Vesna Munic Kos
Cell and molecular biologist and project leader experienced in pharmacology and toxicology.
Main focus of my current research are chemicals (pharmaceuticals and environmental toxins) which accumulate in organisms, and the effects they have on cells. During 13 years of my career in the research of pharmaceutical industry large part of my research was dealing with anti-inflammatories and highly accumulating pharmaceuticals, especially of macrolide class. Now I am studying endocrine disrupting chemicals and the mechanisms of their impact on inflammation and metabolic disorders as well as their toxicokinetic properties.
EU Horizon 2020 project GOLIATH – Beating Goliath: Generation Of Novel, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Compounds (2019-2023) – principal investigator for Karolinska Institutet
The aim of this project is to develop and evaluate in vitro and in silico methods for identification and testing of endocrine disrupting chemicals contributing to metabolic disorders. Karolinska Institutet is one of 14 participating institutions from all over Europe and one from USA. Here, we work on the development and evaluation of in vitro methods for identification of metabolism disrupting chemiclas affecting adipogenesis and the development of insulin resistance in adipocytes.
The evaluation of in vitro skeletal muscle models for the assessment of metabolism disrupting chemicals contributing to insulin resistance – Swedish Research Council Formas (2020-2023) - co-applicant
The aim of this project is to analyze the impact of metabolism disrupting chemicals on various in vitro skeletal muscle models mainly related to insulin sensitivity and glucose utilisation, and their possible contribution to the development of insulin resistance and type 2 diabetes.
Intracellular exposure: a new parameter for prediction of toxicological outcome after exposure to endocrine disrupting chemicals? – Swedish Research Council Formas (2018-2023) - co-applicant
This project is a collaboration with Prof. Per Artursson from Uppsala University (Department of Pharmacy), and Prof. Ian Cotgreave from RISE. The aim of the project is to determine the intracellular unbound fraction of selected endocrine disrupting chemicals (EDCs), and assess the impact of this understudied kinetic parameter on the assessment of adverse effects of endocrine disrupting chemicals (EDCs) in various cell based test systems. This research should ultimately help better prediction of toxic effects of chemicals from computational and cell based models.
Predicting the effects of highly accumulating compounds (2014-2019) – principal investigator
By being present in high concentrations, accumulating chemicals may pose a chronic threat for an organism. 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.
In my research, I am using in vitro techniques to analyze the consequences of compound’s accumulation in cells and their binding to biological membranes. I am looking at how these compounds affect various processes in cells, physiological functions of membranes and extracellular membrane vesicles, especially in the context of immune system and inflammation. In collaboration, we do structure-property relationship studies to improve detection and prediction of accumulating chemicals.
EU-ToxRisk – An Integrated European ‘Flagship’ Programme Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st century (2016-2022) - collaborator
For this project we have introduced a quantitative high content imaging assay that we now use for screening of various chemicals on their potential effects on neuron differentiation and degradation. Parameters describing neurite length, number, branching points and straightness, together with cell body area and cell number are quantified using our high content analysis system.
Obesity III: Obesogen assays: Limitations, strengths, and new directions. Kassotis CD, Vom Saal FS, Babin PJ, Lagadic-Gossmann D, Le Mentec H, Blumberg B, Mohajer N, Legrand A, Munic Kos V, Martin-Chouly C, Podechard N, Langouët S, Touma C, Barouki R, Ji Kim M, Audouze K, Choudhury M, Shree N, Bansal A, Howard S, Heindel JJ. Biochem Pharmacol. 2022, 115014. https://pubmed.ncbi.nlm.nih.gov/35393121/
