalis L. allowed the identification of 96 components in total, comprising 94.7% and 86.0% of the total oils compositions, respectively. Regarding the shoots essential oil, the major of 87 identified volatile compounds were phytol (14.1%), tricosane-6,8-dione (13.4%), patchouli alcohol (7.9%) and tricosane (7.2%), whereas patchouli alcohol (20.0%), heneicosane (11.5%) and tricosane (8.4%) were dominant among the 66 volatiles in the flower oil. Nonterpenoid compounds had the highest contribution in S. officinalis shoots essential oil (53.7%), while in the flower oil, constituents were almost evenly distributed between the oxygenated sesquiterpenoid (41.2%) and nonterpenoid compounds (39.5%).
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http://dx.doi.org/10.1080/14786419.2017.1350668DOI Listing
February 2018

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity.

PLoS One 2017 23;12(6):e0179675. Epub 2017 Jun 23.

Department of Pediatrics, Medical University of Vienna, Vienna, Austria.

Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482457PMC
October 2017

A novel heterocyclic compound improves working memory in the radial arm maze and modulates the dopamine receptor D1R in frontal cortex of the Sprague-Dawley rat.

Behav Brain Res 2017 08 16;332:308-315. Epub 2017 Jun 16.

Neuroproteomics Laboratory, Science Park, Ilkovicova 8, SK-84104 Bratislava, Slovakia. Electronic address:

A series of compounds have been shown to enhance cognitive function via the dopaminergic system and indeed the search for more active and less toxic compounds is continuing. It was therefore the aim of the study to synthetise and test a novel heterocyclic compound for cognitive enhancement in a paradigm for working memory. Specific and effective dopamine re-uptake inhibition DAT (IC50=4,1±0,8μM) made us test this compound in a radial arm maze (RAM) in the rat. CE-125 (4-((benzhydrylsulfinyl)methyl)-2-cyclopropylthiazole), was tested for dopamine (DAT), serotonin and norepinephrine re-uptake inhibition by a well-established system. The working memory index (WMI) was evaluated in male Sprague Dawley rats that were intraperitoneally injected with CE-125 (1 or 10mg/kg body weight). In order to evaluate basic neurotoxicity, the open field, elevated plus maze, rota rod studies and the forced swim test were carried out. Frontal cortex was taken at the last day of the RAM test and dopamine receptors D1R and D2R, DAT and phosphorylated DAT protein levels were determined. On the 10th day both doses were increasing the WMI as compared to the vehicle-treated group. In both, trained and treated groups, D1R levels were significantly reduced while D2R levels were unchanged. DAT levels were comparable between all groups while phosphorylated DAT levels were increased in the trained group treated with 1mg/kg body weight. CE-125 as a probably non-neurotoxic compound and specific reuptake inhibitor was shown to increase performance (WMI) and modulation of the dopaminergic system is proposed as a possible mechanism of action.
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http://dx.doi.org/10.1016/j.bbr.2017.06.023DOI Listing
August 2017

Essential oil composition of Erica spiculifolia Salisb - first report.

Nat Prod Res 2018 Jan 19;32(2):222-224. Epub 2017 Jun 19.

a Faculty of Science and Mathematics, Department of Chemistry , University of Niš , Niš , Serbia.

The essential oil isolated from Erica spiculifolia Salisb. by hydrodistillation was analysed by GC-MS. One hundred compounds representing 92.6% of total oil were identified. Among the detected compounds 38 were monoterpenoids (46.2%), 30 were sesquiterpenoids (31.7%), 2 diterpene (0.4%) and 30 compounds (14.3%) were with various non-terpenoid structures. Oxygenated monoerpenes were by far the main class (45.3%) with α-terpineol (7.5%) endo-borneol (7.2%), pinocarveol (5.9%) and thymol (3.7%) as the major compounds. The predominant components of sesquiterpenes were caryophyllene oxide (5.0%), caryophyllene (4.2%), τ -murrolol (3.5%), spathulenol (2.9) and α-cadinol (2.3%).
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http://dx.doi.org/10.1080/14786419.2017.1340287DOI Listing
January 2018

Characterization of sections of the Sava River based on fish community structure.

