Archives: Projekti

IMI projekti

Analysis of Butyrylcholinesterase Interactions with Novel Inhibitors and Reactivators – AnalyseBChE

3 Oct 2018 – 2 Oct 2022

PROJECT ABSTRACT
The inhibition of the enzyme butyrylcholinesterase (BChE) in human tissues by binding of compounds to its active site serine is important for the detoxification and scavenging of xenobiotics such as organophosphates (OP) as well as for the metabolism of pro-drugs and drugs such as the carbamate bambuterol and the phenothiazine ethopropazine. Despite of the importance of BChE, its kinetic reactions were investigated mostly as comparative studies on the related enzyme acetylcholinesterase (AChE), which has a vital function in cholinergic neurotransmission. Moreover, reactivators of inhibited BChE, as well as drugs for the treatment of neurodegenerative diseases were empirically synthesized before the BChE crystal structure was resolved. Due to specific structural requirements, its binding affinity, inhibition and reactivation rates have not been rigorously investigated. It is known from our recent analyses that reactivation rates are influenced by experimental design and reactivation assays need to account for side reactions – oximolysis, reversible inhibition, and adequate dilution in Ellman reaction in order to effectively quench the reactivation reaction. Therefore, this project utilizes known and new compounds to gain a better understanding of the mechanistic basis of cholinesterase family interactions and their limitations. The biochemical mechanism of enzyme interactions will be comprehensively studied on a molecular level with in silico, in vitro, and ex vivo methods. Kinetic constants of the studied interactions will be determined based on known kinetic models, while in need of unusual regression analysis new kinetic models will be developed. These comprehensive analyses will explain structural requirements for compounds interacting with BChE and gain a platform for synthesis of reactivators of phosphylated BChE and potentially active drugs in disorders that involve BChE inhibition. Many of the findings that should arise from this project will impact the mechanisms of hydrolytic catalysis, extending beyond the field of cholinesterases.

SELECT PUBLICATIONS

  1. T. Zorbaz, P. Mišetić, N. Probst, S. Žunec, A. Zandona, G. Mendaš, V. Micek, N. Maček Hrvat, M. Katalinić, A. Braïki, L. Jean, P.-Y. Renard,V. Gabelica Marković, Z. Kovarik. Pharmacokinetic evaluation of brain penetrating morpholine-3-hydroxy-2-pyridine oxime as an antidote for nerve agent poisoning. ACS Chemical Neuroscience (2020) [IF=3.861, Q1].
  2. I. Šagud, N. Maček Hrvat, A. Grgičević, T. Čadež, J. Hodak, M. Dragojević, K. Lasić, Z. Kovarik, I.Škorić. Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives. Journal of Enzyme Inhibition and Medicinal Chemistry (2020) [IF=4.027, Q1].
  3. N. Macek Hrvat, J. Kalisiak, G. Šinko, Z. Radić, K. B. Sharpless, P. Taylor, Z. Kovarik. Evaluation of high-affinity phenyltetrahydroisoquinoline aldoximes, linked through anti-triazoles, as reactivators of phosphylated cholinesterases. Toxicology Letters (2020) [IF=3,499, Q2].
  4. T. Zorbaz, D. Malinak, K. Kuca, K. Musilek, Z. Kovarik. Butyrylcholinesterase inhibited by nerve agents is efficiently reactivated with chlorinated pyridinium oximes. Chemico-Biological Interactions (2019) [IF=3.407, Q2].
  5. A. Bosak, D. M. Opsenica, G. Šinko, M. Zlatar, Z. Kovarik. Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase. Chemico-Biological Interactions. [IF=3.407, Q2].
  6. Z. Kovarik, N. Maček Hrvat, J. Kalisiak, M. Katalinić,R. K. Sit, T. Zorbaz, Z. Radić, V. V. Fokin, K. B. Sharpless, P. Taylor. Counteracting tabun inhibition by reactivation by pyridinium aldoximes that interact with active center gorge mutants of acetylcholinesterase. Toxicology and Applied Pharmacology. [IF=3,585; Q1].

OTHER PUBLICATIONS

Available at: https://pubmed.ncbi.nlm.nih.gov/?term=Kovarik+Z&sort=date

PUBLIC/INVITED LECTURES

  1. Tamara Zorbaz, David Malinak, Tereza Hofmanova, Nikola Maraković, Suzana Žunec, Nikolina Maček Hrvat, Rudolf Andrys, Miroslav Psotka, Antonio Zandona, Jana Svobodova, Lukas Prchal Sanja Fingler, Maja Katalinić, Zrinka Kovarik, Kamil Musilek. Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents. European Journal of Medicinal Chemistry, 238 (2022) 114377.
  2. Tena Čadež, Dora Kolić, Goran Šinko, Zrinka Kovarik. Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase. Scientific Reports, 11 (2021) 21486.
  3. T. Zorbaz: Pharmacodynamic and pharmacokinetic evaluation of morpholine-3-hydroxy-2-pyridine oxime, centrally active antidote for nerve agent poisoning. HDBMB2019 Congress “Crossroads in Life Sciences”, Lovran, Croatia, 2019.
  4. Z. Kovarik: Nerve agent bioscavengers based on an efficient oxime-assisted reactivation of cholinesterases. 3rd International Conference CBRNE Research and Innovation, Nantes, France, 2019.
  5. Z. Kovarik: Novel oximes in counteracting organophosphates exposure. The 17th Medical Chemical Defense Conference “Chemical Warfare Agents – old problems and new challenges”, Munchen, Germany, 2019.
  6. T. Zorbaz: Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima, IMROH, 3 Dec 2018.
  7. A. Matošević: Synthesis of biscarbamates as potential selective inhibitors of butyrylcholinesterase. 2nd Mini-symposium of Medicinal and Pharmaceutical Chemistry, Young Medicinal Chemist`s Meeting. 6 Nov 2018

