The increasing use of industrial chemicals has raised concerns regarding exposure to endocrine-disrupting chemicals (EDCs), which interfere with developmental, reproductive and metabolic processes. Of particular concern is their interaction with adipose tissue, a vital component of the endocrine system regulating metabolic and hormonal functions. The SGBS (Simpson Golabi Behmel Syndrome) cell line, a well-established human-relevant model for adipocyte research, closely mimics native adipocytes' properties. It responds to hormonal stimuli, undergoes adipogenesis and has been successfully used to study the impact of EDCs on adipose biology. In this study, we screened human exposure-relevant doses of various EDCs on the SGBS cell line to investigate their effects on viability, lipid accumulation and adipogenesis-related protein expression. Submicromolar doses were generally well tolerated; however, at higher doses, EDCs compromised cell viability, with cadmium chloride (CdCl2) showing the most pronounced effects. Intracellular lipid levels remained unaffected by EDCs, except for tributyltin (TBT), used as a positive control, which induced a significant increase. Analysis of adipogenesis-related protein expression revealed several effects, including downregulation of fatty acid-binding protein 4 (FABP4) by dibutyl phthalate, upregulation by CdCl2 and downregulation of perilipin 1 and FABP4 by perfluorooctanoic acid. Additionally, TBT induced dose-dependent upregulation of C/EBPα, perilipin 1 and FABP4 protein expression. These findings underscore the importance of employing appropriate models to study EDC-adipocyte interactions. Conclusions from this research could guide strategies to reduce the negative impacts of EDC exposure on adipose tissue.
- MeSH
- adipogeneze * účinky léků MeSH
- buněčné linie MeSH
- endokrinní disruptory * toxicita MeSH
- fluorokarbony toxicita MeSH
- kapryláty toxicita MeSH
- lidé MeSH
- metabolismus lipidů účinky léků MeSH
- proteiny vázající mastné kyseliny * metabolismus genetika MeSH
- trialkylcínové sloučeniny toxicita MeSH
- tuková tkáň účinky léků metabolismus MeSH
- tukové buňky účinky léků metabolismus MeSH
- viabilita buněk * účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The potential of acridines (amsacrine) as a topoisomerase II inhibitor or poison was first discovered in 1984, and since then, a considerable number of acridine derivatives have been tested as topoisomerase inhibitors/poisons, containing different substituents on the acridine chromophore. This review will discuss a series of studies published over the course of the last decade, which have investigated various novel acridine derivatives against topoisomerase II activity.
In comparison with analytical tools, bioassays provide higher sensitivity and more complex evaluation of environmental samples and are indispensable tools for monitoring increasing in anthropogenic pollution. Nevertheless, the disadvantage in cellular assays stems from the material variability used within the assays, and an interlaboratory adaptation does not usually lead to satisfactory test sensitivities. The aim of this study was to evaluate the influence of material variability on CXCL12 secretion by T47D cells, the outcome of the CXCL-test (estrogenic activity assay). For this purpose, the cell line sources, sera suppliers, experimental and seeding media, and the amount of cell/well were tested. The multivariable linear model (MLM), employed as an innovative approach in this field for parameter evaluation, identified that all the tested parameters had significant effects. Knowledge of the contributions of each parameter has permitted step-by-step optimization. The most beneficial approach was seeding 20,000 cells/well directly in treatment medium and using DMEM for the treatment. Great differences in both basal and maximal cytokine secretions among the three tested cell lines and different impacts of each serum were also observed. Altogether, both these biologically based and highly variable inputs were additionally assessed by MLM and a subsequent two-step evaluation, which revealed a lower variability and satisfactory reproducibility of the test. This analysis showed that not only parameter and procedure optimization but also the evaluation methodology must be considered from the perspective of interlaboratory method adaptation. This overall methodology could be applied to all bioanalytical methods for fast multiparameter and accurate analysis.
Polycyclic aromatic hydrocarbons (PAHs) and ultraviolet radiation (UV) represent genotoxic factors that commonly occur in the living and working environment. The dermal form of exposure represents a significant part of the total load of dangerous chemical and physical environmental factors to which an organism is subjected. However, simultaneous dermal exposures to PAHs (pharmaceutical crude coal tar [CCT]) and UV (UVA and UVB) also have therapeutic uses. A typical example is Goeckerman therapy (GT) for psoriasis. The question of the therapeutic efficacy of GT and the related level of genotoxic danger is still under discussion. The aim of the present study was to compare four GT variants (G1-G4) in terms of efficacy and acceptable genotoxic hazard. Efficacy was expressed by the psoriasis area of severity index (PASI) score, genotoxic hazard by chromosomal aberration in peripheral lymphocytes. The lowest risk of genotoxic hazard and the lowest efficiency was observed in G1 variant (3% of the CCT and UVA + UVB). The efficacy of G2 (4% CCT and UVA + UVB), G3 (4% CCT and UVB), and G4 variants (5% CCT and UVA + UVB) was comparable. The highest risk of genotoxic hazard was found in the G3 variant. In the terms of sufficient efficacy and acceptable genotoxic hazard, a combination of 4% or 5% of CCT and UVA and UVB seems to be acceptable (variants G2 and G4).