Obesity II: Establishing Causal Links Between Chemical Exposures and Obesity. Heindel JJ, Howard S, Agay-Shay K, Arrebola JP, Audouze K, Babin PJ, Barouki R, Bansal A, Blanc E, Cave MC, Chatterjee S, Chevalier N, Choudhury M, Collier D, Connolly L, Coumoul X, Garruti G, Gilbertson M, Hoepner LA, Holloway AC, Howell G 3rd, Kassotis C, Kay MK, Ji Kim M, Lagadic-Gossmann D, Langouet S, Legrand A, Li Z, Le Mentec H, Lind L, Monica Lind P, Lustig RH, Martin-Chouly C, Munic Kos V, Podechard N, Roepke TA, Sargis RM, Starling A, Tomlinson CR, Touma C, Vondracek J, Vom Saal F, Blumberg B. Biochem Pharmacol. 2022, 115015. https://pubmed.ncbi.nlm.nih.gov/35395240/
High throughput screening of bisphenols and their mixtures under conditions of low-intensity adipogenesis of human mesenchymal stem cells (hMSCs). Norgren K, Tuck A, Vieira Silva A, Burkhardt P, Öberg M, Munic Kos V. Food Chem Toxicol. 2022, 161:112842. https://doi.org/10.1016/j.fct.2022.112842
Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Delp J, Cediel‑Ulloa A, Suciu I, Kranaster P, van Vugt‑Lussenburg BMA, Munic Kos V, van der Stel W, Carta G, Hougaard Bennekou S, Jennings P, van de Water B, Forsby A, Leist M. Arch Toxicol, 2021; 95, 591–615, https://doi.org/10.1007/s00204-020-02970-5
Novel class of fast acting antimalarial agents: substituted 15-membered azalides. Peric M, Pesic D, Alihodzic S, Fajdetic A, Herreros E, Gamo FJ, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer-Bazaga S, Martinez Martinez MS, Gargallo-Viola D, Mathis A, Kessler A, Banjanac M, Padovan J, Bencetic, V, Munic Kos V, Bukvic M, Erakovic Haber V, Spaventi R. Br J Pharmacol, 2021; 178:363–377 https://pubmed.ncbi.nlm.nih.gov/33085774/
Existing highly accumulating lysosomotropic drugs with potential for repurposing to target COVID-19. Norinder U, Tuck A, Norgren K, Munic Kos V. Biomed Pharmacother 2020, 130:110582 https://www.sciencedirect.com/science/article/pii/S0753332220307757?via%3Dihub
The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds. Legler J, Zalko D, Jourdan F, Jacobs M, Fromenty B, Balaguer P, Bourguet W, Munic Kos V, Nadal A, Beausoleil C, Cristobal S, Remy S, Ermler S, Margiotta-Casaluci L, Griffin J, Blumberg B, Chesne C, Hoffmann S, Andersson P, Kamstra J. Int J Mol Sci 2020; 21:3480. https://pubmed.ncbi.nlm.nih.gov/32423144/
QSAR Models for Predicting Five Levels of Cellular Accumulation of Lysosomotropic Macrocycles. Norinder U, Munic Kos V. Int J Mol Sci. 2019; 20(23):5938. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928787/
Quantification of intracellular accumulation and retention of lysosomotropic macrocyclic compounds by high-throughput imaging of lysosomal changes. Easwaranathan A, Inci B, Ulrich S, Brunken L, Nikiforova V, Norinder U, Swanson S, Munic Kos V. J Pharm Sci. 2019; 108:652-660. https://www.ncbi.nlm.nih.gov/m/pubmed/30419273/#fft
Lysosomotropic cationic amphiphilic drugs inhibit adipocyte differentiation in 3T3-L1K cells via accumulation in cells and phospholipid membranes, and inhibition of autophagy. Kagebeck P, Nikiforova V, Brunken L, Easwaranathan A, Ruegg J, Cotgreave I, Munic Kos V. Eur J Pharmacol. 2018; 829:44-53. https://www.ncbi.nlm.nih.gov/pubmed/29627311
Cellular accumulation and lipid binding of perfluorinated alkylated substances (PFASs) - A comparison with lysosomotropic drugs. Sanchez Garcia D, Sjödin M, Hellstrandh M, Norinder U, Nikiforova V, Lindberg J, Wincent E, Bergman Å, Cotgreave I, Munic Kos V. Chem Biol Interact. 2018; 281:1-10. https://www.ncbi.nlm.nih.gov/pubmed/29248446
Around the macrolide - Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation. Koštrun S, Munic Kos V, Matanović Škugor M, Palej Jakopović I, Malnar I, Dragojević S, Ralić J, Alihodžić S. Eur J Med Chem. 2017; 133:351-364. https://www.ncbi.nlm.nih.gov/pubmed/28410508
A comparison of in vitro ADME properties and pharmacokinetics of azithromycin and selected 15-membered ring macrolides in rodents. Milić A, Mihaljević VB, Ralić J, Bokulić A, Nožinić D, Tavčar B, Mildner B, Munić V, Malnar I, Padovan J. Eur J Drug Metab Pharmacokinet. 2014; 39(4):263-76. http://www.ncbi.nlm.nih.gov/pubmed/24114177
Structure-property relationship for cellular accumulation of macrolones in human polymorphonuclear leukocytes (PMNs). Munić Kos V, Koštrun S, Fajdetić A, Bosnar M, Kelnerić Ž, Stepanić V, Eraković Haber V. Eur J Pharm Sci. 2013; 49(2):206-19. http://www.ncbi.nlm.nih.gov/pubmed/23474356
Macrolactonolides: a novel class of anti-inflammatory compounds. Tomašković L, Komac M, Makaruha Stegić O, Munić V, Ralić J, Stanić B, Banjanac M, Marković S, Hrvačić B, Čipčić Paljetak H, Padovan J, Glojnarić I, Eraković Haber V, Mesić M, Merćep M. Bioorg Med Chem. 2013; 21(1):321-32. http://www.ncbi.nlm.nih.gov/pubmed/23199485
