The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H2O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO3 (complex 1) or BF4 (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC50 values were 2.46 and 4.88 μM), CYP2C9 (IC50 values were 16.34 and 37.25 μM), and CYP2C19 (IC50 values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents.

• Publikační typ
• časopisecké články MeSH

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b']dipyran-4-one, (pomiferin) and bpy = 2,2'-bipyridine, dimebpy = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2',3'-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2-13.0 μM for the best performing complexes 3 and 5. All the complexes 1-5 showed the best activity against the A2780R cells (IC50 = 2.2-6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.

• MeSH
• antiflogistika farmakologie   MeSH
• apoptóza účinky léků   MeSH
• benzopyrany chemie   farmakologie   MeSH
• flavonoidy metabolismus   farmakologie   MeSH
• isoflavony chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• lidé MeSH
• měď chemie   metabolismus   farmakologie   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The fluorescent molecule diphenylhexatriene (DPH) has been often used in combination with fluorescence anisotropy measurements, yet little is known regarding the non-linear optical properties. In the current work, we focus on them and extend the application to fluorescence, while paying attention to the conformational versatility of DPH when it is embedded in different membrane phases. Extensive hybrid quantum mechanics/molecular mechanics calculations were performed to investigate the influence of the phase- and temperature-dependent lipid environment on the probe. Already, the transition dipole moments and one-photon absorption spectra obtained in the liquid ordered mixture of sphingomyelin (SM)-cholesterol (Chol) (2:1) differ largely from the ones calculated in the liquid disordered DOPC and solid gel DPPC membranes. Throughout the work, the molecular conformation in SM:Chol is found to differ from the other environments. The two-photon absorption spectra and the ones obtained by hyper-Rayleigh scattering depend strongly on the environment. Finally, a stringent comparison of the fluorescence anisotropy decay and the fluorescence lifetime confirm the use of DPH to gain information upon the surrounding lipids and lipid phases. DPH might thus open the possibility to detect and analyze different biological environments based on its absorption and emission properties.

• MeSH
• cholesterol chemie   MeSH
• difenylhexatrien chemie   MeSH
• fluorescenční barviva chemie   MeSH
• fluorescenční polarizace MeSH
• lipidové dvojvrstvy chemie   MeSH
• molekulární konformace MeSH
• sfingomyeliny chemie   MeSH
• simulace molekulární dynamiky MeSH
• tranzitní teplota MeSH
• vztahy mezi strukturou a aktivitou MeSH
• změna skupenství MeSH
• Publikační typ
• časopisecké články MeSH

This study presents a toxicological evaluation of two types of carbon dots (CD), similar in size (<10 nm) but differing in surface charge. Whole-genome mRNA and miRNA expression (RNAseq), as well as gene-specific DNA methylation changes, were analyzed in human embryonic lung fibroblasts (HEL 12469) after 4 h and 24 h exposure to concentrations of 10 and 50 µg/mL (for positive charged CD; pCD) or 10 and 100 µg/mL (for negative charged CD, nCD). The results showed a distinct response for the tested nanomaterials (NMs). The exposure to pCD induced the expression of a substantially lower number of mRNAs than those to nCD, with few commonly differentially expressed genes between the two CDs. For both CDs, the number of deregulated mRNAs increased with the dose and exposure time. The pathway analysis revealed a deregulation of processes associated with immune response, tumorigenesis and cell cycle regulation, after exposure to pCD. For nCD treatment, pathways relating to cell proliferation, apoptosis, oxidative stress, gene expression, and cycle regulation were detected. The expression of miRNAs followed a similar pattern: more pronounced changes after nCD exposure and few commonly differentially expressed miRNAs between the two CDs. For both CDs the pathway analysis based on miRNA-mRNA interactions, showed a deregulation of cancer-related pathways, immune processes and processes involved in extracellular matrix interactions. DNA methylation was not affected by exposure to any of the two CDs. In summary, although the tested CDs induced distinct responses on the level of mRNA and miRNA expression, pathway analyses revealed a potential common biological impact of both NMs independent of their surface charge.

• MeSH
• apoptóza účinky léků   genetika   MeSH
• exprese genu účinky léků   genetika   MeSH
• extracelulární matrix genetika   MeSH
• fibroblasty účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• metylace DNA účinky léků   genetika   MeSH
• mikro RNA genetika   MeSH
• nádory genetika   MeSH
• oxidační stres účinky léků   genetika   MeSH
• plíce účinky léků   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• signální transdukce účinky léků   genetika   MeSH
• stanovení celkové genové exprese metody   MeSH
• uhlík farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH