The Role of COVID-19-Associated Fear, Stress and Level of Social Support in Development of Suicidality in Patients Diagnosed with Affective and Stress-Induced Psychiatric Disorders during the COVID-19 Pandemic-A Comparative Analysis.

Only a few studies seem to address suicidality as an effect of the COVID-19 pandemic in persons previously affected by psychiatric disorders. The relationship between fear and stress caused by the COVID-19 pandemic and the level of social support and suicidality in patients diagnosed with affective and stress-induced psychiatric disorders prior to the onset of the COVID-19 pandemic were investigated. This study was observational and involved 100 participants. The examined period was from April 2020 to April 2022. The Fear of COVID-19 Scale (FCV-19S), the Oslo Social Support Scale 3 (OSSS-3) and general psychiatric interviews were used to obtain data. A statistically significant relationship between the impact of COVID-19-related distress on the occurrence of suicidality and the year of the pandemic χ2(2, N = 100) = 8.347, p = 0.015 was observed. No statistically significant correlation was found between suicidal behavior, stress intensity, fear and the score on the social support scale (p > 0.05). Fear related to the COVID-19 pandemic can only be seen as a contributor to suicidality. Overall, social support does not always act protectively. Previously stressful experiences such as wars, poverty and natural disasters seem to play a significant role in the resilience to each new public health crisis.

Valorisation of Lignocellulosic Wastes, the Case Study of Eucalypt Stumps Lignin as Bioadsorbent for the Removal of Cr(VI).

The main objective of this work was to assess Eucalyptus globulus lignin as an adsorbent and compare the results with kraft lignin, which has previously been demonstrated to be an effective adsorbent. Eucalypt lignin was extracted (by the dioxane technique), characterised, and its adsorption properties for Cr(VI) ions were evaluated. The monomeric composition of both types of lignin indicated a high content of guaiacyl (G) and syringyl (S) units but low content of p-hydroxyphenyl (H), with an H:G:S ratio of 1:50:146 (eucalypt lignin) and 1:16:26 (kraft lignin), as determined by Py-GC/MS. According to elemental analysis, sulphur (2%) and sodium (1%) were found in kraft lignin, but not in eucalypt lignin. The adsorption capacity of the eucalypt lignin was notably higher than the kraft lignin during the first 8 h, but practically all the ions had been absorbed by both the eucalypt and kraft lignin after 24 h (93.4% and 95%, respectively). Cr(VI) adsorption onto both lignins fitted well using the Langmuir adsorption isotherm model, with capacities of 256.4 and 303.0 mg/g, respectively, for eucalypt and kraft. The study's overall results demonstrate the great potential of eucalypt lignin as a biosorbent for Cr(VI) removal from aqueous solutions.

'Green' coagulant application with activated carbon: dosing sequence and removal of selected micropollutants and effluent organic matter from municipal wastewater.

Combination of 'green' coagulation and powdered activated carbon adsorption was tested for removal of benzophenone (BP), benzophenone-3 (BP-3) and caffeine (CF) from treated municipal wastewater at realistic concentration levels (1-2 µg/L). At the same time it was tracked how the process affected effluent organic matter (EfOM) by measuring chemical oxygen demand (COD). Green coagulant was produced from dry common bean seed in laboratory. Combined coagulation-adsorption experiments were performed by applying different dosing sequences of process materials. Removal of hydrophobic BP and BP-3 by separate adsorption (from 79 to 98%) was not significantly hindered by the addition of the coagulant (activated carbon dose of 5 or 20 mg/L). However, in some cases negative effects were observed for hydrophilic caffeine, depending on the carbon dose, dosing sequence and presence of total suspended solids (TSS). Thus, when coagulant was firstly added into water without TSS before low activated carbon dose of 5 mg/L, caffeine removal dropped from 26% to 5%. Conversely, when TSS were present in the water sample, the removal of caffeine was not hindered under the same PAC dose and dosing sequence. The importance of the process optimisation related to removal of organic micropollutans of different hydrophilicity has been shown in this paper. Removal of around 30% of COD regardless of the dosing sequence was achieved.

Fast detection of apricot product frauds by added pumpkin via planar chromatography and chemometrics: Greenness assessment by analytical eco-scale.