AWARDS

  1. Z. Kovarik: Annual Award for the Outstanding Contribution to the Molecular Life Sciences, Croatian Society of Biochemistry and Molecular Biology (HDBMB), 2018.
  2. Z. Kovarik: Annual Award for Science, natural sciences; Ministry of Science and Education, Croatia, 2018. (PDF)
  3. Z. Kovarik: Panel Excellence Award, NATO, Science and Technology Organization.
  4. T. Zorbaz: Poster Award at the Congress of the Croatian Society of Biochemistry and Molecular Biology HDBMB2019 „Crossroads in Life Sciences“, Lovran, Croatia, 2019.
  • Panel Excellence Award from The North Atlantic Treaty Organization and Annual Award from the Croatian Society of Biochemistry and Molecular Biology

  • Poster Award at the Croatian Society of Biochemistry and Molecular Biology Congress „Crossroads in Life Sciences“, Lovran, Croatia (25-28 Sep 2019)

 

Persistent organic pollutants – estimate of effects on the environment and the stability of human genetic material

  • Project funded by the Institute – institutional funding of research, 2018-2021

Participants:

Biochemistry and Organic Analytical Chemistry Unit, IMI

Mutagenesis Unit, IMI

Department of Ecology, Agronomy and Aquaculture of the University of Zadar

  • Bosiljka Mustać

Institute of Physics Belgrade, National Institute of the Republic of Serbia

 

Persistent organochlorine compounds in human milk and their potential effect on the level of primary DNA damage in human cells

  • Ministry of Science and Education, Croatian-Serbian bilateral cooperation, 2019-2022

Head from the Serbian partner institution

Participating researchers (IMI)

Participant from the University of Zadar

  • Marijana Matek Sarić, Department of Health Studies, University of Zadar

Partipicants from the Serbian partner institution

  • Aleksandar Popović, Department of Applied Chemistry Faculty of Chemistry of the University of Belgrade
  • Andreja Stojić, Institute of Physics Belgrade, National Institute of the Republic of Serbia
  • Tijana Miličević, Institute of Physics Belgrade, National Institute of the Republic of Serbia
  • Mirjana Perišić, Institute of Physics Belgrade, National Institute of the Republic of Serbia

 

Science-Based Risk Governance of Nanotechnology (RISKGONE)

Partners: 22 partners, 15 EU countries, USA and Iran

Web: https://riskgone.wp.nilu.no/

Duration: 2019-2023

Project coordinator: NILU, Norsk institutt for luftforskning, Kjeller, Norway

  • Coordinator: Prof Maria Dusinska
  • Deputy Coordinator: Dr. Tommaso Serchi
  • Project manager: Dr. Eleonora Marta Longhin

The RiskGONE project aims to establish a pan-European nano-technology risk governance council equipped with a solid framework for risk assessment and risk management procedures for consistent governance of engineered nanomaterials.

WHY RiskGONE?

Engineered nanomaterials are used in a wide range of products providing novel or improved functions and a ground-braking innovation potential thanks to their unprecedented physico-chemical features. However, there is still limited knowledge about the risks connected to the widespread use of nanomaterials. Potential risks include human and environmental health. Their understanding by all stakeholders (including general public, academia, regulators, civil society and companies) is pivotal for the correct governance of this technology. This calls for a flexible and robust public policy framework that can balance between uncertainty, benefits, hazards and risks.
Such framework must be based on scientific evidence supporting a clear understanding of risks, their assessment and management within wider societal considerations.

OUR OBJECTIVES

  • Establish a science-based nanomaterials safety governance body, in the form of a pan-European transparent, science- based and self-sustained Risk Governance Council, representing EU Member States and public authorities, scientific experts, civil society and industry.
  • Provide transparent and understandable risk-assessment and decision-making tools based on a Cloud Platform.
  • Develop a modular risk governance decision-making framework addressing different aspects of governance (such as social and economic impact, health risk, etc.).
  • Produce nano-specific draft guidance documents to support risk governance of nanomaterials.
  • Allow for smooth communication between stakeholders and civil society for what concerns governance of nanomaterials.

PROJECT STRUCTURE & PARTNERSHIPS

The project’s activities are balanced between experimental and theoretical work. RiskGONE will focus on:

  • Risk governance framework and council
  • Risk-benefit assessment
  • Characterisation in vitro dosimetry and environmental fate
  • Human hazard assessment
  • Eco-toxicological hazard assessment
  • Ethical issues

RiskGONE actively contributes to the activities of the Nano Safety Cluster.
RiskGONE is also part of a cluster of H2020 projects addressing specific support tools to better predict human health and environmental impacts of nanomaterials, as well as to guide the decision-making process, and the more holistic safety governance of nanomaterials.

 

Cancer Nanomedicine – from the bench to the bedside (Nano2Clinic)

Homepage: https://www.nano2clinic.eu/

Duration: 2018-2022

  • Head: Prof Barbara Klajnert-Maculewicz

Summary
Finding efficient cancer therapies is an urgent and still unresolved problem. In the fight against this disease, scientists are devoting tremendous efforts towards the utilisation of nanomedicines. Nanotherapeutics exhibit major benefits with respect to unmodified drugs, including improved half-life, more efficient tumour targeting, and reduced side effects. However, only a few nanotherapeutics have reached commercial level, most still being in the investigational phase. Accordingly, this Action aims to develop and strengthen industry-academia relations with the ultimate goal: of fostering the clinical translation of nanomedicine from bench to bedside. This will be achieved by creating the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, pre-clinical testing of efficacy, pharmacokinetics, and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation and innovative solutions, the Action will provide a timely instrument to rationalise and focus research efforts at the EU level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and socially-burdening human pathologies. By virtue of its quality, the Action network will also generate research core teams of excellence for funding applications, patent filling, and discovery of major scientific impact. The network will also be actively devoted to raising awareness on the high potential on nanomedicine through publications in international peer-reviewed journals, and presentations at open events.

 

ENRAS – ENsuring RAdiation Safety

European Regional Development Fund

Homepage: http://ol.ijs.si/enras/?page_id=216&lang=en

Duration: 1 Oct 2018-30 Sep 2020

  • Head: Boštjan Crnić, “Jožef Stefan” Institute, Ljubljana, Slovenija
  • Head for Croatia: Branko Petrinec

Summary
The ENRAS (ENsuring RAdiation Safety) project will help develop cross-border services in the field of ensuring safety (civil protection) in cases of nuclear or radiological accidents. The shared challenge within the project is to enable harmonised and safe joint interventions in cases of such accidents. The main goal is to strengthen cross-border cooperation among subjects participating in the area of protection for the purpose of more effective rescue and intervention, increasing training and skills, and establishing the first system for joint interventions in cross-border areas.

