In Vitro Toxicology Sciences
Vesna Munic Kos, PhD, senior research fellow
Accumulating chemicals may pose a chronic threat for an organism, when present in high concentrations. As our knowledge about biological systems expands it is necessary to constantly revalidate our conclusions about the safety of such chemicals because of their prolonged presence.
Therefore, the main focus of my research are chemicals (pharmaceuticals and environmental toxins) which accumulate in organisms. During 13 years of my career in the research of pharmaceutical industry large part of my research was dealing with highly accumulating pharmaceuticals, especially of macrolide class.
Predicting the effects of highly accumulating compounds
In this research project we use in vitro techniques to analyze the consequences of compound’s accumulation in cells and their binding to biological membranes. We are looking at how these compounds affect various processes in cells, physiological functions of membranes and extracellular membrane vesicles. In collaboration we use structure-property relationship studies to improve detection and prediction of accumulating chemicals.
Developing cell based methods
Additionally, we are developing cell based methods for various types of screenings of environmental toxicants and pharmaceuticals. We mostly use cell function assays, high content quantitative imaging techniques and gene expression analyses on human and murine primary cells and cell lines.
Previous team members
Diana Sanchez Garcia
Predicting the effects of highly accumulating and lipid binding compounds
The aim of this interdisciplinary project is to improve the detection and prediction of highly accumulating and lipid binding chemicals and to analyze in detail the toxicological consequences of their binding to biological membranes. To achieve this, we use:
- extensive in vitro measurements and comparisons of different toxicological outputs together with quantification of compounds in cells,
- in silico modelling with structure-property relationship studies, and
- physico-chemical methods to assess the molecular properties of accumulating compounds.
Mechanisms of chemical accumulation and adverse effects are studied together with the functionality of biological membranes in the cell and in the extracellular nano- and microvesicles, especially in terms of compounds immunotoxic, neurotoxic and obesogenic effects. Cell-differentiation processes, intercellular communication via extracellular vesicles, as well as protein-lipid interactions within cells is being assessed in prolonged exposure to accumulating compounds. Looking at these processes is relatively new in toxicology, but it is necessary to estimate the risk associated with accumulating and lipid-binding compounds.
The project started in 2015 and it focuses on pharmaceuticals and environmental toxicants (persistent organic pollutants) with accumulating properties, aiming to find common points as well as the differences between subclasses of these compounds.
Cell culture – primary cells and cell lines
Isolation of human and rodent cells
High content cell imaging and quantitative image analysis
Isolation and function of extracellular vesicles (exosomes)
Fluorimetry/spectrofotometry/luminometry plate based assays
qRT-PCR – gene expression analysis
- Karolinska Institutet
Feel free to contact me for possibilities of collaboration at firstname.lastname@example.org .
Sanchez Garcia D, Sjödin M, Hellstrandh M, Norinder U, Nikiforova V, Lindberg J, Wincent E, Bergman Å, Cotgreave I, Munic Kos V. Cellular accumulation and lipid binding of perfluorinated alkylated substances (PFASs) – A comparison with lysosomotropic drugs. Chem Biol Interact. 2017 Dec 14; 281:1-10. doi: 10.1016/j.cbi.2017.12.021. [Epub ahead of print]
Koštrun S, Munic Kos V, Matanović Škugor M, Palej Jakopović I, Malnar I, Dragojević S, Ralić J, Alihodžić S. Around the macrolide – Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation, Eur J Med Chem. 2017; 133:351-364
Munić Kos V, Koštrun S, Fajdetić A, Bosnar M, Kelnerić Ž, Stepanić V, Eraković Haber V Structure-property relationship for cellular accumulation of macrolones in human polymorphonuclear leukocytes (PMNs). Eur J Pharm Sci. 2013; 49(2):206-19,
Matijašić M, Munić Kos V, Nujić K, Cužić S, Padovan J, Kragol G, Alihodžić S, Mildner B, Verbanac D, Eraković Haber V. Fluorescently labeled macrolides as a tool for monitoring cellular and tissue distribution of azithromycin. Pharmacol Res. 2012; 66(4):332-42.
Polancec DS, Munic Kos V, Banjanac M, Vrancic M, Cuzic S, Belamaric D, Parnham MJ, Polancec D, Erakovic Haber V. Azithromycin drives in vitro GM-CSF/IL-4-induced differentiation of human blood monocytes toward dendritic-like cells with regulatory properties. J Leukoc Biol. 2012; 91(2):229-43.
Banjanac M, Munić Kos V, Nujić K, Vrančić M, Belamarić D, Crnković S, Hlevnjak M, Eraković Haber V. Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells. Pharmacol Res. 2012; 66(4):357-62.
Nujić K, Banjanac M, Munić V, Polančec D, Eraković Haber V. Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype. Cell Immunol. 2012; 279(1):78-86.
Vrančić M, Banjanac M, Nujić K, Bosnar M, Murati T, Munić V, Stupin Polančec D, Belamarić D, Parnham MJ, Eraković Haber V. Azithromycin distinctively modulates classical activation of human monocytes in vitro. Br J Pharmacol. 2012; 165(5):1348-60.
Munić V, Banjanac M, Koštrun S, Nujić K, Bosnar M, Marjanović N, Ralić J, Matijašić M, Hlevnjak M, Eraković Haber V. Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis. Pharmacol Res. 2011; 64(3):298-307.
Stepanić V, Koštrun S, Malnar I, Hlevnjak M, Butković K, Ćaleta I, Dukši M, Kragol G, Makaruha-Stegić O, Mikac L, Ralić J, Tatić I, Tavčar B, Valko K, Zulfikari S, Munić V. Modeling cellular pharmacokinetics of 14- and 15-membered macrolides with physicochemical properties. J Med Chem. 2011; 54(3):719-33.
Munić V, Kelnerić Z, Mikac L, Eraković Haber V. Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays. Eur J Pharm Sci. 2010; 41(1):86-95.
Vesna Munic Kos (University of Zagreb) – PhD thesis: Interaction of macrolides and mammalian ABC transporters, 2007
Inna Sitnik (Uppsala University) – Master thesis: Intercellular communication via exosomes as a target for lipid binding compounds, 2017
Arrabi Easwaranathan (KTH Royal Institute of Technology) – Master thesis: Development of in vitro and in silico models for compounds accumulating in lysosomes, 2017
Diana Sanchez Garcia (KTH Royal Institute of Technology) – Master thesis: Quantification of cellular accumulation and lipid binding properties for phospholipidosis inducing drugs and bioaccumulating environmental toxicants, 2016
Patrik Kagebeck (Uppsala University) – Master thesis: Differentiation of Mesenchymal Stem Cells and Cell Line 3T3-L1K into Adipocytes as an In vitro Toxicological Model, 2016
Erica Selin (Karolinska Institutet) – Bachelor thesis: Impact of phospholipidosis inducing drugs on differentiation and function of human macrophages in prolonged exposure, 2016
Eric Wassen (Stockholm University) – Master thesis: Impact of highly accumulating compounds on cell differentiation in prolonged culture, 2015
Mario Matijasic (University of Zagreb) – PhD thesis: Monitoring cellular and tissue distribution of azithromycin using fluorescently-labeled macrolides, 2011
I am open for supervising interns and Master students, and for co-supervising PhD students. Post-docs wishing to apply jointly for post-doc grants are also welcome. Please send your CV to email@example.com.
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