The European Commission requires that fruit products distributed on the market meet standards of high quality and authenticity. For the quality assessment of apricot products susceptible to food fraud, an environmentally friendly, simple and cost-effective analytical profiling was developed by high-performance thin-layer chromatography multi-imaging (HPTLC-FLD/Vis). The new phytochemical profiling was applied for analysis of authentic samples (7 apricot and 5pumpkin samples) and simulated adulterated products (11 mixture samples prepared by addition of 2.5-53% pooled pumpkin to pooled apricot). Based on the analytical eco-scale assessment, the HPTLC-FLD/Vis method was proven as an excellent green analytical method with low energy and solvent consumption. Chemometric data analysis confirmed the difference between apricot and apricot-pumpkin mixtures based on the phytochemical profile. Chemical markers responsible for their differentiation were identified. The results indicated that frauds by adding pumpkin to apricot products can be detected at added contents as low as 2.5%.

Modelling and efficiency evaluation of the continuous biosorption of Cu(II) and Cr(VI) from water by agricultural waste materials.

As a result of intensive anthropogenic activities, population growth and unplanned urbanization, enormous quantities of organic and inorganic pollutants are discharged into the environment every year. The primary hazardous substances of concern regarding their environmental load and health effects are heavy metals. Heavy metal pollution of aquatic ecosystems, including resources of drinking water and water intended for food processing, has been of increasing interest. Biosorption technology is a promising strategy, as it utilizes industrial or agricultural wastes to remove metals from aqueous media passively, and they represent efficient, cost-effective and environmentally friendly alternatives to traditional adsorbents such as activated carbon. In this paper, the efficiency of biosorption of copper and chromium ions was examined using different agricultural waste biomass - sugar beet shreds, poplar sawdust and wheat straw. The possibility of applying a parallel sigmoidal (PS) model to describe the biosorption process was investigated to confirm its applicability to different types of biomass and various kinds of heavy metal ions. The results showed that the biosorption of copper ions using poplar sawdust and wheat straw consist of two steps. The moiety of one step in the overall process, defined by the parameter p, was determined to be 0.85 for poplar sawdust and 0.86 for wheat straw. These values, being less than 1, clearly indicate that the process consists of two simultaneous, kinetically different steps that shift in their dominance over the process and thus could be successfully modelled by the PS model. These studies also deal with the phenomenological examination of an unusual breakthrough curve obtained for the chromium ions biosorption by sugar beet shreds, by the comparative view of the process flow and changing the pH of the effluent. The clarification of the appearance of a double curve with a negative trend in one part allows adjusting the biosorption conditions to avoid the initial blockage of chromium ion binding to the adsorbent and thus increase the adsorption process efficiency.

Na, K-ATPase as a Biological Target for Gold(III) Complexes: A Theoretical and Experimental Approach.

BACKGROUND: Gold-based complexes represent a new class of potential metallodrugs. Although their action mechanism is not entirely understood, it was shown that gold complexes inhibit some enzymes' activities. Among them, Na,K-ATPase is emerging as an essential target for various anticancer drugs. The functionalization of nanoparticles by gold(III) complexes could facilitate their delivery into the cells and enable the following of their distribution in the target tissues. OBJECTIVE: The paper presents an overview of Na,K-ATPase interaction with representative and structurally related cytotoxic gold(III) complexes. The results obtained by the employment of theoretical methods (DFT and docking studies) combined with the experimental approach involving a variety of nanotechnology-base techniques (UV/Vis, Raman and fluorescence spectroscopy, CD, AFM, DLS) are discussed. Detailed information was obtained on the enzyme's conformational and structural changes upon binding the gold(III) complexes. The experimentally determined reaction parameters (constants of dissociation and the reaction stoichiometry) were predicted theoretically. CONCLUSION: The presented results offer further support to the view that Na,K-ATPase may be a relevant biomolecular target for cytotoxic gold(III) compounds of medicinal interest.

Drug delivery systems based on nanoparticles and related nanostructures.

A new approach to drug design based on nanoparticles and related nanostructures for effective drug delivery, is of great importance in future medical treatment, especially for cancer therapy. Nanomaterials hold tremendous potential for increasing the efficiency of drug delivery, with a high degree of biocompatibility. Additionally, for biomedical applications, they must be biodegradable, have prolonged circulation half-life, not tend to aggregate or cause an inflammatory response in the body and to be cost-effective. The efficacy of such structures is highly dependent on their chemical properties as well as on shape, charge, size, surface modifications and loading method. Here we focused on the potential of using different kinds of nanoparticles and similar nanostructures loaded with various drugs in order to achieve specific targeting and controlled drug release. Thereby, computational modeling on NPs-based drug delivery could help in providing a better understanding of all parts of the delivery system. This review emphasizes recent advances in the usage of various types of nanoparticles and similar nanostructures for drug delivery, aiming to provide a critical review of less toxic and more effective treatment.