Sci Total Environ 2017 Jan 14;574:264-271. Epub 2016 Oct 14.

Institute for Biological Research, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia.

Sampling was undertaken, with the same fishing gear and along the Sava River, from its source to its confluence, in September 2014 and September 2015. In total, 44 fish species were identified, of which 37 were native species and 7 were alien. Fish samples revealed independence in terms of both species composition and their abundance under different hydrological conditions. During flooding and high water levels in 2014, pelagic fish species were sampled in greater proportion than at lower water levels in 2015 when benthic fish species were more abundant. The flood wave in 2014 was accompanied by catch of common carp, Cyprinus carpio, a typical lower rhithron fish species in the upper course, and of tench, Tinca tinca, a typical potamon fish species of backwaters, in the main channel of the lower Sava River. One specimen of bighead goby, Ponticola kessleri, which is common in the potamon fish community, was caught during the 2015 sampling close to the boundary between the upper and middle sections of the Sava. This is the first record of Ponto-Caspian gobies in the inland waters of Slovenia. Its finding far upstream indicates a strong effect of an as yet unidentified stress along the Sava River up to the spot where the bighead goby was sampled. Finally, these results indicate that pelagic fish species are more resistant to the stressful effect of flooding than benthic species, and that the structure of fish communities is influenced/affected by flooding as a short-term stressor. The progressively increasing number of alien fish species downstream in the Sava River point to the effects of long-term human-induced stressors in the area.
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http://dx.doi.org/10.1016/j.scitotenv.2016.09.072DOI Listing
January 2017

Evaluation of genotoxic potential throughout the upper and middle stretches of Adige river basin.

Sci Total Environ 2016 Nov 21;571:1383-91. Epub 2016 Jul 21.

University of Belgrade, Faculty of Biology, Belgrade, Serbia.

In this study a comprehensive genotoxicological survey throughout the upper and middle stretches of Adige river basin is presented. The study was carried out at 7 sites located along the Adige main course and one the most significant tributaries, the Noce creek, both presenting different levels of pollution pressure. To give an insight into the nature of the genotoxic activity we employed the battery of prokaryotic and eukaryotic assays. Mutagenicity in water samples was evaluated by SOS/umuC test in Salmonella typhimurium TA1535/pSK1002. The level of DNA damage as a biomarker of exposure (comet assay) and biomarker of effect (micronucleus assay) and the level of oxidative stress as well (Fpg - modified comet assay) were studied in blood cells of Salmo cenerinus Nardo, 1847 and Salmo marmoratus Cuvier, 1829. Within the applied bioassays, comet assay showed the highest potential for discriminating the sampling sites which are under lesser extent of pressure (sampling sites 1-Barnes at Bresimo and 4-Noce downstream S. Giustina) from the sites under high pressure (sampling sites 5-Noce at Mezzolombardo and 6/7-Adige upstream and downstream municipality of Trento). Significant correlation between the standard and Fpg - modified comet assay indicated that oxidative stress could be a major contributor to observed DNA damage in collected specimens.
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http://dx.doi.org/10.1016/j.scitotenv.2016.07.099DOI Listing
November 2016

Identification of Phenolic Compounds from Seed Coats of Differently Colored European Varieties of Pea (Pisum sativum L.) and Characterization of Their Antioxidant and In Vitro Anticancer Activities.

Nutr Cancer 2016 Aug-Sep;68(6):988-1000. Epub 2016 Jun 27.

b Faculty of Chemistry , University of Belgrade , Belgrade , Serbia.

