Репозиторий Университета

© 2019 Rad51 is a key protein in DNA repair by homologous recombination and an important target for development of drugs in cancer therapy. 4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS) has been used in clinic during the past 30 years as an inhibitor of anion transporters and channels. Recently DIDS has been demonstrated to affect Rad51-mediated homologous pairing and strand exchange, key processes in homologous recombination. Consequently, DIDS has been considered as a potential revertant of radio- and chemo-resistance of cancer cells, the major causes of therapy failure. Here, we have investigated the behavior of DIDS towards serum albumins. The effects of environmental factors, primarily, solvent polarity, on DIDS stability were evaluated, and the mechanisms of interaction of DIDS with human or bovine serum albumin were analyzed using isothermal calorimetry, circular dichroism and fluorescence spectroscopies. DIDS interaction with both serum albumins have been demonstrated, and the interaction characteristics have been determined. By comparing these characteristics for several DIDS derivatives, we have identified the DIDS moiety essential for the interaction. Furthermore, site competition data indicate that human albumin has two DIDS-binding sites: a high-affinity site in the IIIA subdomain and a low-affinity one in the IB subdomain. Molecular docking has revealed the key molecular moieties of DIDS responsible for its interactions in each site and shown that the IB site can bind two ligands. These findings show that binding of DIDS to serum albumin may change the balance between the free and bound DIDS forms, thereby affecting its bioavailability and efficacy against Rad51.

© 2019, Pleiades Publishing, Ltd. Abstract: It is shown that the efficacy of the photosensitized oxidation of organic substrates in aqueous media (with the oxidation of tryptophan being used as an example) does not depend on adding biologically active dinitrosyl iron complexes (DNICs) with thiol-containing ligands to the reaction medium if it contains Pluronic F127, a poly(ethylene oxide)–poly(propylene oxide)– poly(ethylene oxide) triblock copolymer, at concentrations higher than the critical micelle concentration. Photosensitizer molecules are localized in Pluronic micelles and are shielded from the damaging impact of NO• radicals that form upon the photodegradation of DNIC molecules. Photodynamic therapy (PDT) sessions (the photoinduced necrosis and apoptosis of cells in pathologically altered tissues and the simultaneous initiation of regeneration and repair of the treated tissues due to the photodecomposition of DNIC molecules) thus become fundamentally possible.

© 2019, The Author(s). Purpose: To assess the accuracy of [68Ga]-PSMA-11 PET/CT or [68Ga]-PSMA-11 PET/MRI (PSMA-11 PET/CT(MRI)) for lymph node (LN) staging using salvage LN dissection (SLND) in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). Patients and methods: In a prospective study, 65 consecutive patients who developed BCR after RP underwent SLND after PSMA-11 PET/CT(MRI) between 2014 and 2018. Extended SLND up to the inferior mesenteric artery was performed in all patients. Regional and template-based correlations between the presence of LN metastases on histopathology and whole-body PSMA-11 PET/CT(MRI) results were evaluated. The diagnostic accuracy of PSMA-11 PET/CT(MRI) was also evaluated in relation to PSA level at the time of SLND. Results: The median age of the patients at the time of SLND was 65 years (IQR 63–69 years) and the median PSA level was 1.4 ng/ml (IQR 0.8–2.9 ng/ml). Before SLND, 50 patients (77%) had additional therapy after RP (26.2% androgen-deprivation therapy and 50.8% radiotherapy). The median number of LNs removed on SLND was 40 (IQR 33–48) and the median number of positive nodes was 4 (IQR 2–6). LN metastases were seen in 13.8% of resected LNs (317 of 2,292). LNs positive on PSMA-11 PET/CT(MRI) had a median diameter of 7.2 mm (IQR 5.3–9 mm). Metastatic LNs in regions negative on PSMA-11 PET had a median diameter of 3.4 mm (IQR 2.1–5.4 mm). In a regional analysis, the sensitivity of PSMA-11 PET/CT(MRI) ranged from 72% to 100%, and the specificity from 96% to 100%. Region-specific positive and negative predictive values ranged from 95% to 100% and 93% to 100%, respectively. Conclusion: PSMA-11 PET/CT(MRI) has a very good performance for the identification of LN metastases in patients with BCR after RP. The high diagnostic accuracy in the regional and subregional analyses demonstrates the potential of this approach to enable a region-directed instead of a complete bilateral therapeutic intervention. The performance of PSMA-11 PET/CT(MRI) is dependent on the PSA level and the size of the metastatic deposit.

