PTP1b is a protein tyrosine phosphatase involved in the inactivation of insulin receptor. Since inhibition of PTP1b may prolong the action of the receptor, PTP1b has become a drug target for the treatment of type II diabetes. In the present study, prediction of inhibition using docking analysis targeted specifically to the active or allosteric site was performed on 87 compounds structurally belonging to 10 different groups. Two groups, consisting of 15 thiomorpholine and 10 thiazolyl derivatives exhibiting the best prediction results, were selected for in vitro evaluation. All thiomorpholines showed inhibitory action (with IC = 4-45 μΜ, Ki = 2-23 μM), while only three thiazolyl derivatives showed low inhibition (best IC = 18 μΜ, Ki = 9 μΜ). However, free binding energy (E) was in accordance with the IC values only for some compounds. Docking analysis targeted to the whole enzyme revealed that the compounds exhibiting IC values higher than expected could bind to other peripheral sites with lower free energy, E, than when bound to the active/allosteric site. A prediction factor, E- (Σ × 0.16), which takes into account lower energy binding to peripheral sites, was proposed and was found to correlate well with the IC values following an asymmetrical sigmoidal equation with r = 0.9692.
Melatonin (MLT) is a natural oncostatic factor of the human body as well as an antioxidant thus protects the nuclear DNA from oxidative damage. It also has the ability to reduce the side effects of various drugs when used as a combination therapy. The anti-neoplastic agent melphalan (MEL), which encompasses a number of side effects, is a strong alkylating agent and a potent inducer of sister chromatid exchanges (SCEs). The aim of the current in vitro study was to investigate the ability of MLT to reduce the genotoxic effect of MEL on normal human cultured peripheral lymphocytes. Cells were treated with both agents at various concentrations (MLT 100, 200 and 400 microM and MEL 330, 490 and 650 nM) and incubated for 72 h prior harvesting. The levels of cytostaticity, cytotoxicity and genotoxicity were qualitatively evaluated using the proliferation rate index, the mitotic index and the SCE methodology, respectively. Our results demonstrated the protective effect of MLT on cells treated with MEL in vitro. The greatest protective effect of MLT at 100 and 400 microM was illustrated against 330 nM of MEL in comparison with all other doses of MEL. These observations imply that MLT may be proved useful in reducing some of the toxic effects associated with certain classes of chemotherapeutic agents and other chemical and physical mutagens and carcinogens, acting both as an antioxidant-radical scavenger and a protective mechanism against cellular damage due to exposure to free radical-producing agents. It is essential to investigate substances with protective properties which are normally produced from the human body.
Heterometal oxide nanoparticles of bioessential metals are shedding new light to nanoparticleinspired bioapplications. Pairing bioreactive elements like copper and iron can affect the redox dynamic and biological profile of the nanomaterial. Given the complexity of physicochemical properties, biological activity and toxicity concerns, extensive exploration is demanded, especially when active and less active oxidation states participate as in case of cuprous-ferric delafossite CuFeO2 (copper(I)-iron(III)), a less widespread nanomaterial. In that vein, CuFeO2 nanoparticles were synthesized and biological profile was evaluated in comparison with cuprous oxide (Cu2O NPs) counterpart, an already established antimicrobial agent. Interactions with bacteria, proteins and DNA were examined. Cu2O NPs exhibited stronger antibacterial activity (IC50 <25 μg/ml) than CuFeO2 NPs (IC50>100 μg/ml). In vitro exposure of nanoparticles on plasmid DNA unveiled toxicity in the form of DNA damage for Cu2O and enhanced biocompatibility for CuFeO2 NPs. Genotoxicity estimated by the frequency of sister chromatid exchanges, cytostaticity based on the proliferating rate indices and cytotoxicity based on the mitotic indices at human peripheral lymphocyte cultures were all significantly lower in the case of CuFeO2 NPs. Furthermore, through in vitro albumin denaturation assay, CuFeO2 NPs showed better performance in protein denaturation protection, correlating in superior antiinflammatory activity than Cu2O and similar to acetylsalicylic acid. Synergy of copper(I)iron(III) in nanoscale is apparent and gives rise to fruitful bioapplications and perspectives.
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