To date little has been done on identification of major phenolic compounds responsible for anticancer and antioxidant properties of pea (Pisum sativum L.) seed coat extracts. In the present study, phenolic profile of the seed coat extracts from 10 differently colored European varieties has been determined using ultrahigh-performance liquid chromatography-linear trap quadrupole orbitrap mass spectrometer technique. Extracts of dark colored varieties with high total phenolic content (up to 46.56 mg GAE/g) exhibited strong antioxidant activities (measured by 2,2-diphenyl-1-picrylhydrazyl or DPPH assay, and ferric ion reducing and ferrous ion chelating capacity assays) which could be attributed to presence of gallic acid, epigallocatechin, naringenin, and apigenin. The aqueous extracts of dark colored varieties exert concentration-dependent cytotoxic effects on all tested malignant cell lines (human colon adenocarcinoma LS174, human breast carcinoma MDA-MB-453, human lung carcinoma A594, and myelogenous leukemia K562). Correlation analysis revealed that intensities of cytotoxic activity of the extracts strongly correlated with contents of epigallocatechin and luteolin. Cell cycle analysis on LS174 cells in the presence of caspase-3 inhibitor points out that extracts may activate other cell death modalities besides caspase-3-dependent apoptosis. The study provides evidence that seed coat extracts of dark colored pea varieties might be used as potential cancer-chemopreventive and complementary agents in cancer therapy.
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http://dx.doi.org/10.1080/01635581.2016.1190019DOI Listing
December 2017

Dittrichia graveolens (L.) Greuter Essential Oil: Chemical Composition, Multivariate Analysis, and Antimicrobial Activity.

Chem Biodivers 2016 Jan;13(1):85-90

Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, SR-18000 Niš, (phone: +381-63-1094273; fax: +381-18-533014).

The chemical composition and in vitro antimicrobial activities of Dittrichia graveolens (L.) Greuter essential oil was studied. Moreover, using agglomerative hierarchical cluster (AHC) and principal component analyses (PCA), the interrelationships of the D. graveolens essential-oil profiles characterized so far (including the sample from this study) were investigated. To evaluate the chemical composition of the essential oil, GC-FID and GC/MS analyses were performed. Altogether, 54 compounds were identified, accounting for 92.9% of the total oil composition. The D. graveolens oil belongs to the monoterpenoid chemotype, with monoterpenoids comprising 87.4% of the totally identified compounds. The major components were borneol (43.6%) and bornyl acetate (38.3%). Multivariate analysis showed that the compounds borneol and bornyl acetate exerted the greatest influence on the spatial differences in the composition of the reported oils. The antimicrobial activity against five bacterial and one fungal strain was determined using a disk-diffusion assay. The studied essential oil was active only against Gram-positive bacteria.
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http://dx.doi.org/10.1002/cbdv.201500028DOI Listing
January 2016

Deciphering nifedipine in vivo delivery from modified release dosage forms: Identification of food effect.

Acta Pharm 2015 Dec;65(4):427-41

With the increased reliance on in vitro dissolution testing as an indicator of in vivo drug behavior and the trend towards the in silico modeling of dosage form performance, the need for bioperformance dissolution methodology development has been enhanced. Determination of the in vivo drug delivery profile is essential for the bioperformance dissolution test development and in vitro/in vivo correlation modeling, as well as the understanding of absorption mechanisms. The aim of this study was to compare different methods in terms of their usefulness and applicability in deciphering in vivo delivery of nifedipine administered in modified release dosage forms. A detailed survey of publications on nifedipine pharmacokinetics was done and used to identify the magnitude of food effect. In vitro dissolution testing was performed under various experimental conditions. Obtained results indicate the potential for using the developed in silico model coupled with discriminative in vitro dissolution data for identification of the in vivo drug product behavior.
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http://dx.doi.org/10.1515/acph-2015-0039DOI Listing
December 2015

Chemical composition of the essential oil of Laserpitium latifolium from Serbia.

Nat Prod Commun 2015 Apr;10(4):649-51

The essential oil of aerial parts ofLaserpitium latifolium L. from Serbia, obtained by hydro distillation, was analyzed by GC-MS and GC-FID applying liquid injection mode; thirty-four compounds were registered (99.9% of the total oil). The essential oil clearly belongs to the monoterpenoid chemotype, with monoterpenoids constituting 99.8% of the total oil. Sabinene (47.8%), α-pinene (25.0%) and β-pinene (7.1%) were the major constituents.
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April 2015

In vitro--in silico--in vivo drug absorption model development based on mechanistic gastrointestinal simulation and artificial neural networks: nifedipine osmotic release tablets case study.

Eur J Pharm Sci 2014 Oct 6;62:212-8. Epub 2014 Jun 6.

