The review summarizes literature data on the DNA-binding, DNA-protecting and DNA-damaging activities of a range of natural human endogenous and exogenous compounds. Small natural organic molecules ...bind DNA in a site-specific mode, by arranging tight touch with the structure of the major and minor grooves, as well as individual bases in the local duplex DNA. Polyphenols are the best-studied exogenous compounds from this point of view. Many of them demonstrate hormetic effects, producing both beneficial and damaging effects. An attempt to establish the dependence of DNA damage or DNA protection on the concentration of the compound turned out to be successful for some polyphenols, daidzein, genistein and resveratrol, which were DNA protecting in low concentrations and DNA damaging in high concentrations. There was no evident dependence on concentration for quercetin and kaempferol. Probably, the DNA-protecting effect is associated with the affinity to DNA. Caffeine and theophylline are DNA binders; at the same time, they favor DNA repair. Although most alkaloids damage DNA, berberine can protect DNA against damage. Among the endogenous compounds, hormones belonging to the amine class, thyroid and steroid hormones appear to bind DNA and produce some DNA damage. Thus, natural compounds continue to reveal beneficial or adverse effects on genome integrity and provide a promising source of therapeutic activities.
•Numerous polyphenols and other natural compounds bind DNA in vitro.•Small organic molecules that bind to DNA can both exogenous and endogenous.•The DNA binding compound can damage and protect DNA against other genotoxic agents.•Conditions, when a compound damages or protects DNA are difficult to elucidate.
The DNA-binding activities of compounds used as remedies can display DNA-protection, but also damaging effects in biological systems. The current review compiles literature data on DNA-binding ...activities of drugs widely used as remedies with different therapeutic indications. The compounds are classified according their mechanism of action: enzyme inhibitors, ion channel inhibitors, inhibitors of viral RNA replication and HIV protease and receptor agonists. DNA binding was reported for such widely used drugs as paracetamol, aspirin, metformin, statins and many others. The capability of the drug to bind DNA is sometimes coupled to genotoxic effects, but in some cases - to genome protection. Data on atoms and chemical groups involved in the drug-DNA interactions are also presented. In many cases the same atoms are involved in both interactions of the compounds with proteins and DNA.
•Numerous widely used drugs bind DNA in vitro.•The DNA binding compound can either damage or protect DNA against other genotoxic agents.•Conditions, when a compound damages or protects DNA are difficult to elucidate.
Olive leaf extract (OLE) is used in traditional medicine as a food supplement and as an over-the-counter drug for a variety of its effects, including anti-inflammatory and anti-atherosclerotic ones. ...Mechanisms through which OLE could modulate these pathways in human vasculature remain largely unknown. Serum amyloid A (SAA) plays a causal role in atherosclerosis and cardiovascular diseases and induces pro-inflammatory and pro-adhesive responses in human coronary artery endothelial cells (HCAEC). Within this study we explored whether OLE can attenuate SAA-driven responses in HCAEC. HCAEC were treated with SAA (1,000 nM) and/or OLE (0.5 and 1 mg/ml). The expression of adhesion molecules VCAM-1 and E-selectin, matrix metalloproteinases (MMP2 and MMP9) and microRNA 146a, let-7e, and let-7g (involved in the regulation of inflammation) was determined by qPCR. The amount of secreted IL-6, IL-8, MIF, and GRO-α in cell culture supernatants was quantified by ELISA. Phosphorylation of NF-κB was assessed by Western blot and DNA damage was measured using the COMET assay. OLE decreased significantly released protein levels of IL-6 and IL-8, as well as mRNA expression of E-selectin in SAA-stimulated HCAEC and reduced MMP2 levels in unstimulated cells. Phosphorylation of NF-κB (p65) was upregulated in the presence of SAA, with OLE significantly attenuating this SAA-induced effect. OLE stabilized SAA-induced upregulation of microRNA-146a and let-7e in HCAEC, suggesting that OLE could fine-tune the SAA-driven activity of NF-κB by changing the microRNA networks in HCAEC. SAA induced DNA damage and worsened the oxidative DNA damage in HCAEC, whereas OLE protected HCAEC from SAA- and H
O
-driven DNA damage. OLE significantly attenuated certain pro-inflammatory and pro-adhesive responses and decreased DNA damage in HCAEC upon stimulation with SAA. The reversal of SAA-driven endothelial activation by OLE might contribute to its anti-inflammatory and anti-atherogenic effects in HCAEC.