© 2019, Springer Science+Business Media, LLC, part of Springer Nature. The aim of the present study was to compare the cardiodynamic parameters in the isolated rat heart in animals chronically treated with cisplatin, platinum(IV) complex and its diamine ligand. Sixty Wistar albino rats (8 weeks old) were divided into five groups: three experimental and two control groups. Animals in all groups were treated with a dose of 4 mg/kg body weight once a week for 4 weeks with different substances; experimental groups received cisplatin, ligand and octahedral platinum(IV) complex, and control groups received saline and dimethyl sulfoxide. After sacrificing the animals, hearts were isolated and perfused according to the Langendorff technique at gradually increased coronary perfusion pressures (40–120 cmH2O). The following parameters of cardiac function were continuously recorded: maximum and minimum rate of change of pressure in the left ventricle, systolic and diastolic left ventricular pressure, heart rate and coronary flow. The results showed statistically significant differences between all experimental groups in maximum and minimum rate of pressure development as well as in systolic pressure of the left ventricle, whereas cisplatin, ligand and the platinum(IV) complex had effects on heart contractility without significant influences on coronary circulation. The findings of the present study could be important for a better understanding of anticancer drug cardiac side effects. Our results indicate that compared to cisplatin as a “gold standard”, novel platinum complexes and ligands do not possess fewer negative effects on the heart, indicating insufficient safety for their usage in terms of affecting cardiac function, a result that can be of great interest for further investigations.

© 2018 Peptide and protein neurotoxins, such as α-conotoxins from Cone snails and α-neurotoxins from snake venoms, are excellent tools to identify distinct nicotinic acetylcholine receptor (nAChR) subtypes. Here we compared the rat/human species specificity of α7 nAChR towards peptide and protein neurotoxins and found that α-conotoxin analogues [K11A]TxIB and [H5D]RegIIA are much more potent on the rat versus human α7 receptor expressed in Xenopus oocytes. In the hope to determine the key residue responsible for the difference in α-conotoxin analogues affinities, ten single mutants of rat α7 nAChR were obtained because there are 10 differences in the extracellular ligand-binding domains of these species, and only K185R mutation decreased the affinity for α-conotoxins [K11A]TxIB and [H5D]RegIIA, down to their low affinities for human α7 nAChR. On the other hand, the reverse mutation R185K in human α7 nAChR resulted in the greatest increase in the affinity for both conotoxins, while a double mutation hα7[S183N, R185K] made the potency of the receptor for them as high as that of rat α7 nAChR. The effects of mutations at position 185 were investigated also with some other α-conotoxins and cobra venom α-cobratoxin and found to have similar but much less pronounced effects on their species specificity. Molecular modeling provided possible explanation for the high species selectivity of [K11A]TxIB and [H5D]RegIIA towards α7 nAChR, opening the new way for design of their analogues with improved affinity to the human receptor.

© 2017, Springer Science+Business Media, LLC. The overview demonstrates how the use of only one physico-chemical approach, viz., the electron paramagnetic resonance method, allowed detection and identification of dinitrosyl iron complexes with thiol-containing ligands in various animal and bacterial cells. These complexes are formed in biological objects in the paramagnetic (electron paramagnetic resonance-active) mononuclear and diamagnetic (electron paramagnetic resonance-silent) binuclear forms and control the activity of nitrogen monoxide, one of the most universal regulators of metabolic processes in the organism. The analysis of electronic and spatial structures of dinitrosyl iron complex sheds additional light on the mechanism whereby dinitrosyl iron complex with thiol-containing ligands function in human and animal cells as donors of nitrogen monoxide and its ionized form, viz., nitrosonium ions (NO+).