 

Molecular mechanisms underlying the toxicity of antidotes and potential drugs – CellToxTargets

Duration: 1 Mar 2018 – 28 Feb 2023

Funding: 1,693,000.00 HRK

Summary
The project presents the new innovative approach in the field of antidote research for poisoning with organophosphates (OP), having the applications in overall drug discovery. The main goal of the project is to answer how the antidotes and drugs act on cell level and uncover the trigger mechanism leading to the side-effects or even severe effects that could occur in vivo. The specific cell-based screening will be applied to define the mechanism behind such unwanted toxicity of compounds and to aid a more efficient selection of a lead candidate for drug development. Within the proposed project, we will test several defined sets of structurally related antidotes/drugs. This will allow us to use, after obtaining sufficient cell-based data, a structure-activity approach to define the possible structural features of tested compounds triggering certain effects. Thus, features like these could be modified in the early lead compound structure refinement process without performing any in vivo studies. More efficient feedback will be given to studies designing drugs and aid the challenging development of an effective treatment primarily for OP poisoning. We also expect to identify new possible targets on the cell level and explore their therapeutic potential. One such target in treating exposure to OPs, NRE, was identified in our earlier research. Therefore, we will study the role and function of this unexplored enzyme and answer whether it could be considered as a potential target in OP treatment or even has an indication for being a target molecule in treatment of other diseases. Our findings should open up a new perspective with potential impact beyond the original scope. Beside the scientific part, the newly established experienced and skilled research team will stimulate a technology transfer through collaborations, continuous upgrading and improvement of methods and training in specific skills.

Research team

Implementation plan through two main project activities

  • Cell-based research for determining effects of new antidotes and drugs.

  • NRE´s role in the cell and potential to be evaluated as a new target for OP poisoning treatment.

NEWS:

Final Symposium “Cell-Based Research in Toxicology and Drug Design” of the project “Molecular mechanisms underlying the toxicity of antidotes and potential drugs – CellToxTargets”.

The Symposium „Cell–Based Research in Toxicology and Drug Design” was held at the hotel Dubrovnik in Zagreb on January 26th, 2023, with the main objective to disseminate results obtained within the project HrZZ-UIP-05-7260 CellToxTargets and to discuss them with colleagues from different field of research. Organization of the Symposium was supported by the Croatian Science Foundation (grant no. HrZZ-UIP-2017-05-7260, CellToxTargets) and by the Institute for Medical Research and Occupational Health. Also, the organization was sponsored by companies Kefo ltd., Jasika ltd. and Medic ltd.

The Symposium brought together 31 participants including experienced scientists, each expert in a specific field (from kinetics to metabolism and cell-based research), along with the PhD students and postdoctoral fellows, as well as the representatives from the industry, who all presented their recent research achievements.

The scientific programme was divided into five sessions spanning topics from new approaches in drug development, cholinesterase ligand-based drugs and biochemistry in drug-related research, giving the participants floor for fruitful discussion and opening new possibilities for collaborations and ideas for future studies.

We were very pleased that we could host eminent scientists Prof Miguel Castanho and Dr Vera Neves from the Institute of Molecular Medicine Lisbon, Portugal, Prof Pierre-Yves Renard from the Normandie Univ, UNIROUEN, Rouen, France, and Dr Jelena Krstić from the Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, Austria, delivering four inspiring lectures presenting new and interesting findings in different areas of biochemistry and molecular biology.

The Symposium has been a rewarding scientific and personal experience for us, and we would like to express our sincere thanks to all of the speakers and participants for sharing their results, and contributing to the excellence of our scientific program. We thank Croatian Science Foundation and the Institute for Medical Research and Occupational Health for their support, and the sponsors whose contribution was invaluable to the overall success of the Symposium.

Select publications

Book chapters:

  1. Marš, Tomaž; Miš, Katarina; Katalinić, Maja; Pegan, Katarina; Grubič, Zoran; Pirkmajer, Sergej The effects of organophosphates in the early stages of human skeletal muscle regeneration. Handbook of Toxicology of Chemical Warfare Agents (Third Edition), Gupta, Ramesh C. (ed.). London: Academic Press, 2020. pp 829-841.

Journal articles:

  1. Zandona, Antonio; Zorbaz, Tamara; Miš, Katarina; Pirkmajer, Sergej; Katalinić, Maja. Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells. Arhiv za higijenu rada i toksikologiju, 73 (2022), 277-284. . [IF=2.078, Q4]
  2. Gašo Sokač, Dajana; Zandona, Antonio; Roca, Sunčica; Vikić-Topić, Dražen; Lihtar, Gabriela; Maraković, Nikola; Bušić, Valentina; Kovarik, Zrinka; Katalinić, Maja. Potential of vitamin B6 dioxime analogues to act as cholinesterase ligands. International journal of molecular sciences, 23 (2022), 21; 13388, 18 doi:10.3390/ijms232113388. [IF=6.208, Q1]
  3. Zorbaz, Tamara; Malinak, David; Hofmanova, Tereza; Maraković, Nikola; Žunec, Suzana; Maček Hrvat, Nikolina; Andrys, Rudolf; Psotka, Miroslav; Zandona, Antonio; Svobodova, Jana et al. Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents. European journal of medicinal chemistry, 238 (2022), 114377, 16 doi:10.1016/j.ejmech.2022.114377. [IF=6.514, Q1]
  4. Matošević, Ana; Radman Kastelic, Andreja; Mikelić, Ana; Zandona, Antonio; Katalinić, Maja; Primožič, Ines; Bosak, Anita; Hrenar, Tomica. Quinuclidine-Based Carbamates as Potential CNS Active Compounds. Pharmaceutics, 13 (2021), 3; 420, 15 doi:10.3390/pharmaceutics13030420. [IF=5.215, Q1]
  5. Zandona, Antonio; Jagić, Karla; Dvoršćak, Marija; Madunić, Josip; Klinčić, Darija; Katalinić, Maja. PBDEs found in house dust impact human lung epithelial cell homeostasis. Toxics, 10 (2022), 97-112 doi:10.3390/toxics10020097. [IF=4.146, Q2]
  6. Zandona, Antonio; Maraković, Nikola; Mišetić, Petra; Madunić, Josip; Miš, Katarina; Padovan, Jasna; Pirkmajer, Sergej; Katalinić, Maja. Activation of (un)regulated cell death as a new perspective for bispyridinium and imidazolium oximes. Archives of toxicology, 95 (2021), 2737-2754 doi:10.1007/s00204-021-03098-w. [IF=5.153, Q1]
  7. Jurič, Andreja; Zandona, Antonio; Tariba Lovaković, Blanka; Rašić, Dubravka; Pizent, Alica; Kozina, Goran; Katalinić, Maja; Lucić Vrdoljak, Ana; Brčić Karačonji, Irena. Cytotoxic, genotoxic, and oxidative stress-related effects of lysergic acid diethylamide (LSD) and phencyclidine (PCP) in the human neuroblastoma SH- SY5Y cell line. Arhiv za higijenu rada i toksikologiju, 72 (2021), 4; 333-342. [IF=1.948, Q3]
  8. Matošević, Ana; Radman Kastelic, Andreja; Mikelić, Ana; Zandona, Antonio; Katalinić, Maja; Primožič, Ines; Bosak, Anita; Hrenar, Tomica. Quinuclidine-Based Carbamates as Potential CNS Active Compounds. Pharmaceutics, 13 (2021), 3; 420, 15 doi:10.3390/pharmaceutics13030420. [IF=6.321, Q1]
  9. Zandona, Antonio; Lihtar, Gabriela; Maraković, Nikola; Miš, Katarina; Bušić, Valentina; Gašo-Sokač, Dajana; Pirkmajer, Sergej; Katalinić, Maja. Vitamin B3-based biologically active compounds as inhibitors of human cholinesterases. International Journal of Molecular Sciences (2020). doi:10.3390/ijms21218088 [IF=4.556, Q1]
  10. Zandona, Antonio; Katalinić Maja. Nicotinic acetylcholine receptors: Diversity and physiological importance for neurodegenerative disorders and development of organophosphate  antidotes. Periodicum Biologorum (2020). U postupku objavljivanja [IF=0.883, Q3]
  11. Zandona, Antonio; Katalinić, Maja; Šinko, Goran; Radman Kastelic, Andreja; Primožič, Ines; Kovarik, Zrinka. Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers. Archives of toxicology (2020). doi:10.1007/s00204-020-02811-5 [IF = 5.059, Q1]
  12. Klinčić, Darija; Herceg Romanić, Snježana; Katalinić, Maja; Zandona, Antonio; Čadež, Tena; Matek Sarić, Marijana; Šarić, Tomislav; Aćimov, Dejan. Persistent organic pollutants in tissues of farmed tuna from the Adriatic Sea. Marine Pollution Bulletin (2020), 158:111413, 7 doi:10.1016/j.marpolbul.2020.111413 [IF = 4.049, Q1]
  13. Zorbaz, Tamara; Mišetić, Petra; Probst, Nicolas; Žunec, Suzana; Zandona, Antonio; Mendaš, Gordana; Micek, Vedran; Maček Hrvat, Nikolina; Katalinić, Maja; Braïki, Anissa et al. Pharmacokinetic evaluation of brain penetrating morpholine-3-hydroxy-2-pyridine oxime as an antidote for nerve agent poisoning. ACS Chemical Neuroscience (2020), 11(7):1072-1084. doi:10.1021/acschemneuro.0c00032 [IF = 4.486, Q1]
  14. Zorbaz et al. Pyridinium oximes with ortho-positioned chlorine moiety exhibit improved physico- chemical properties and efficient reactivation of human acetylcholinesterase inhibited by several nerve agents. Journal of Medicinal Chemistry, (2018), 61(23):10753-10766. doi:10.1021/acs.jmedchem.8b01398 [IF = 6.253, Q1].

Other publications are available at
https://www.bib.irb.hr/pregled/projekti/HRZZ-UIP-2017-05-7260

Lectures

  1. Katalinić, Maja. Where we are going from here? Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  2. Vrhovac Madunić, Ivana. Interaction of renal and hepatic organic cation transporters (OCT) with oximes. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  3. Žunec, Suzana; Katalinić Maja. Metabolic stability as a challenge facing drug oriented research. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  4. Lulić, Ana-Marija. Characterization of lysophospholipase PNPLA7 as a potential target for drug development. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  5. Zandona, Antonio. Structure – cytotoxicity relationship of cholinesterase-based ligands Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  6. Katalinić, Maja. Molecular mechanisms underlying the toxicity of antidotes and potential drugs – HrZZ-UIP-2017-05-7260. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  7. Zandona, Antonio; Maraković, Nikola; Katalinić Maja. Oximes developed as antidotes for organophosphates present a scaffold for new research(es) candidates. Book of abstracts of 6th Mini Symposium of Section of Medicinal and Pharmaceutical Chemistry. Zagreb, 2022. str. 2-2.
  8. Žunec, Suzana; Vadlja, Donna; Zandona, Antonio; Ramić, Alma; Primožič, Ines; Katalinić, Maja. Cell response to N-alkyl quaternary quinuclidine oxime treatment. 11th International Congress of the Turkish Society of Toxicology : Abstract Book, Basran, Nursen (ur.). Antalya, 2022. str. 64-64.
  9. Maja Katalinić: Activation of (un)regulated cell death as a new perspective for oxime research. 7th Symposium Apoptosis and Neoplasms, Zagreb, 2021.
  10. Zandona, Antonio; Miš, Katarina Miš; Pirkmajer, Sergej; Katalinić, Maja. Cytotoxic effects of vitamin B3 derivatives in cultured cells. 6th Croatian Congress of Toxicology with International Participation CROTOX 2021
  11. Katalinić, Maja; Zandona, Antonio; Madunić, Josip; Vrhovac Madunić, Ivana; Miš, Katarina; Pirkmajer, Sergej. 3rd SYMPOSIUM & WORKSHOP “Skeletal muscle research – from cell to human 2019”: Neural and muscle cells in organophosphorus compound antidote research“, 26-28.05.2019. Ljubljana, Slovenia.
  12. Katalinić Maja. Molecular mechanisms underlying the toxicity of antidotes and potential drugs. Workshop: „Reactivators and Medical Countermeasures against Nerve Agents and Pesticides“, 14-16.05.2018., Zagreb, Croatia. Arhiv za higijenu rada i toksikologiju 2018; 69:A32-A43.

