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Ključne besede: cytotoxicity, genomic instability, in silico, indoor air pollution, public health, environmental toxicology
Objavljeno v DiRROS: 20.03.2026; Ogledov: 508; Prenosov: 357
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Povzetek: In this study, the chemopreventive effects of rosmarinic acid (RA), a major phenolic acid of the plant Rosmarinus officinalis L., against the carcinogenic naturally occurring mycotoxin aflatoxin B1 (AFB1) were investigated using both in silico and in vitro approaches. The in silico investigation of the chemical reactions between rosmarinic acid and the carcinogenic metabolite of AFB1, aflatoxin B1 exo-8,9-epoxide (AFBO), was conducted by activation free energies calculations with DFT functionals M11-L and MN12-L, in conjunction with the 6-311++G(d,p) flexible basis set and implicit solvation model density (SMD), according to a newly developed quantum mechanics-based protocol for the evaluation of carcinogen scavenging activity (QM-CSA). Following the computational analyses, the chemoprotective effects of RA were further studied in vitro in human hepatocellular carcinoma HepG2 cells by analyzing its influence on AFB1-induced genotoxicity using a comet assay, γH2AX, and p-H3, while its impact on cell proliferation and cell cycle modulation was assessed using flow cytometry. Our computational results revealed that the activation free energy required for the reaction of RA with AFBO (14.86 kcal/mol) is significantly lower than the activation free energy for the competing reaction of AFBO with guanine (16.88 kcal/mol), which indicates that RA acts as an efficient natural scavenger of AFBO, potentially preventing AFB1-specific DNA adduct formation. The chemoprotective activity of RA was confirmed through in vitro experiments, which demonstrated a statistically significant (p < 0.05) reduction in AFB1-induced single- and double-strand breaks in HepG2 cells exposed to a mixture of AFB1 and RA at non-cytotoxic concentrations. In addition, RA reversed the AFB1-induced reduction in cell proliferation.
Ključne besede: rosmarinic acid, aflatoxin B1, chemopreventive effects, antigenotoxic effects, density functional theory, chemical carcinogen scavenger, toxicology
Objavljeno v DiRROS: 03.07.2025; Ogledov: 1033; Prenosov: 859
Celotno besedilo (1,41 MB)
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Povzetek: Indoor air pollution is a recognized emerging threat, claiming millions of lives annually. People are constantly exposed to ambient and indoor air pollution. The latest research shows that people in developed countries spend up to 90% of their time indoors and almost 70% at home. Although impaired IAQ represents a significant health risk, it affects people differently, and specific populations are more vulnerable: children, the elderly, and people with respiratory illnesses are more sensitive to these environmental risks. Despite rather extensive research on IAQ, most of the current understanding about the subject, which includes pollution sources, indoor–outdoor relationships, and ventilation/filtration, is still quite limited, mainly because air quality monitoring in the EU is primarily focused on ambient air quality and regulatory requirements are lacking for indoor environments. Therefore, the EDIAQI project aims to improve guidelines and awareness for advancing the IAQ in Europe and beyond by allowing user-friendly access to information about indoor air pollution exposures, sources, and related risk factors. The solution proposed with EDIAQI consists of conducting a characterization of sources and routes of exposure and dispersion of chemical, biological, and emerging indoor air pollution in multiple cities in the EU. The project will deploy cost-effective/user-friendly monitoring solutions to create new knowledge on sources, exposure routes, and indoor multipollutant body burdens. The EDIAQI project brings together 18 organizations from 11 different European countries that provide interdisciplinary skills and expertise in various fields, including environmental science and technology, medicine, and toxicology, as well as policy design and public engagement.
Ključne besede: indoor air pollution, health risk, vulnerable populations, IAQ (Indoor Air Quality), EDIAQI project, monitoring solutions, exposure routes
Objavljeno v DiRROS: 06.11.2024; Ogledov: 1903; Prenosov: 2410
Celotno besedilo (2,15 MB)
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Povzetek: The newly emerging cyanobacterial cytotoxin cylindrospermopsin (CYN) is increasingly found in surface freshwaters, worldwide. It poses a potential threat to humans after chronic exposure as it was shown to be genotoxic in a range of test systems and is potentially carcinogenic. However, the mechanisms of CYN toxicity and genotoxicity are not well understood. In the present study CYN induced formation of DNA double strand breaks (DSBs), after prolonged exposure (72 h), in human hepatoma cells, HepG2. CYN (0.1–0.5 µg/mL, 24–96 h) induced morphological changes and reduced cell viability in a dose and time dependent manner. No significant increase in lactate dehydrogenase (LDH) leakage could be observed after CYN exposure, indicating that the reduction in cell number was due to decreased cell proliferation and not due to cytotoxicity. This was confirmed by imunocytochemical analysis of the cell-proliferation marker Ki67. Analysis of the cell-cycle using flow-cytometry showed that CYN has an impact on the cell cycle, indicating G0/G1 arrest after 24 h and S-phase arrest after longer exposure (72 and 96 h). Our results provide new evidence that CYN is a direct acting genotoxin, causing DSBs, and these facts need to be considered in the human health risk assessment.
Ključne besede: cylindrospermopsin, cell-cycle, cell-proliferation, double-strand breaks, HepG2 cells
Objavljeno v DiRROS: 02.08.2024; Ogledov: 1488; Prenosov: 1369
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Povzetek: Tyrosine kinase inhibitors (TKIs) are designed for targeted cancer therapy. The consumption of these drugs during the last 20 years has been constantly rising. In the zebrafish (Danio rerio) embryo toxicity test, we assessed the toxicity of six TKIs: imatinib mesylate, erlotinib, nilotinib, dasatinib, sorafenib and regorafenib. Imatinib mesylate and dasatinib induced lethal effects, while regorafenib, sorfenib and dasatinib caused a significant increase of sub-lethal effects, predominantly oedema, no blood circulation and formation of blood aggregates. The analyses of the changes in the expression of selected genes associated with the hormone system after the exposure to imatinib mesylate, dasatinib and regorafenib demonstrated that all three tested TKIs deregulated the expression of oestrogen receptor esr1, cytochrome P450 aromatase (cypa19b) and hydroxysteroid-dehydrogenase (hsd3b), regorafenib, and also thyroglobulin (tg). The expression of genes involved in the DNA damage response (gadd45 and mcm6) and apoptosis (bcl2) was deregulated only by exposure to regorafenib. The data indicate that common mechanisms, namely antiangiogenic activity and interference with steroidogenesis are involved in the TKI induced sub-lethal effects and potential hormone disrupting activity, respectively. The residues of TKIs may represent an environmental hazard; therefore, further ecotoxicological studies focusing also on the effects of their mixtures are warranted.
Ključne besede: aquatic toxicity, tyrosine kinase inhibitors, zebrafish embryo toxicity test, gene expression, environmental hazard
Objavljeno v DiRROS: 16.07.2024; Ogledov: 1418; Prenosov: 1006
Celotno besedilo (9,13 MB)
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