Fluorescently labeled macrolides as a tool for monitoring cellular and tissue distribution of azithromycin. Matijašić M, Munić Kos V, Nujić K, Cužić S, Padovan J, Kragol G, Alihodžić S, Mildner B, Verbanac D, Eraković Haber V. Pharmacol Res. 2012; 66(4):332-42. http://www.ncbi.nlm.nih.gov/pubmed/22749903
Azithromycin drives in vitro GM-CSF/IL-4-induced differentiation of human blood monocytes toward dendritic-like cells with regulatory properties. Polancec DS, Munic Kos V, Banjanac M, Vrancic M, Cuzic S, Belamaric D, Parnham MJ, Polancec D, Erakovic Haber V.J Leukoc Biol. 2012; 91(2):229-43. http://www.ncbi.nlm.nih.gov/pubmed/22131344
Anti-inflammatory mechanism of action of azithromycin in LPS-stimulated J774A.1 cells. Banjanac M, Munić Kos V, Nujić K, Vrančić M, Belamarić D, Crnković S, Hlevnjak M, Eraković Haber V. Pharmacol Res. 2012; 66(4):357-62. http://www.ncbi.nlm.nih.gov/pubmed/22766077
Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype. Nujić K, Banjanac M, Munić V, Polančec D, Eraković Haber V. Cell Immunol. 2012; 279(1):78-86. http://www.ncbi.nlm.nih.gov/pubmed/23099154
Azithromycin distinctively modulates classical activation of human monocytes in vitro. Vrančić M, Banjanac M, Nujić K, Bosnar M, Murati T, Munić V, Stupin Polančec D, Belamarić D, Parnham MJ, Eraković Haber V. Br J Pharmacol. 2012; 165(5):1348-60. http://www.ncbi.nlm.nih.gov/pubmed/21726210
Intensity of macrolide anti-inflammatory activity in J774A.1 cells positively correlates with cellular accumulation and phospholipidosis. Munić V, Banjanac M, Koštrun S, Nujić K, Bosnar M, Marjanović N, Ralić J, Matijašić M, Hlevnjak M, Eraković Haber V. Pharmacol Res. 2011; 64(3):298-307. http://www.ncbi.nlm.nih.gov/pubmed/21473915
Modeling cellular pharmacokinetics of 14- and 15-membered macrolides with physicochemical properties. 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. J Med Chem. 2011; 54(3):719-33. http://www.ncbi.nlm.nih.gov/pubmed/21207938
Characterization of rhodamine-123, calcein and 5(6)-carboxy-2',7'-dichlorofluorescein (CDCF) export via MRP2 (ABCC2) in MES-SA and A549 cells. Munić V, Hlevnjak M, Eraković Haber V. Eur J Pharm Sci. 2011; 43(5):359-69. http://www.ncbi.nlm.nih.gov/pubmed/21605668
Differences in assessment of macrolide interaction with human MDR1 (ABCB1, P-gp) using rhodamine-123 efflux, ATPase activity and cellular accumulation assays. Munić V, Kelnerić Z, Mikac L, Eraković Haber V. Eur J Pharm Sci. 2010; 41(1):86-95. http://www.ncbi.nlm.nih.gov/pubmed/20621639
Cloning and molecular characterization of apical efflux transporters (ABCB1, ABCB11 and ABCC2) in rainbow trout (Oncorhynchus mykiss) hepatocytes. Zaja R, Munić V, Klobucar RS, Ambriović-Ristov A, Smital T. Aquat Toxicol. 2008; 90(4):322-32. http://www.ncbi.nlm.nih.gov/pubmed/19008001
Cloning and mRNA expression analysis of an ABCG2 (BCRP) efflux transporter in rainbow trout (Oncorhynchus mykiss) liver and primary hepatocytes. Zaja R, Munić V, Smital T. Mar Environ Res. 2008; 66(1):77-9. http://www.ncbi.nlm.nih.gov/pubmed/18381223
Modulation of neutrophil and inflammation markers in chronic obstructive pulmonary disease by short-term azithromycin treatment. Parnham MJ, Culić O, Eraković V, Munić V, Popović-Grle S, Barisić K, Bosnar M, Brajsa K, Cepelak I, Cuzić S, Glojnarić I, Manojlović Z, Novak-Mircetić R, Oresković K, Pavicić-Beljak V, Radosević S, Sucić M. Eur J Pharmacol. 2005; 517(1-2):132-43. http://www.ncbi.nlm.nih.gov/pubmed/15964564
Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin, and cethromycin. Bosnar M, Kelnerić Z, Munić V, Eraković V, Parnham MJ. Antimicrob Agents Chemother. 2005; 49(6):2372-7. http://www.ncbi.nlm.nih.gov/pubmed/15917536
Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Culić O, Eraković V, Cepelak I, Barisić K, Brajsa K, Ferencić Z, Galović R, Glojnarić I, Manojlović Z, Munić V, Novak-Mircetić R, Pavicić-Beljak V, Sucić M, Veljaca M, Zanić-Grubisić T, Parnham MJ. Eur J Pharmacol. 2002; 450(3):277-289. http://www.ncbi.nlm.nih.gov/pubmed/12208321
The link between met-enkephalin-induced down-regulation of APN activity and the release of superoxide anion. Marotti T, Balog T, Munić V, Sobocanec S, Abramić M. Neuropeptides. 2000; 34(2):121-8. http://www.ncbi.nlm.nih.gov/pubmed/10985929
Drug Discovery & Development – An Industrial Perspective, Drug and Chemical Target Identification, Pharmacological and Toxicological Experimental Methods