- MeSH
- chromozomální aberace MeSH
- dehet uhelný terapeutické užití MeSH
- lidé MeSH
- lymfocyty MeSH
- polycyklické aromatické uhlovodíky toxicita MeSH
- poškození DNA MeSH
- psoriáza farmakoterapie MeSH
- ultrafialové záření * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Heterocycles have long been the focus of intensive study in attempts to develop novel therapeutic compounds, and acridine, a polynuclear nitrogen molecule containing a heterocycle, has attracted a considerable amount of scientific attention. Acridine derivatives have been studied in detail and have been found to possess multitarget properties, which inhibit topoisomerase enzymes that regulate topological changes in DNA and interfere with the essential biological function of DNA. This article describes some recent advancements in the field of new 9-substituted acridine heterocyclic agents and describes both the structure and the structure-activity relationship of the most promising molecules. The article will also present the IC50 values of the novel derivatives against various human cancer cell lines. The mini review also investigates the topoisomerase inhibition and antibacterial and antimalarial activity of these polycyclic aromatic derivatives.
- MeSH
- akridiny chemie farmakologie toxicita MeSH
- antibakteriální látky chemie farmakologie toxicita MeSH
- antimalarika chemie farmakologie toxicita MeSH
- antitumorózní látky chemie farmakologie toxicita MeSH
- inhibitory topoisomerasy II chemie farmakologie toxicita MeSH
- lidé MeSH
- nádorové buňky kultivované účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Proflavine derivatives are extremely interesting chemotherapeutic agents, which have shown promising pharmaceutical potential due to their wide range of biological activities. This review summarizes the current state of research into the anticancer, antimicrobial, antimalarial and antileishmanial properties of these attractive compounds. Our attention has focused on new classes of proflavine conjugates, which display significant levels of anticancer activity. Highly promising cytotoxic properties have been identified in proflavine conjugates with imidazolidinones, ureas and thioureas. In particular, proflavine-dialkyldithioureas displayed substantial cytotoxic effect against the human leukemia HL-60 cells with IC50 values from 7.2 to 34.0 μm. As well, palladium complexes with proflavine ligand have important biologic activity. The LC50 values of these complexes were significantly lower than that of cisplatin against the SK-BR-3 cell line.
- MeSH
- akriflavin analogy a deriváty farmakologie toxicita MeSH
- antiinfekční látky farmakologie toxicita MeSH
- antitumorózní látky farmakologie toxicita MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- molekulární struktura MeSH
- proflavin analogy a deriváty farmakologie toxicita MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01 ) the prophylactic efficacy of five experimental (K-48, K-53, K-74, K-75, K-203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10-methylacridine) and after the FDA-approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon-induced mortality. Best protection was conferred by the experimental oxime K-48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K-203), 0.21 (K-74), 0.24 (K-75) and 0.26 (pralidoxime), which were significantly more efficacious than 10-methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.
- MeSH
- analýza přežití MeSH
- LD50 MeSH
- obidoxim chlorid aplikace a dávkování farmakologie MeSH
- ochranné látky aplikace a dávkování farmakologie MeSH
- paraoxon chemie toxicita MeSH
- potkani Wistar MeSH
- pralidoximové sloučeniny aplikace a dávkování farmakologie MeSH
- proporcionální rizikové modely MeSH
- reaktivátory cholinesterázy aplikace a dávkování farmakologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Human skin explant (HSE) seems to be a useful model for dermatological/cosmetic testing. HSE prepared from donor superfluous skin from plastic surgery operations is cheap and easily obtainable compared to reconstructed models. The HSE use, however, may be limited by the degeneration processes during cultivation. The aim was to monitor changes in metabolic activity and selected apoptotic, inflammatory and antioxidant parameters during 7 day cultivation. The significant changes were found in the superoxide dismutase-2 level from day 5, glutathione S-reductase level from day 6, metabolic activity and fibulin-5 level from day 4, cyclooxygenase-2, interleukin-6 and interleukin-10 from day 1 to 2. Other selected markers (lipid peroxidation products and glutathione level, glutathione S-transferase, catalase, superoxide dismutase and glutathione S-reductase activity, glutathione peroxidase and glutathione S-reductase levels) were not modified significantly due to high inter-individual variability of skin donors. The HSE microstructure as well as cytokeratin-10 and proliferation marker Ki67 expression was also only minimally affected during cultivation. Collectively, the results demonstrate that HSE represents a good model for short-term studies focused on the physical and chemical agent toxicity, protective potential of compounds or metabolic biotransformation. However, reduced metabolic activity, increased inflammation and the high inter-individual variability and sensitivity of donors have to be taken into consideration.
- MeSH
- antioxidancia metabolismus MeSH
- biologické markery metabolismus MeSH
- biologické modely MeSH
- časové faktory MeSH
- cyklooxygenasa 2 metabolismus MeSH
- glutathionperoxidasa metabolismus MeSH
- glutathionreduktasa metabolismus MeSH
- interleukin-6 metabolismus MeSH
- kůže * imunologie metabolismus patologie MeSH
- lidé MeSH
- superoxiddismutasa metabolismus MeSH
- techniky tkáňových kultur metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
This review describes the synthesis of a wide range of novel tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo- and hetro-hybrids). These tacrine congeners exhibit significant anticholinesterase and cytotoxic properties and may therefore be of considerable potential for the development of new drugs for the treatment of Alzheimer's disease.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie enzymologie MeSH
- antitumorózní látky chemie farmakologie toxicita MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie toxicita MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- objevování léků MeSH
- proliferace buněk účinky léků MeSH
- takrin MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.
- MeSH
- antidota terapeutické užití MeSH
- antioxidancia terapeutické užití MeSH
- atropin terapeutické užití MeSH
- diazepam terapeutické užití MeSH
- lidé MeSH
- otrava organofosfáty farmakoterapie MeSH
- oxidační stres účinky léků MeSH
- oximy terapeutické užití MeSH
- reaktivátory cholinesterázy terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
