1. APS8, a polymeric alkylpyridinium salt blocks [alpha]7 nAChR and induces apoptosis in non-small cell lung carcinomaAna Zovko, Kristina Viktorsson, Rolf Lewensohn, Katja Kološa, Metka Filipič, Hong Xing, William R. Kem, Laura Paleari, Tom Turk, 2013, original scientific article Abstract: Naturally occurring 3-alkylpyridinium polymers (poly-APS) from the marine sponge Reniera sarai, consisting of monomers containing polar pyridinium and nonpolar alkyl chain moieties, have been demonstrated to exert a wide range of biological activities, including a selective cytotoxicity against non-small cell lung cancer (NSCLC) cells. APS8, an analog of poly-APS with defined alkyl chain length and molecular size, non-competitively inhibits α7 nicotinic acetylcholine receptors (nAChRs) at nanomolar concentrations that are too low to be acetylcholinesterase (AChE) inhibitory or generally cytotoxic. In the present study we show that APS8 inhibits NSCLC tumor cell growth and activates apoptotic pathways. APS8 was not toxic for normal lung fibroblasts. Furthermore, in NSCLC cells, APS8 reduced the adverse anti-apoptotic, proliferative effects of nicotine. Our results suggest that APS8 or similar compounds might be considered as lead compounds to develop antitumor therapeutic agents for at least certain types of lung cancer.
Keywords: 3-alkylpyridinium polymers, apoptosis, nicotine, nicotinic acetylcholine receptor, non-small cell lung carcinoma
Published in DiRROS: 02.08.2024; Views: 101; Downloads: 90
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2. Improved protective effect of umbilical cord stem cell transplantation on cisplatin-induced kidney injury in mice pretreated with antithymocyte globulinŽeljka Večerić-Haler, Andreja Erman, Anton Cerar, Helena Motaln, Katja Kološa, Tamara Lah Turnšek, Snežna Sodin-Šemrl, Katja Lakota, Katjuša Mrak Poljšak, Špela Škrajnar, Simona Kranjc Brezar, Miha Arnol, Martina Perše, 2016, original scientific article Abstract: Mesenchymal stem cells (MSCs) are recognised as a promising tool to improve renal recovery in experimental models of cisplatin-induced acute kidney injury. However, these preclinical studies were performed on severely immunodeficient animals. Here, we investigated whether human umbilical cord derived MSC treatment could equally ameliorate acute kidney injury induced by cisplatin and prolong survival in mice with a normal immune system and those with a suppressed immune system by polyclonal antithymocyte globulin (ATG). We demonstrated that ATG pretreatment, when followed by MSC transplantation, significantly improved injured renal function parameters, as evidenced by decreased blood urea nitrogen and serum creatinine concentration, as well as improved renal morphology. This tissue restoration was also supported by increased survival of mice. The beneficial effects of ATG were associated with reduced level of inflammatory protein serum amyloid A3 and induced antioxidative expression of superoxide dismutase-1 (SOD-1), glutathione peroxidase (GPx), and hem oxygenase-1 (HO-1). Infused MSCs became localised predominantly in peritubular areas and acted to reduce renal cell death. In conclusion, these results show that ATG diminished in situ inflammation and oxidative stress associated with cisplatin-induced acute kidney injury, the effects that may provide more favourable microenvironment for MSC action, with consequential synergistic improvements in renal injury and animal survival as compared to MSC treatment alone.
Keywords: mesenchymal stem cells, nephrotoxicity
Published in DiRROS: 25.07.2024; Views: 133; Downloads: 127
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3. Fast assay to predict multipotent mesenchymal stromal cell replicative senescence dynamicsKatja Kološa, Aleš Leskovšek, Teja Rajar, Tamara Lah Turnšek, 2022, original scientific article Abstract: The major obstacle to the application of mesenchymal stromal cells (MSCs) in regenerative medicine is the expansion of the donor-derived cells in vitro to obtain high cell numbers in the shortest possible time. However, MSCs gradually undergo replicative senescence after a variable number of divisions that reduce their therapeutic efficacy, which needs to be determined before administration. The authors developed a fast and simple evaluation assay testing two senescence inducers, mitoxantrone (Mxt) and trichostatin A (TSA), to predict the onset of spontaneous replicative senescence of adipose-derived mesenchymal stromal cells (ASCs) and have confirmed the correlation between induced senescence and spontaneous replicative senescence in the assay using Mxt. This protocol facilitates the standardization of therapeutic ASCs and MSCs from other origins before application.