In this article, cytotoxicity, the mechanisms of cytotoxic activity, genotoxicity, and interaction with DNA and proteins, of two Cu(II) complexes with a salicylaldehyde derivative ...(4-(diethylamino)salicylaldehyde) and α-diimine (2,2′-bipyridine (bipy) and 1,10-phenanthroline (phen)) are reported. Both Cu(II) complexes performed cytotoxic effects against all tested malignant cell lines. Complexes exerted highest cytotoxicity against HeLa and A375 malignant cell lines. The cytotoxic activity of Cu(II) complex with phen as a α-diimine co-ligand was significantly higher in comparison with cytotoxic activity of Cu(II) complex with bipy. Pretreatment with specific inhibitors of caspase-3, caspase-8 or caspase-9, in order to clear up the mode of cell death triggered by two Cu(II) complexes in HeLa cells, indicated the ability of these complexes to induce apoptosis through activation of target caspases. Cu(II)-phen complex exhibited significant antioxidant activity compared with Cu(II)-bipy complex, and showed a better effect on reducing intracellular ROS levels in HeLa cells. Tested complexes did not display genotoxic potential in human peripheral blood leucocytes, but exhibited an antigenotoxic effect in post-treatment, after H2O2 exposure. The study of the in vitro biological properties regarding their affinity towards CT (calf-thymus) DNA and serum albumins showed that the compounds can intercalate to CT DNA, and bind reversibly and tightly to the albumins. Molecular docking studies of the ability of compounds to bind to biomacromolecules are consistent with in vitro studies.
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•Cu(II) complexes with 4-(diethylamino)salicylaldehyde and α-diimines were studied.•Cytotoxic, antioxidant, antigenotoxic study and interaction with DNA and proteins.•The complexes showed good cytotoxic and antioxidant activity.•The complexes exhibited an antigenotoxic effect in post-treatment.•The binding to DNA is via intercalation, and to the albumins is reversibly.
Copper(II) complexes with an α-diimine show a wide variety of biological activities, such as antibacterial, antifungal, antioxidant and anticancer. In this work, we synthesized and structurally ...characterized two novel Cu(II) complexes with methyl 3-formyl-4-hydroxybenzoate (HL) and α-diimines: 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen). Crystal structure analysis shows that the formulas of the compounds are Cu(bipy)(L)(BF
) (1) and Cu(phen)(L)(H
O)(BF
)·H
O (2), with BF
as a ligand in complex 1, which is rarely coordinated to metals. Both complexes have a square pyramidal geometry, while DFT calculations showed that the most stable structures of complexes 1 and 2 in a water/DMSO mixture are square-planar derivatives Cu(bipy)(L)
and Cu(phen)(L)
. The antibacterial activity of compounds was evaluated
on four Gram-negative and four Gram-positive bacterial strains. Complex 2 showed greater antibacterial activity towards all bacterial strains comparable to the control compound Amikacin. Complex 2 exerted a strong cytotoxic effect against the tested cancer cell lines (IC
values ranging from 0.32 to 0.44 μM). Both complexes caused apoptotic cell death in HeLa cells and a noticeable
antiangiogenic effect. In the concentration range of 5 to 100 μM, the complexes showed the absence of a genotoxic effect and displayed a protective effect against oxidative DNA damage induced by H
O
in human peripheral blood cells. The interaction between the compounds and calf-thymus DNA was evaluated by diverse techniques suggesting a tight binding, which was also confirmed by molecular docking. In addition, it was found that the complexes bind tightly and reversibly to bovine and human serum albumin.