Science Popularization

  1. Zandona Antonio, (Bio)chemistry of antidotes, 30.1.2023., učenici 3. i 4. razreda gimnazije Srednja Škola Pakrac, Pakrac.

2. Lulić Ana-Marija i Zandona Antonio, Dan karijera na PMF-u, WorkIn’ Science – WISe, 03.11.20121., PMF, Zagreb., http://wise.pmf.unizg.hr/

3. Katalinić Maja, Challenges in antidote research in organophosphorus poisoning (warfare agents), Professional meeting AZOO, prezentation, 8.7.2020. Zagreb, Croatia.

4. Katalinić Maja, From phosphoric acid to warfare agents, IMIMobil 2019, presentation, IMI Open Doors 2019, 22.3.2018. Karlovac, Croatia. https://www.imi.hr/hr/2019/04/04/imimobil-je-krenuo/

5. Ivana Vrhovac Madunić, Molecular toxicology on IMROH, presentation, University Career Week at J. J. Strossmayer Department of Biology, University of Osijek 14.05.2019. Osijek, Croatia. https://www.imi.hr/hr/2019/20/05/imi-na-sveucilisnom-tjednu-karijera/#!

6. Katalinić Maja, Sarin, VX, Novichok – why are they still a threat? II. Vocational Teacher Days, 22-24.10.2018. Šibenik, Croatia. https://danistrukovnihnastavnika2018.weebly.com/

7. Zandona Antonio, Mechanism of toxicity of xenobiotics and potential drugs, WorkIn’ Science – WISe, 07.11.2018., Faculty of science Zagreb, Croatia http://wise.pmf.unizg.hr/

8. Zandona Antonio, Molecular mechanism of toxicity of antidotes and potential drugs, Youth Science Talks, IMROH Mini Symposium, 21.11.2018., Zagreb, Croatia, https://www.imi.hr/hr/2018/13/11/znanstveni-razgovori-mladih/

9- Zandona Antonio, Katalinić Maja, Molecular mechanism of toxicity of antidotes and potential drugs, Guest appearance in a science show “Treći element” on HTV3, 12.12.2018. in episode called “Pazi otrov!” https://www.youtube.com/watch?v=QcRg3gCQpG4

10. Zandona Antonio, Katalinić Maja, Vrhovac Madunić Ivana, Travel by stations, Scientific Cookies, presentation, Open Doors IMI 2018, 27. and 28.3.2018. https://www.imi.hr/dov2018/program/

Awards

  1. Lulić Ana-Marija: Fellowship to attend on Congress of Croatian Society of Biochemistry and Molecular Biology, Brela, Croatia (2022)
  2. Zandona Antonio: FEBS Bursary for the 25th IUBMB Congress, the 46th FEBS Congress and the 15th PABMB Congress, Lisbon, Portugal (2022)
  3. Zandona Antonio: Fellowship to attend onthe 6th Croatian Congress of Toxicology with International Participation, Rabac, Hrvatska (2021)
  4. Zandona Antonio: IMI Award for at least 3 original scientific papers on which the employee is the first author, and which were published in the previous calendar year in journals indexed in the Web of Science database, Zagreb (2020)
  5. Zandona Antonio: EMBO Short Term Fellowship, Institute for Molecular Medicine, Lisbon, Portugal (2020)
  6. Zandona Antonio: Best Poster Award on „Symposium of PhD students of the Faculty of Science 2020.“, Zagreb, Hrvatska (28.2.2020.)
  7. Zandona Antonio: Poster Award on Congress of Croatian Society of Biochemistry and Molecular Biology, Lovran, Hrvatska (25.-28.9.2019.)
  8. Zandona Antonio: 2nd Prize for the Communication Challenge presentation on FEBS Network in the callange 19th FEBS Young Scientists’ Forum (YSF), Krakow, Poland (3.-6.7.2019.)
  9. Zandona Antonio: Fellowship to attend on 19thFEBS Young Scientists’ Forum (YSF) and 44nd FEBS Congress “From molecules to cells and back”, Krakow, Poland (3.-11.7.2019.)
  10. Zandona Antonio: Fellowship for attend on 13th International Meeting on Cholinesterases and the 7th International Conference on Paraoxonases, Hradec Králové, Czech Republic (9.-14.09.2018.)

Doctoral thesis

  1. Antonio Zandona: Structure – cytotoxicity relationship of oxime reactivators of phosphylated acetylcholinesterase. Faculty of Science, Zagreb (14.6.2021.)

Graduation thesis

  1. Gabriela Lihtar: Effect of nicotinamide structure change on cholinesterase inhibition and cytotoxicity. Faculty of Science, Zagreb (28.2.2020.)
  2. Dunja Kureljak: Cytotoxic effect of imidazole compounds on prostate cancer cells. Faculty of Science, Zagreb (29.9.2021.)

 Poster Award on Congress of Croatian Society of Biochemistry and Molecular Biology, Lovran, Croatia (25.-28.9.2019.)

A brief research presentation on 19th FEBS Young Scientists’ Forumu and attendance on 44nd FEBS Congress “From molecules to cells and back”, Krakow, Poland (3.-11.7.2019.)