Keywords: adipose mesenchymal stromal (stem) cells (ASCs), cell longevity, induced senescence, mesenchymal stromal (stem) cells (MSCs), mitoxantrone, replicative senescence, trichostatin A
Published in DiRROS: 16.07.2024; Views: 106; Downloads: 62
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4. Adverse toxic effects of tyrosine kinase inhibitors on non-target zebrafish liver (ZFL) cellsKatja Kološa, Bojana Žegura, Martina Štampar, Metka Filipič, Matjaž Novak, 2023, original scientific article Keywords: zebrafish liver cells, ZFL, tyrosine kinase inhibitors, cytotoxicity, cell cycle, genotoxicity, environmental hazard
Published in DiRROS: 12.07.2024; Views: 296; Downloads: 128
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5. Exploring the safety of cannabidiol (CBD) : a comprehensive in vitro evaluation of the genotoxic and mutagenic potential of a CBD isolate and extract from Cannabis sativa LAlja Štern, Matjaž Novak, Katja Kološa, Jurij Trontelj, Sonja Žabkar, Tjaša Šentjurc, Metka Filipič, Bojana Žegura, 2024, original scientific article Abstract: Cannabidiol (CBD), a naturally occurring cyclic terpenoid found in Cannabis sativa L., is renowned for its diverse
pharmacological benefits. Marketed as a remedy for various health issues, CBD products are utilized by patients
as a supplementary therapy or post-treatment failure, as well as by healthy individuals seeking promised advantages. Despite its widespread use, information regarding potential adverse effects, especially genotoxic
properties, is limited. The present study is focused on the mutagenic and genotoxic activity of a CBD isolate
(99.4 % CBD content) and CBD-rich Cannabis sativa L extract (63.6 % CBD content) in vitro. Both CBD samples
were non-mutagenic, as determined by the AMES test (OECD 471) but exhibited cytotoxicity for HepG2 cells
(~IC50 (4 h) 26 µg/ml, ~IC50 (24 h) 6–8 µg/ml, MTT assay). Noncytotoxic concentrations induced upregulation of
genes encoding metabolic enzymes involved in CBD metabolism, and CBD oxidative as well as glucuronide
metabolites were found in cell culture media, demonstrating the ability of HepG2 cells to metabolize CBD. In this
study, the CBD samples were found non-genotoxic. No DNA damage was observed with the comet assay, and no
influence on genomic instability was observed with the cytokinesis block micronucleus and the γH2AX and p-H3
assays. Furthermore, no changes in the expression of genes involved in genotoxic stress response were detected in
the toxicogenomic analysis, after 4 and 24 h of exposure. Our comprehensive study contributes valuable insights
into CBD’s safety profile, paving the way for further exploration of CBD’s therapeutic applications and potential
adverse effects.
Keywords: cannabidiol, CBD, metabolism, cytotoxicity, genotoxicity, mutagenicity
Published in DiRROS: 09.07.2024; Views: 136; Downloads: 138
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6. Nature-inspired substituted 3-(imidazol-2-yl) morpholines targeting human topoisomerase IIα : dynophore-derived discoveryBarbara Herlah, Matej Janežič, Iza Ogris, Simona Golič Grdadolnik, Katja Kološa, Sonja Žabkar, Bojana Žegura, Andrej Perdih, 2024, original scientific article Abstract: The molecular nanomachine, human DNA topoisomerase IIα, plays a crucial role in replication, transcription, and recombination by catalyzing topological changes in the DNA, rendering it an optimal target for cancer chemotherapy. Current clinical topoisomerase II poisons often cause secondary tumors as side effects due to the accumulation of double-strand breaks in the DNA, spurring the development of catalytic inhibitors. Here, we used a dynamic pharmacophore approach to develop catalytic inhibitors targeting the ATP binding site of human DNA topoisomerase IIα. Our screening of a library of nature-inspired compounds led to the discovery of a class of 3-(imidazol-2-yl) morpholines as potent catalytic inhibitors that bind to the ATPase domain. Further experimental and computational studies identified hit compound 17, which exhibited selectivity against the human DNA topoisomerase IIα versus human protein kinases, cytotoxicity against several human cancer cells, and did not induce DNA double-strand breaks, making it distinct from clinical topoisomerase II poisons. This study integrates an innovative natural product-inspired chemistry and successful implementation of a molecular design strategy that incorporates a dynamic component of ligand-target molecular recognition, with comprehensive experimental characterization leading to hit compounds with potential impact on the development of more efficient chemotherapies.
Keywords: topoisomerase II, catalytic inhibitors, chemotherapy, DNA damage, cancer
Published in DiRROS: 03.06.2024; Views: 356; Downloads: 235
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7. Genotoxicity and heating performance of VxFe3-xO4 nanoparticles in health applicationsBeatriz Sanz-Sagué, Amaia Sáenz-Hernández, Bojana Žegura, Alja Štern, Katja Kološa, Iza Rozman, 2024, original scientific article Abstract: The applications of magnetic nanoparticles (MNPs) as biocatalysts in different biomedical areas have been evolved very recently. One of the main challenges in this field is to design affective MNPs surfaces with catalytically active atomic centres, while producing minimal toxicological side effects on the hosting cell or tissues. MNPs of vanadium spinel ferrite (VFe2O4) are a promising material for mimicking the action of natural enzymes in degrading harmful substrates due to the presence of active V5+ centres. However, the toxicity of this material has not been yet studied in detail enough to grant biomedical safety. In this work, we have extensively measured the structural, compositional, and magnetic properties of a series of VxFe3-xO4 spinel ferrite MNPs to assess the surface composition and oxidation state of V atoms, and also performed systematic and extensive in vitro cytotoxicity and genotoxicity testing required to assess their safety in potential clinical applications. We could establish the presence of V5+ at the particle surface even in water-based colloidal samples at pH 7, as well as different amounts of V2+ and V3+ substitution at the A and B sites of the spinel structure. All samples showed large heating efficiency with Specific Loss Power values up to 400 W/g (H0 = 30 kA/m; f = 700 kHz). Samples analysed for safety in human hepatocellular carcinoma (HepG2) cell line with up to 24h of exposure showed that these MNPs did not induce major genomic abnormalities such as micronuclei, nuclear buds, or nucleoplasmic bridges (MNIs, NBUDs, and NPBs), nor did they cause DNA double-strand breaks (DSBs) or aneugenic effects—types of damage considered most harmful to cellular genetic material. The present study is an essential step towards the use of these type of nanomaterials in any biomedical or clinical application.
Keywords: magnetic nanoparticles, vanadium ferrite, cytotoxicity, genotoxicity, specific power absorption, cell viability
Published in DiRROS: 23.05.2024; Views: 251; Downloads: 270
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