Department of Pharmaceutical Technology, University of Belgrade, Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address:

In vitro--in vivo correlations (IVIVC) are generally accepted as a valuable tool in modified release formulation development aimed at (i) quantifying the in vivo drug delivery profile and formulation related effects on absorption; (ii) establishing clinically relevant dissolution specifications and (iii) supporting the biowaiver claims. The aim of the present study was to develop relevant IVIVC models based on mechanistic gastrointestinal simulation (GIS) and artificial neural network (ANN) analysis and to evaluate their applicability and usefulness in biopharmaceutical drug characterisation. Nifedipine osmotic release tablets were selected as model drug product on the basis of their robustness, dissolution limited drug absorption and the availability of relevant literature data. Although the osmotic release tablets have been designed to be robust against the influence of physiological conditions in the gastrointestinal tract, notable differences in nifedipine dissolution kinetics were observed depending on the in vitro experimental conditions employed. The results obtained indicate that both GIS and ANN model developed were sensitive to input kinetics represented by the in vitro profiles obtained under various experimental conditions. Different in silico approaches may be successfully employed in the in vitro--in silico--in vivo model development. However, the results obtained may differ and relevant outcomes are sensitive to the methodology employed.
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http://dx.doi.org/10.1016/j.ejps.2014.05.030DOI Listing
October 2014

Chemical composition of Angelica pancicii essential oil determined by liquid and headspace GC-MS techniques.

Nat Prod Commun 2014 Feb;9(2):271-2

The essential oil of the Balkan endemic species, Angelica pancicii, obtained by hydrodistillation, was analyzed by GC and GC-MS, applying the liquid injection mode. These results were compared with the chemical composition of volatiles achieved by the "headspace" injection mode, followed by GC and GC-MS (HS-GC-MS). A total of 40 compounds were identified in the essential oil (98.8% of the total oil) and 44 by HS-GC-MS (99.8% of the total oil). The most abundant class of compounds in both cases was monoterpenoids, which formed 92.7% of the essential oil (97.7% by HS-GC-MS) of total identified compounds. The major components in both cases were beta-phellandrene (54.9% and 60.1%, respectively), alpha-pinene (14.5% and 20.1%, respectively) and alpha-phellandrene (4.5% and 4.3%, respectively).
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February 2014

The influence of Al3+ ion on porcine pepsin activity in vitro.

J Enzyme Inhib Med Chem 2008 Dec;23(6):1002-10

Department of Physical Chemistry, Vinca-Institute of Nuclear Science, Belgrade, Serbia.

The in vitro effect of Al(3+) ions in the concentration range 1.7 x 10(-6) M-8.7 x 10(-3) M on pepsin activity at pH 2, via kinetic parameters and its electrophoretic mobility was evaluated. Kinetic study demonstrated the existence of an activation effect of Al(3+) at pH 2 on pepsin molecule. Kinetic analysis with respect to concentrations of haemoglobin showed that Al(3+) ions increase the maximal velocity (V(max)) and k(cat) values rather than apparent affinity for substrate (K(S)) implying the non-competitive nature of activation which indicated that aluminium was a non-essential activator of partial non-competitive type. The values of the equilibrium constants K(S) and K(mA) for dissociation of corresponding complexes were evaluated as 0.904 +/- 0.083 mM and 8.56 +/- 0.51 microM, respectively. Dissociation constant K(A), of activator from enzyme-activator complex calculated via kinetic and direct measurement of Al(3+) binding data, as well as activation constant A(50), the activator concentration that gives a rate equal to half at a saturating concentration of activator, were found to be 8.82 +/- 0.90 microM, 8.39 +/- 0.76 microM, and 8.05 +/- 0.48 microM respectively. Native PAGE electrophoresis shows the decrease in electrophoretic mobility of pepsin and confirms modification of the electric charge and conformational changes of pepsin caused by bound Al(3+) on the pepsin molecule. Al(3+) induced conformational changes of pepsin were verified by UV-VIS and IR spectra. Moreover, the absence of conformational changes in the haemoglobin molecule in the presence of Al(3+) ions confirms that the obtained activation is a consequence of conformational changes caused only in the pepsin molecule.
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http://dx.doi.org/10.1080/14756360701841095DOI Listing
December 2008