Additional activities during the project

Katalinić Maja:
Secretary of Croatian Society of Biochemistry and Molecular Biology, HDBMB (2017-)
Member of the Committee on Science and Society, HDBMB (2017-)
Member of the Organisation Committee FEBS2020, Ljubljana, Slovenia
Chair FEBS Young Scientits’ Forum 2020, Lovran, Croatia

Lulić Ana-Marija:
Training at Institute for Pathophysiology, MF, Ljubljana, Slovenia (2021)
Training at Institute for Pathophysiology, MF, Ljubljana, Slovenia (2022)

Zandona Antonio:
Training at Institute for Molecular Medicine, Lisabon, Portugal (2021)
Training at Institute for Pathophysiology, MF, Ljubljana, Slovenia (2019)
Training at Institute for Anatomy, MF, Ljubljana, Slovenia (2019)
Representative of Assistants to the Scientific Council of the Institute (2018-2020)

Madunić Josip:
Postdoc at UCONN, Connecticut, USA (2019-2020)

Vrhovac Madunić Ivana:
Postdoc at UCONN, Connecticut, USA (2019-2020)
Training at Nacional Institute for Biology, Ljubljana, Slovenija (2022.)

 

Development, validation and application of analytical methods for PBDE determination – DeValApp

Duration: 1 Oct 2018 – 30 Sep 2023

Funding: 1,424,500.00 HRK

Summary
The purpose of the proposed project is to develop and validate analytical methods for determining specific polybrominated diphenyl ether (PBDE) congeners in complex samples of house dust and human milk. PBDEs are widespread in the environment, they accumulate in the food chain and enter human organism where they can exert a number of negative impacts. House dust is recognized as an important source of exposure to PBDEs because of their intensive use as flame retardants in objects widely used in households (furniture, textiles, electrical and electronic devices). On the other hand, human milk is a reliable bioindicator of people’s exposure to these compounds. The development of analytical methods will involve the examination and comparison of various types of extraction techniques, whereby along with the solid phase extraction and ultrasonic extraction, particular emphasis will be put on the application of an unused technique, microwave extraction. Techniques and conditions for the cleanup of the extract from the interfering compounds and matrix components before the final instrument analysis will be investigated. The sensitivity and selectivity of gas-chromatographic determination of PBDEs by electron capture detectors, mass spectrometer and coupled tandem mass spectrometry will be determined. Validated methods will be confirmed by analysis of certified reference samples. During the project, house dust will be sampled in the homes of milk donors. The optimized and validated analytical methods will be used for PBDE analysis in collected samples. Results on PBDE levels and distribution will be the first of a kind in Croatia and will be used to assess the importance of PBDE intake in the body by inhaling house dust and exposure of general population to PBDEs. From all of the above mentioned, it will be concluded whether there is a potential risk to human health with a special emphasis on sensitive population groups of nursing mothers, infants and young children.

Research team

Darija Klinčić, PhD
Senior Research Associate
Principal Investigator

Marija Dvoršćak, PhD
Scientific Associate

Karla Jagić, PhD
Senior Research Assistant (PostDoc)

Other associates: Andreja Jurič, PhD, Senior Research Assistant (PostDoc)

Short Symposium entitled “Indoor contaminants” held to conclude the project UIP-2017-05-6713 “Development, validation and application of analytical methods for PBDE determination (DeValApp)”

On September 8th, 2023, a Short Symposium entitled “Indoor contaminants” was held at the Institute for Medical Research and Occupational Health in Zagreb. The Symposium’s main goal was to share and discuss findings from the project “Development, validation and application of analytical methods for PBDE determination (DeValApp)“ (HrZZ-UIP-2017-05-6713). The project started in 2018 as part of the program “Installation Research Projects” financed by the Croatian Science Foundation, and with whose support and support of the Institute for Medical Research and Occupational Medicine, the symposium was organized.

The scientific programme of this Short Symposium was divided into two sessions where the outcomes of the five-year research project were presented. These findings included concepts developed during project implementation that covered novel research areas and opened up opportunities for collaboration with other research groups. Also, participants had the opportunity for a fruitful discussion which opened up new possibilities for further investigations into various environmental and human samples. The presented results show the success of this project, but its greatest value is the formed research group and the scientific foundation that has been created, which enables further research to contribute to general knowledge about pollutants in our environment and their impact on human health.

A total of 50 participants attended the Symposium, and the DeValApp team hosted eminent scientists Dr Jelena Živančev and Dr Nataša Đurišić-Mladenović from the University of Novi Sad, Faculty of Technology, Novi Sad, Serbia, who delivered inspiring lectures presenting Horizon Europe Twinning project (TwiNSol-CECs) as well as their experience in areas of environmental protection and monitoring different classes of contaminants.

The Short Symposium “Indoor contaminants” was an enriching scientific experience for us. We express our gratitude to all of the presenters and participants for sharing their research, thereby improving the excellence of the Short Symposium. We also express our gratitude to the Croatian Science Foundation and the Institute for Medical Research and Occupational Health for their support that was crucial to the overall success of our Short Symposium.

Implementation plan

Publications

  1. Kljaković-Gašpić, M. Dvoršćak, T. Orct, A. Sekovanić, D. Klinčić, K. Jagić, D. Šebešćen, E. Klasiček, D. Zanellar, Metal(loid)s and persistent organic pollutants in yellow European eel from the Raša River, Croatia, Marine Pollution Bulletin (2023) doi:10.1016/j.marpolbul.2022.114527. https://www.sciencedirect.com/science/article/abs/pii/S0025326X22012097?via%3Dihub (LINK)
  2. Jakovljević, M. Dvoršćak, K. Jagić, D. Klinčić, Polycyclic Aromatic Hydrocarbons in Indoor Dust in Croatia: Levels, Sources, and Human Health Risks, International Journal of Environmental Research and Public Health (2022) doi:10.3390/ijerph191911848. https://www.mdpi.com/1660-4601/19/19/11848 (LINK)
  3. Dvoršćak, I. Jakovljević, K. Jagić, B. Tariba Lovaković, D. Klinčić, Polybrominated diphenyl ethers and polycyclic aromatic hydrocarbons in dust from different indoor environments in Zagreb, Croatia: Levels and human exposure assessment, Indoor Air (2022) doi:10.1111/ina.13145. https://onlinelibrary.wiley.com/doi/10.1111/ina.13145 (LINK)
  4. Tariba Lovaković, K. Jagić, M. Dvoršćak, D. Klinčić, Trace elements in indoor dust—Children’s health risk considering overall daily exposure, Indoor Air (2022) doi:10.1111/ina.13104.      https://onlinelibrary.wiley.com/doi/full/10.1111/ina.13104 (LINK)
  5. Dvoršćak, K. Jagić, L. Besednik, I. Šimić, D. Klinčić, First application of microwave-assisted extraction in the analysis of polybrominated diphenyl ethers in human milk, Microchemical Journal (2022) doi:10.1016/j.microc.2022.107447. https://www.sciencedirect.com/science/article/abs/pii/S0026265X22002752?via%3Dihub (LINK)
  6. Zandona Antonio, K. Jagić Karla, M. Dvoršćak Marija, J. Madunić Josip, D. Klinčić Darija, M. Katalinić Maja PBDEs found in house dust impact human lung epithelial cell homeostasis, Toxics (2022) doi:10.3390/toxics10020097. https://www.mdpi.com/2305-6304/10/2/97 (LINK)
  7. Jagić, M. Dvoršćak, D. Klinčić, Analysis of brominated flame retardants in the aquatic environment: a review, Arhiv za higijenu rada i toksikologiju (2021) doi:10.2478/aiht-2021-72-3576. https://sciendo.com/article/10.2478/aiht-2021-72-3576 (LINK)
  8. Klinčić, B. Tariba Lovaković, K. Jagić, M. Dvoršćak, Polybrominated diphenyl ethers and the multi- element profile of house dust in Croatia: Indoor sources, influencing factors of their accumulation and health risk assessment for humans, Science of the Total Environment (2021) doi:10.1016/j.scitotenv.2021.149430. https://www.sciencedirect.com/science/article/abs/pii/S0048969721045046?via%3Dihub (LINK)
  9. Jagić, M. Dvoršćak, A. Jurič, T. Safner, D. Klinčić, Optimization and validation of two-step method for determination of polybrominated diphenyl ethers in Croatian house dust samples, Analytical Methods (2021) doi:10.1039/D1AY00695A. https://pubs.rsc.org/en/content/articlelanding/2021/AY/D1AY00695A (LINK)
  10. Jagić, M. Dvoršćak, A. Jurič, T. Safner, D. Klinčić, Preliminary results on polybrominated diphenyl ether contamination status in Croatian households and insights into children’s exposure, Environmental Toxicology and Pharmacology (2021) doi:10.1016/j.etap.2021.103603. https://www.sciencedirect.com/science/article/abs/pii/S1382668921000223?via%3Dihub (LINK)
  11. Klinčić, M. Dvoršćak, K. Jagić, G. Mendaš, S. Herceg Romanić, Levels and distribution of polybrominated diphenyl ethers in humans and environmental compartments: a comprehensive review of the last five years of research, Environmental Science and Pollution Research (2020) doi:10.1007/s11356-020-07598-7. https://link.springer.com/article/10.1007/s11356-020-07598-7 (LINK)

Presentations

  • Sanja Stipičević, Persistent Organic Pollutants (POPs), ToxLearn4EU Summer School, IMROH, Zagreb, 12.07.2023.
  • Sanja Stipičević, Human Exposure to Persistent Organic Pollutants from the Environment, Career Week, J. J. Strossmayer University of Osijek, 16.05.2023.
  • Karla Jagić, Flame Retardants: Two Sides of the Medal, Incubator of Ideas @IMI, 27.04.2023.
  • Marija Dvoršćak, Unwelcome guests in house dust – polybrominated diphenyl ethers, Elementary school Djurdjevac, 21.05.2021.

  • Darija Klinčić, Presentation of scientific-research work within the DeValApp project, IMI, 07.05.2021.
  • Marija Dvoršćak, Polybrominated diphenyl ethers – how we are exposed to them, IMI, 02.12.2020.
  • Marija Dvoršćak, Side by side with polybrominated diphenyl ethers, Professional Meeting of Biology Teachers AZOO, 08.07.2020., webinar
  • Marija Dvoršćak, Persistent organic pollutants – from application to side effects, County professional meeting for biology teachers in specialized schools of Zagreb, 02.03.2020., Craft School for Personal Services, Zagreb

  • Marija Dvoršćak, Persistent organic pollutants in environment and humans (organochlorine and organobromine compounds), presentation, part of classes held at IMROH 2019 for students of the Medical School Vrapče, subject Hygiene and Preventive Medicine (21.10.-26.11.2019.)
  • Darija Klinčić, Brominated flame retardants and their impact on human health, Experiences and news of the health profession for the purpose of improving and modernizing teaching (IMI, ASOO), 22.11.2018., IMROH, Zagreb
  • Marija Dvoršćak, Coexistence with the brominated compounds, Scientific Discussions of Young Scientists, 21.11.2018., IMROH, Zagreb

Participation at scientific meetings

  • Karla Jagić:  43rd International Symposium on Halogented Persistent Organic Pollutants (Dioxin 2023), Maastricht, Netherlands, poster presentation, 10.-14.09.2023.

  • Marija Dvoršćak; Darija Klinčić, Karla Jagić: 13th International Congress of the Serbian Society of Toxicology and 1st TOXSEE Regional Conference – Present and Future of toxicology: challenges and opportunities, Belgrade, Serbia, three poster presentations, 10. -13.05.2023.
  • Karla Jagić: 22nd European Meeting on Environmental Chemistry (EMEC22), Ljubljana, Slovenia, poster presentation, 05.-08.12.2022.
  • Darija Klinčić, Marija Dvoršćak: 11th International Congress of the Turkish Society of Toxicology, Kemer, Turkey, two poster presentations, 02.-05.11.2022.

  • Karla Jagić: 10th International Symposium on Flame Retardants (BFR2022), Athens, Greece, poster presentation, 04.-07.09.2022.

  • Ivana Jakovljević: XIV. Meeting of Young Chemical Engineers, Zagreb, Croatia, poster presentation, 24.-25.02.2022.
  • Karla Jagić:  21st European Meeting on Environmental Chemistry (EMEC21), Novi Sad, Serbia, oral presentation, 30.11.-03.12.2021.