Two aspects of honeydew honey authenticity: Application of advance analytical methods and chemometrics.

Taking into account a growing market and small number of articles related to honeydew honey, a metabolomic approach associated with multivariate analysis and modelling was proposed to discriminate five varieties of honey. Advanced analytical techniques were used for determination of 20 elements, 14 carbohydrates and stable carbon isotope ratio. No chemical marker has been found within sugar compounds, but several elements (Ba, Ca, Mg, Sr, Mn, Al, Co, Ni, Se) were marked as characteristic of honey type and allow classification of three botanical origins (Abies alba, Quercus frainetto, Quercus ilex). Sugars turanose, trehalose, arabinose and raffinose, elements Ba, Sr, P, Cd and Se, and δ13C values of honey, have different concentrations in honeys of the same botanical origin but harvested in different season. In addition to a confirmation of authenticity in terms of production, the values of δ13C of protein could be a good indicator of botanical origin.

Conjugates of Gold Nanoparticles and Antitumor Gold(III) Complexes as a Tool for Their AFM and SERS Detection in Biological Tissue.

Citrate-capped gold nanoparticles (AuNPs) were functionalized with three distinct antitumor gold(III) complexes, e.g., [Au(N,N)(OH)2][PF6], where (N,N)=2,2'-bipyridine; [Au(C,N)(AcO)2], where (C,N)=deprotonated 6-(1,1-dimethylbenzyl)-pyridine; [Au(C,N,N)(OH)][PF6], where (C,N,N)=deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine, to assess the chance of tracking their subcellular distribution by atomic force microscopy (AFM), and surface enhanced Raman spectroscopy (SERS) techniques. An extensive physicochemical characterization of the formed conjugates was, thus, carried out by applying a variety of methods (density functional theory-DFT, UV/Vis spectrophotometry, AFM, Raman spectroscopy, and SERS). The resulting gold(III) complexes/AuNPs conjugates turned out to be pretty stable. Interestingly, they exhibited a dramatically increased resonance intensity in the Raman spectra induced by AuNPs. For testing the use of the functionalized AuNPs for biosensing, their distribution in the nuclear, cytosolic, and membrane cell fractions obtained from human lymphocytes was investigated by AFM and SERS. The conjugates were detected in the membrane and nuclear cell fractions but not in the cytosol. The AFM method confirmed that conjugates induced changes in the morphology and nanostructure of the membrane and nuclear fractions. The obtained results point out that the conjugates formed between AuNPs and gold(III) complexes may be used as a tool for tracking metallodrug distribution in the different cell fractions.

Non-thermal plasma needle as an effective tool in dimethoate removal from water.

Intensive use of pesticides requires innovative approaches for their removal from the environment. Here we report the method for degradation of dimethoate in water using non-thermal plasma needle and analyze kinetics of dimethoate removal and possible degradation pathways. The effects of dimethoate initial concentration, plasma treatment time, Argon flow rate and the presence of radical promoters on the effectiveness of proposed method are evaluated. With argon flow rate of 0.5 slm (standard litres per minute) 1 × 10-4 M dimethoate can be removed within 30 min of treatment. Using UPLC analysis it was confirmed that one of the decomposition products is dimethoate oxo-analogue omethoate, which is in fact more toxic than dimethoate. However, the overall toxicity of contaminated water was reduced upon the treatment. The addition of H2O2 as a free radical promoter enhances dimethoate removal, while K2S2O8 results with selective conversion to omethoate. Using mass spectrometry in combination with the theoretical calculations, possible degradation pathways were proposed. The feasibility of the proposed method for dimethoate degradation in real water samples is confirmed. The proposed method is demonstrated as a highly effective approach for dimethoate removal without significant accumulation of undesirable toxic products and secondary waste.

A new approach for modelling and optimization of Cu(II) biosorption from aqueous solutions using sugar beet shreds in a fixed-bed column.