•Protective effect of commercial dry olive leaf extract against adrenaline induced DNA damage was tested using comet assay.•Two different experimental protocols were employed, pretreatment and ...post-treatment.•The antigenotoxic and antioxidant properties of dry olive leaf extract are indicated.•The genoprotective effect of the extract is concentration-dependant.•Several mechanisms contributing to its protective action are proposed.
Excessive release of stress hormone adrenaline is accompanied by generation of reactive oxygen species which may cause disruption of DNA integrity leading to cancer and age-related disorders. Phenolic-rich plant product dry olive leaf extract (DOLE) is known to modulate effects of various oxidants in human cells. The aim was to evaluate the effect of commercial DOLE against adrenaline induced DNA damage in human leukocytes by using comet assay. Peripheral blood leukocytes from 6 healthy subjects were treated in vitro with three final concentrations of DOLE (0.125, 0.5, and 1mg/mL) for 30min at 37°C under two different protocols, pretreatment and post-treatment. Protective effect of DOLE was assessed from its ability to attenuate formation of DNA lesions induced by adrenaline. Compared to cells exposed only to adrenaline, DOLE displayed significant reduction (P<0.001) of DNA damage at all three concentrations and under both experimental protocols. Pearson correlation analysis revealed a significant positive association between DOLE concentration and leukocytes DNA damage (P<0.05). Antigenotoxic effect of the extract was more pronounced at smaller concentrations. Post-treatment with 0.125mg/mL DOLE was the most effective against adrenaline genotoxicity. Results indicate genoprotective and antioxidant properties in dry olive leaf extract, strongly supporting further explorations of its underlying mechanisms of action.
•IA is blend of six species of medicinal mushrooms.•Significant antigenotoxic effects of IA were detected by comet assay in vitro.•Evaluation of IA antioxidant properties showed remarkable OH ...scavenging ability.
Immune Assist (IA) is produced from extract of six species of medical mushrooms: Agaricus blazei - Cordyceps sinensis - Grifola frondosa - Ganoderma lucidum - Coriolus versicolor - Lentinula edodes. The genoprotective potential of IA was evaluated for the first time. Significant antigenotoxic effects were detected in human peripheral blood cells against H2O2 induced DNA damage, in the pretreatment and in the posttreatment. The most efficient concentration of IA in pretreatment was 500 μg/mL, while in posttreatment it was the concentration of 250 μg/mL. Kinetics of attenuation of H2O2 induced DNA damage in posttreatment with the optimal concentration of IA showed significant decrease in the number of damaged cells at all time periods (15–60 min), reaching the greatest reduction after 15 and 45 min. Remarkable ·OH scavenging properties and moderate reducing power, together with the modest DPPH scavenging activity, could be responsible for the great attenuation of DNA damage after 15 min of exposure to IA, while reduction of DNA damage after 45 min could be the result in additional stimulation of the cell’s repair machinery. Our results suggest that IA displayed antigenotoxic and antioxidant properties. A broader investigation of its profile in biological systems is needed.
The acute toxicity of surface-modified TiO2 nanoparticles (NPs) with caffeic acid (CA) was compared with those of its separate constituents (free CA and bare TiO2 NPs) upon their oral administration ...in laboratory mice. Prior to in vivo experiments, the interfacial charge transfer (ICT) complex between surface Ti atoms and CA is thoroughly characterized. Composition and stability constants of ICT complex were determined using Job's method and Banesi-Hildebrand analysis, respectively. The experimental data were supported with quantum chemical calculations based on density functional theory (DFT). Acute toxicity signs, including biochemical alterations and extensive histopathological changes in the liver tissue of mice were detected 14 days after oral administration of bare TiO2 NPs. However, the clinical signs of toxicity, the fractional contribution of organs, biochemical parameters of liver and kidney function, and histopathological changes in liver upon treatment with surface-modified TiO2 NPs with CA were not observed. Also, the genotoxic potential of the ICT complex and its constituents were evaluated in leukocytes of whole blood cells in vivo by comet assay. Both, bare and surface-modified TiO2 NPs did not display DNA damaging effect in time frame of 24 h upon their oral administration in mice.