  • Marija Dvoršćak: 41st International Symposium on Halogenated Persistent Organic Pollutants (DIOXIN2021), virtual congress, poster presentation, 08.-11.11.2021.
  • Karla Jagić: 27th Croatian Meeting of Chemists and Chemical Engineers (HSKIKI 2021), Veli Lošinj, Croatia, poster presentation, 05.-08.10.2021.

  • Marija Dvoršćak: 6th Croatian Congress of Toxicology (CROTOX 2021), Rabac, Croatia, poster presentation, 03.-06.10.2021.

  • Karla Jagić: 6th Croatian Congress of Toxicology (CROTOX 2021), Rabac, Croatia, oral presentation, 03.-06.10.2021.

  • Karla Jagić: 56th Congress of the European Societies of Toxicology (EURUTOX 2021), virtual congress, poster presentation, 27.09.-01.10.2
  • Karla Jagić: Air Protection 2021, Medulin, Croatia, poster presentation, 15.-17.09.2021.

  • Karla Jagić: 5th Faculty of Science PhD student Symposium, Zagreb, Hrvatska, flash and poster presentation, 24.-25.04.2021

  • Karla Jagić: 18th Ružička Days, Vukovar, Croatia, 16.-18.09.2020.

  • Karla Jagić: 4th Symposium of PhD students of the Faculty of Science 2020, Zagreb, Croatia, 28.02.2020.

  • Karla Jagić: XIII Meeting of Young Chemical Engineers, Zagreb, Croatia, 20.-21.02.2020.

Science Popularization

  • Darija Klinčić, Marija Dvoršćak, Karla Jagić: workshop „The fun side of chemistry“ as part of IMImobil, 01.06.2023., Elementary school Pavlek Miškina, Zagreb

  • Darija Klinčić, Marija Dvoršćak, Karla Jagić: workshop “Chemistry is magic, but real” and “Colorful chemistry” as part of IMImobil, 26.04.2021., Elementary school Ivana Brlić-Mažuranić, Prigorje Brdovečko

  • Darija Klinčić, Development, validation and application of analytical methods for PBDE determination,  WorkIn’ Science – WISe, 07.11.2018., Faculty of Science, Zagreb, http://wise.pmf.unizg.hr/

List of publications:

https://www.bib.irb.hr/pretraga/?operators=and|6605|text|project-id

Additional activities during the project

  • Karla Jagić: course „The basics of working in WordPress“, online, 21.11.-23.11.2022.
  • Karla Jagić, Marija Dvoršćak: „Risk assessment of regulated products (EFSA)“, online, 28.09.-30.09.2022.
  • Karla Jagić: online course „Health risk assessment on endocrine disruptors“, 26.-30.09.2022.
  • Karla Jagić: seminar „Environmental chemistry towards global change (Chem2Change)“, online, 15.-16.03.2022.
  • Marija Dvoršćak, Karla Jagić: seminar „Introduction to LC-MS“, Labtim, Zagreb, 07.02.2022.
  • Karla Jagić: scientific school „A comprehensive approach to the research of anthropogenic pressures on the environment“, online, 07.-10.12.2021.
  • Karla Jagić: summer academy – lecture series „9th BfR-Summer Academy on Risk Assessment and Risk Communication in Food Safety 2021“, online, 23.-27.08.2021.
  • Darija Klinčić, Karla Jagić: summer school “ 17th edition of RECETOX Summer School”, RECETOX, online, 21.-25.06.2021.
  • Karla Jagić: summer school “15th Summer School on Toxic Compounds in the Environment 2019”, 17.-21.06.2019., RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic

  • Karla Jagić: summer school “XIX. International Chromatography School”, 10.-11.06.2019., Faculty of Chemical Engineering and Technology, Zagreb, Croatia

Doctoral dissertation

  • Karla Jagić: Trace analysis of polybrominated diphenyl ethers in household dust and human milk for human health risk assessment, Faculty of Science, University of Zagreb, 26.10.2022.

Graduation thesis

  • Defence of Diploma thesis: Lucija Besednik, Microwave assisted extraction of polybrominated diphenyl ethers from human milk, Faculty of Science, Zagreb (18.09.2020.)

  • the preparation of Diploma thesis of Lucija Besednik, graduate student of Analytical Chemistry and Biochemstry at Faculty of Science

Student practices

  • Leader: Marija Dvoršćak – student practices held as part of undergraduate and graduate studies

Awards

  • Karla Jagić: Award of the Institute for Medical Research and Occupational Medicine for at least 3 original scientific papers on which the employee is the first author, and which were published in the previous calendar year (2021) in journals indexed in the Web of Science database
  • Darija Klinčić: Award of the Institute for Medical Research and Occupational Medicine for at least 3 original scientific papers on which the employee is the first author, and which were published in the previous calendar year (2020) in journals indexed in the Web of Science database
  • Karla Jagić: Young Scientist Award, 6th Croatian Congress of Toxicology (CROTOX 2021), Rabac, Croatia (03.-06.10.2021.)
  • Karla Jagić: Best Poster Award at „4th Symposium of PhD students of the Faculty of Science 2020.“, Zagreb, Hrvatska (28.2.2020.)

Collaboration – projects

  • 2022. – 2024. – “Meet the toxicity – live safely (MeeTox)” – Erasmus+ project of Serbian Society of Toxicology, Croatian Society of Toxicology, Faculty of Pharmacy (Serbia) and Institute for Medical Research and Occupational Health (Croatia)

  • 2022. – 2023. – “Polybrominated diphenyl ethers in the dust from public spaces – do they pose a risk to human health?”, Foundation of the Croatian Academy of Sciences and Arts (HAZU), Karla Jagić
  • 2020. – 2021. – “Development of analytical methods for the purpose of obtaining the first data on the exposure of people in Croatia to brominated compounds”, Foundation of the Croatian Academy of Sciences and Arts (HAZU), Marija Dvoršćak

PROJECT DAY (08.09.2023.)

  • Brochure

TEAM BUILDING

  • Visiting Cerovac Caves and Memorial Center „Nikola Tesla“

  • at CROTOX 2021, Rabac

  • tour de Rijeka and hiking on Učka