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Povzetek: RECQ1 helicase has multiple roles in DNA replication, including restoration of the replication fork and DNA repair, and plays an important role in tumour progression. Its expression is highly elevated in glioblastoma as compared to healthy brain tissue. We studied the effects of small hairpin RNA (shRNA)-induced silencing of RECQ1 helicase on the increase in cell number and the invasion of U87 glioblastoma cells. RECQ1 silencing reduced the rate of increase in the number of U87 cells by 30%. This corresponded with a 40% reduction of the percentage of cells in the G2 phase of the cell cycle, and an accumulation of cells in the G1 phase. These effects were confirmed in vivo, in the brain of zebrafish (Danio rerio) embryos, by implanting DsRed-labelled RECQ1 helicase-silenced and control U87 cells. The growth of resulting tumours was quantified by monitoring the increase in xenograft fluorescence intensity during a three-day period with fluorescence microscopy. The reduced rate of tumour growth, by approximately 30% in RECQ1 helicase-silenced cells, was in line with in vitro measurements of the increase in cell number upon RECQ1 helicase silencing. However, RECQ1 helicase silencing did not affect invasive behaviour of U87 cells in the zebrafish brain. This is the first in vivo confirmation that RECQ1 helicase is a promising molecular target in the treatment of glioblastoma.
Ključne besede: cancer, cell cycle, DNA damage, intravital imaging, RNA interference, theranostics
Objavljeno v DiRROS: 25.07.2024; Ogledov: 26; Prenosov: 14
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Ključne besede: electroporation, pulsed electric field treatment, damage-associated molecular pattern molecules, immunogenic cell death, electrochemotherapy
Objavljeno v DiRROS: 15.07.2024; Ogledov: 99; Prenosov: 41
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Povzetek: 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.
Ključne besede: topoisomerase II, catalytic inhibitors, chemotherapy, DNA damage, cancer
Objavljeno v DiRROS: 03.06.2024; Ogledov: 285; Prenosov: 129
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Povzetek: Background. Microcystins (MCs) are cyclic heptapeptides that are considered tobe liver specific toxins. They are potent tumour promoters and recent studies indicate that they are also genotoxic. In this study we measured DNA damage in lymphocytes, liver, kidney (cortex and medulla), lung, spleen and brain cells of male Fisher F344 rats that were exposed to sublethal dose (every second day 10 Ugžkg b.w.č i.p) of microeysrin-YR (MCYR) for one month. Methods. At the end of exposure the animals were sacrificed, the lymphocytes were isolated from blood taken from jugular vein, liver cells were obtained byperfusion with collagenase A and the cells from other organs were isolated by incubating small tissue pieces with eollagenase A. The DNA damage in isolated cells was measured with the single cells gel electrophoresis (SCGE) also called the comet assay. Results. A significant increase of the % tail DNAin MCYR-exposed animals compared to the nonexposed control ones was observed in brain (2.5 fold), liver (2.1 fold), kidney medulla (1.9 fold), kidney cortex (1.8 fold) and lung (1.7 fold) cells, while the DNA from lymphocytes and spleen cells was not affected. Conclusion. This study demonstrated that subehronic exposure to sublethal doses of MCs can induce systemicgenotoxicity in mammals, and it affects not only the liver but also other vital organs.
Ključne besede: DNA damage, comet assay, cyanobacteria, bacterial toxins, rats, inbred F344
Objavljeno v DiRROS: 20.02.2024; Ogledov: 310; Prenosov: 74
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Povzetek: Bridges can be subjected to damaging environmental actions due to flooding and seismic hazards. Flood actions that result in scour are a leading cause of bridge failure, while seismic actions that induce lateral forces may lead to high ductility demand that exceeds pier capacity. When combined, seismic actions and scour can lead to effects that depend on the governing scour condition affecting a bridge. Loss of stiffness under scour can reduce the ductility capacity of a bridge but can also lead to an increase in flexibility that may reduce seismic inertial forces. Conversely, increased flexibility can lead to deck collapse due to support loss, so there exists some uncertainty about the combined effect of both phenomena. A necessary step towards the performance assessment of bridges under flooding and seismic actions is to calibrate numerical models that can reproduce structural responses under different actions. A further step is verifying the achievement of performance goals defined by codes. Structural health monitoring (SHM) techniques allow the computation of performance parameters that are useful for calibrating numerical models and performing direct checks of performance goal compliance. In this paper, various strategies employed to monitor bridge health against scour and seismic actions are discussed, with a particular focus on vibration-based damage identification methods.
Ključne besede: scour, seismic, damage, hazard, vibration-based methods
Objavljeno v DiRROS: 29.11.2023; Ogledov: 378; Prenosov: 186
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