The potential use of sugar beet shreds for copper ions removal from aqueous solution in a fixed-bed column was investigated. Experiments were performed using Box-Behnken experimental design on three levels and three variables: concentration of the inlet solution (50-150 mg L-1), adsorbent dosage (8-12 g) and pH of the inlet solution (4.0-5.0). The obtained breakthrough curves were fitted with two common empirical models, Bohart-Adams and dose-response. Observing the asymmetric shape of the breakthrough curves, the new mathematical model was proposed. The new model proposes the breakthrough curve composed of two parts, sum of which gives the asymmetrical S-shaped curve, accurately matching experimental data. Regarding the lowest SSer (7.8·10-4) and highest R2 (0.9998), new model exhibited the best fit comparing to the commonly used models. RSM and ANN modelling were employed for process variables evaluation and optimization. The most influential parameter exhibiting negative influence on target response (critical time) was concentration of the inlet solution, while the adsorbent dosage exhibited positive influence. Optimization procedure revealed that the highest critical time (341.4 min) was achieved at following conditions: C0 = 50 mg·L-1, ma = 12 g and pH 4.53 by ANN, while RSM considered pH as insignificant factor and obtained 314.8 min as the highest response.

UV-C light irradiation enhances toxic effects of chlorpyrifos and its formulations.

UV-C irradiation is widely used in the food industry. However, the health effects from dietary exposure to the irradiated pesticide residues retained in foodstuffs are underestimated. In this study, technical chlorpyrifos (TCPF) and its oil in water (EW) and emulsifiable concentrate (EC) formulations were irradiated by UV-C, and their photodegradation products were subjected to toxicity assessment, including determination of acetylcholinesterase (AChE) activity, genotoxicity and oxidative stress using human blood cells as a model system. Toxicity studies were performed using the chlorpyrifos concentrations in the range of those proposed as the maximum residue levels in plant commodities. TCPF, EW and EC photodegradation products induced DNA damage and oxidative stress, and their genotoxicity did not decrease as a function of irradiation time. Irradiated TCPF and EC are more potent AChE inhibitors than irradiated EW. Accordingly, the application of UV-C irradiation must be considered when processing the plants previously treated with chlorpyrifos formulations.

Towards better quality criteria of European honeydew honey: Phenolic profile and antioxidant capacity.

Concerning the particular nutritive value of honeydew honey compared to blossom honey, and small number of studies defining botanical origin of honeydew honey, comprehensive analysis of phenolic profile of 64 honeydew honey samples of specific botanical origin was performed. Two advanced techniques of liquid chromatography hyphenated with mass spectrometry were used for identification of a total of 52 compounds and quantification of 25 of them. Pattern recognition analysis applied on data on phenolic compounds content confirmed that quercetin, naringenin, caffeoylquinic acid, hydroxyphenylacetic acid, apigenin and genistein, could be considered as potential markers of botanical origin of honeydew honey. Spectroscopic and electrochemical approaches were applied for the evaluation of the antioxidant capacity. Quercus sps. samples, Quercus frainetto and Quercus ilex, showed high biological activity and specific chemical composition. Additionally, cyclic voltammetry profiles were used for characterization and natural clustering of honeydew honey for the first time.

Interaction of Au(iii) and Pt(ii) complexes with Na/K-ATPase: experimental and theoretical study of reaction stoichiometry and binding sites.

The present paper deals with investigation of the interaction between selected simple structure Au(iii) ([AuCl4]-, [AuCl2(dmso)2]+, [AuCl2(bipy)]+) and Pt(ii) ([PtCl2(dmso)2]) complexes with Na/K-ATPase as the target enzyme, using an experimental and theoretical approach. Reaction stoichiometries and binding constants for these enzyme/complex systems were determined, while kinetic measurements were used in order to reveal the type of inhibition. Based on the results obtained by quantum mechanical calculations (electrostatic surface potential (ESP), volume and surface of the complexes) the nature of the investigated complexes was characterized. By using the solvent accessible surface area (SASA) applied on specific inhibitory sites (ion channel and intracellular domains) the nature of these sites was described. Docking studies were used to determine the theoretical probability of the non-covalent metal binding site positions. Inhibition studies implied that all the investigated complexes decreased the activity of the enzyme while the kinetic analysis indicated an uncompetitive mode of inhibition for the selected complexes. Docking results suggested that the main inhibitory site of all these complexes is located in the ion translocation pathway on the extracellular side in the E2P enzyme conformation, similar to the case of cardiac glycosides, specific Na/K-ATPase inhibitors. Also, based on our knowledge, the hydrolyzed forms of [AuCl4]- and [PtCl2(dmso)2] complexes were investigated for the first time by theoretical calculations in this paper. Thereby, a new inhibitory site situated between the M2 and M4 helices was revealed. Binding in this site induces conformational changes in the enzyme domains and perturbs the E1-E2P conformational equilibrium, causing enzyme inhibition.

Ruthenium(II)-N-alkyl phenothiazine complexes as potential anticancer agents.

In recent years, the search for effective anticancer compounds based on transition metal complexes has been the focus of medical investigations. The synergy between the ruthenium(II) and N-alkylphenothiazine counter-ions (chlorpromazine hydrochloride, thioridazine hydrochloride and trifluoperazine dihydrochloride, respectively) through the formation of three different complexes (1-3) was investigated. We explored whether the selected counter-ions and complexes might affect redox homeostasis and genome integrity of normal human blood cells, and induce an inhibition of Na+/K+-ATPase and AChE at pharmacologically relevant doses. Our results have shown that counter-ions and complexes did not affect the activity of Na+/K+-ATPase, while AChE activity was inhibited in a dose-dependent manner. All investigated compounds disturbed the viability and redox homeostasis of lymphocytes. Complexes 1 and 2 displayed potent cytotoxic and prooxidant action while complex 3 behaved as a weaker genotoxic inducer. Still, the tested complexes appeared to be less genotoxic and more cytostatic than the corresponding counter-ions. The effects of selected complexes were also tested in PC12 and U2OS cancer cells with special attention being given to the ability of phenothiazines to affect dopamine D2 receptors. Using the confocal laser scanning microscopy, we observed that all the complexes reduced cell viability. Although all investigated complexes have been bound to the dopamine receptor D2-eGFP, only complex 3 reduced its surface density and increased its lateral mobility in investigated cell lines. Albeit the role of alternative targets for complex 3 cannot be ruled out, its effects should be further examined as potential treatment strategy against cancer cells that overexpress D2.

Sulphur-containing Amino Acids: Protective Role Against Free Radicals and Heavy Metals.

BACKGROUND: Sulphur is an abundant element in biological systems, which plays an important role in processes essential for life as a constituent of proteins, vitamins and other crucial biomolecules. The major source of sulphur for humans is plants being able to use inorganic sulphur in the purpose of sulphur-containing amino acids synthesis. Sulphur-containing amino acids include methionine, cysteine, homocysteine, and taurine. Methionine and cysteine are classified as proteinogenic, canonic amino acids incorporated in protein structure. Sulphur amino acids are involved in the synthesis of intracellular antioxidants such as glutathione and N-acetyl cysteine. Moreover, naturally occurring sulphur-containing ligands are effective and safe detoxifying agents, often used in order to prevent toxic metal ions effects and their accumulation in human body. METHODS: Literature search for peer-reviewed articles was performed using PubMed and Scopus databases, and utilizing appropriate keywords. RESULTS: This review is focused on sulphur-containing amino acids - methionine, cysteine, taurine, and their derivatives - glutathione and N-acetylcysteine, and their defense effects as antioxidant agents against free radicals. Additionally, the protective effects of sulphur-containing ligands against the toxic effects of heavy and transition metal ions, and their reactivation role towards the enzyme inhibition are described. CONCLUSION: Sulphur-containing amino acids represent a powerful part of cell antioxidant system. Thus, they are essential in the maintenance of normal cellular functions and health. In addition to their worthy antioxidant action, sulphur-containing amino acids may offer a chelating site for heavy metals. Accordingly, they may be supplemented during chelating therapy, providing beneficial effects in eliminating toxic metals.

Modulators of Acetylcholinesterase Activity: From Alzheimer's Disease to Anti-Cancer Drugs.

BACKGROUND: Acetylcholinesterase (AChE) is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs for different neurodegenerative diseases (such as Alzheimer's and Parkinson's) as well as toxins. At the same time, there are increasing evidence that in non-neuronal context, AChE is involved in the regulation of cell proliferation, differentiation, apoptosis and cell-cell interaction. An irregular expression of AChE has been found in different types of tumors, suggesting the involvement of AChE in the regulation of tumor development. Having all this in mind, there is a possibility that some AChE inhibitors could be used as anti-cancer agents. OBJECTIVE: This contribution will discuss a broad range of possible application of different AChE inhibitors as drugs, from well-known anti-Alzheimer's disease drugs to their use in cancer treatment in future. Emphasis will be put on various known AChE inhibitors classes, whose application as drugs could be controversy, as well as on newly investigated natural products, which can also modulate AChE activity. CONCLUSION: It is not clear a patient treated for neurodegenerative condition prone to increased risk for some types of cancer and vice versa. This is necessary to keep in mind during rational drug design process for all therapies, which are based on AChE as a target molecule.

The impact of concentration and administration time on the radiomodulating properties of undecylprodigiosin in vitro.

Undecylprodigiosin pigment (UPP) is reported to display cytotoxic activity towards various types of tumours. Nevertheless, its efficacy in modifying the cellular response to ionising radiation is still unknown. In this study, the radiomodulating effects of UPP were investigated. The effects of UPP were assessed in vitro by treating cultures of human peripheral blood with UPP and ionising radiation using two treatment regimens, the UPP pre-irradiation treatment and UPP post-irradiation treatment. The activity of UPP was investigated evaluating its effects on the radiation-induced micronuclei formation, cell proliferation, and induction of apoptosis. The redox modulating effects of UPP were examined measuring the catalase activity and the level of malondialdehyde, as a measure of oxidative stress. The results showed that UPP effects on cellular response to ionising radiation depend on its concentration and the timing of its administration. At low concentration, the UPP displayed radioprotective effects in γ-irradiated human lymphocytes while at higher concentrations, it acted as a radiosensitiser enhancing either mitotic catastrophe or apoptosis depending on the treatment regimen. The UPP modified redox processes in cells, particularly when it was employed prior to γ-irradiation. Our data highlight the importance of further research of the potential of UPP to sensitize tumour cells to radiation therapy by inhibiting pathways that lead to treatment resistance.

The influence of oxo-bridged binuclear gold(III) complexes on Na/K-ATPase activity: a joint experimental and theoretical approach.

The in vitro effects of oxo-bridged binuclear gold(III) complexes, i.e., [(bipy2Me)2Au2(µ-O)2][PF6]2 (Auoxo6), Au2[(bipydmb-H)2(µ-O)][PF6] (Au2bipyC) and [Au2(phen2Me)2(µ-O)2](PF6)2 (Au2phen) on Na/K-ATPase, purified from the porcine cerebral cortex, were investigated. All three studied gold complexes inhibited the enzyme activity in a concentration-dependent manner achieving IC50 values in the low micromolar range. Kinetic analysis suggested an uncompetitive mode of inhibition for Auoxo6 and Au2bipyC, and a mixed type one for Au2phen. Docking studies indicated that the inhibitory actions of all tested complexes are related to E2-P enzyme conformation binding to ion channel and intracellular part between N and P sub-domain. In addition, Au2phen was able to inhibit the enzyme by interacting with its extracellular part as well. Toxic effects of the gold(III) complexes were evaluated in vitro by following lactate dehydrogenase activity in rat brain synaptosomes and incidence of micronuclei and cytokinesis-block proliferation index in cultivated human lymphocytes. All investigated complexes turned out to induce cytogenetic damage consisting of a significant decrease in cell proliferation and an increase in micronuclei in a dose-dependent manner. On the other hand, lactate dehydrogenase activity, an indicator of membrane integrity/viability, was not affected by Auoxo6 and Au2bipyC, while Au2phen slightly modified its activity.

Na/K-ATPase as a target for anticancer metal based drugs: insights into molecular interactions with selected gold(iii) complexes.

Na/K-ATPase is emerging as an important target for a variety of anticancer metal-based drugs. The interactions of Na/K-ATPase (in its E1 state) with three representative and structurally related cytotoxic gold(iii) complexes, i.e. [Au(bipy)(OH)2][PF6], bipy = 2,2'-bipyridine; [Au(pydmb-H)(CH3COO)2], pydmb-H = deprotonated 6-(1,1-dimethylbenzyl)-pyridine and [Au(bipydmb-H)(OH)][PF6], bipyc-H = deprotonated 6-(1,1-dimethylbenzyl)-2,2'-bipyridine, are investigated here in depth using a variety of spectroscopic methods, in combination with docking studies. Detailed information is gained on the conformational and structural changes experienced by the enzyme upon binding of these gold(iii) complexes. The quenching constants of intrinsic enzyme fluorescence, the fraction of Trp residues accessible to gold(iii) complexes and the reaction stoichiometries were determined in various cases. Specific hypotheses are made concerning the binding mode of these gold(iii) complexes to the enzyme and the likely binding sites. Differences in their binding behaviour toward Na/K-ATPase are explained on the ground of their distinctive structural features. The present results offer further support to the view that Na/K-ATPase may be a relevant biomolecular target for cytotoxic gold(iii) compounds of medicinal interest and may thus be involved in their overall mode of action.