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•Acute toxicity signs detected upon oral administration of pristine TiO2 nanoparticles (NPs) in mice.•Toxic action of TiO2 NPs is less upon formation of interfacial charge transfer (ICT) complex with caffeic acid (CA).•Detailed experimental and quantum chemical characterization of ICT complex between TiO2 NPs and CA.
Abstract
Dry olive leaf extract (DOLE) and its active component oleuropein (OLE) were applied as reducing and stabilizing agents to prepare colloidal 20–25 nm silver nanoparticles (Ag NPs). The Ag ...NPs were characterized using transmission electron microscopy, X-ray diffraction analysis, and absorption spectroscopy. The cytotoxic actions of coated Ag NPs, and their inorganic and organic components, were examined against trophoblast cells and human peripheral blood lymphocytes (PBLs), Gram-positive, Gram-negative bacteria, and yeast. The genotoxic potential was evaluated in PBLs in vitro with the comet assay. Ag/DOLE and Ag/OLE induced cytotoxic effects in both types of cells after 24 h exposure when silver concentrations were 0.025–0.2 mM. However, the most pronounced cytotoxicity exhibits Ag/OLE. Both colloids also caused reduced ROS production in both cell types at 0.1 mM and 0.2 mM, while bare Ag NPs did not alter ROS levels at any of the conditions. Functionalized Ag/DOLE and Ag/OLE did not show genotoxic effects in PBLs, while bare AgNPs increased DNA damage significantly only at 0.2 mM. Regarding the antimicrobial effects, the Ag/OLE had MIC values for all evaluated microorganisms from 0.0625 to less than 0.0312 mM. Also, the antimicrobial effect of Ag/DOLE was significantly higher on Gram-negative bacteria and yeast than on Gram-positive bacteria. Obtained results indicate that Ag/OLE induced the most pronounced biological effects, beneficial for its application as an antimicrobial agent, but with potential risks from exposure to high concentrations that could induce cytotoxicity in healthy human cells.
Graphical Abstract
Graphical Abstract
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•Antigenotoxic potential of DOLE was investigated on the human whole blood in vitro, using comet assay.•E2 and DES were used as DNA damage inducers, expressing a genotoxic ...effect.•DOLE exhibited antigenotoxic properties.
Phenolic groups of steroidal or nonsteroidal estrogens can redox cycle, leading to oxidative stress, where creation of reactive oxygen species are recognized as the main mechanism of their DNA damage properties. Dry olive (Olea europaea L.) leaf extract is known to contain bioactive and antioxidative components and to have an ability to modulate the effects of various oxidants in cells. The main goal of this study was to investigate antigenotoxic potential of a standardized dry olive leaf extract on DNA damage induced by 17β-estradiol and diethylstilbestrol in human whole blood cells in vitro, using comet assay. Our results indicated that both hormones showed a genotoxic effect at a concentration of 100 μM (P < 0.05, n = 6). Dry olive leaf extract was efficient in reducing number of cells with estrogen-induced DNA damage at tested concentrations (0.125, 0.5 and 1 mg/mL) (P < 0.05, n = 6) and under two experimental protocols, pre-treatment and post-treatment, exhibiting antigenotoxic properties. Analysis of antioxidant properties of the extract revealed moderate ABTS radical scavenging properties and reducing power. Overall, our results suggested that the protective potential of dry olive leaf extract could arise from the synergistic effect of its scavenging activity and enhancement of the cells' antioxidant capacity.
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