Redox cycling metals: Pedaling their roles in metabolism and their use in the development of novel therapeutics

Essential metals, such as iron and copper, play a critical role in a plethora of cellular processes including cell growth and proliferation. However, concomitantly, excess of these metal ions in the body can have deleterious effects due to their ability to generate cytotoxic reactive oxygen species (ROS). Thus, the human body has evolved a very well-orchestrated metabolic system that keeps tight control on the levels of these metal ions. Considering their very high proliferation rate, cancer cells require a high abundance of these metals compared to their normal counterparts. Interestingly, new anti-cancer agents that take advantage of the sensitivity of cancer cells to metal sequestration and their susceptibility to ROS have been developed. These ligands can avidly bind metal ions to form redox active metal complexes, which lead to generation of cytotoxic ROS. Furthermore, these agents also act as potent metastasis suppressors due to their ability to up-regulate the metastasis suppressor gene, N-myc downstream regulated gene 1. This review discusses the importance of iron and copper in the metabolism and progression of cancer, how they can be exploited to target tumors and the clinical translation of novel anti-cancer chemotherapeutics

Vyuziti latek chelatujicich zelezo pri prevenci poskozeni myokardu oxidativnim stresem.

Oxidative stress has been recognized as an important factor in the pathophysiology of a number of cardiovascular diseases, including the cardiotoxicity of anthracycline cytostatics (e.g. daunorubicin, doxorubicin) which are among the most important anticancer drugs.Their cardiac adverse effects seriously limit their clinical usefulness, as severe cardiomyopathy and congestive heart failure may develop in the late course, or any time after the completion of an anthracycline-containing chemotherapy. Although the definite pathophysiology of anthracycline-induced cardiotoxicity remains unknown, it is generally believed that the intracellular production of highly toxic hydroxyl free radicals plays the principal role. This production is largely dependent on the catalysis with bivalent iron ions. Consequently, therapeutic intervention aimed to displace free or loosely bound cellular iron may attenuate various free radical-mediated cell injuries, including the cardiotoxicity of anthracyclines. This can be achieved by the use of iron chelating agents.Several parts of the text are in English.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi

Transport and retention of surfactant- and polymer-stabilized engineered silver nanoparticles in silicate-dominated aquifer material.

Packed column experiments were conducted to investigate the transport and blocking behavior of surfactant- and polymer-stabilized engineered silver nanoparticles (Ag-ENPs) in saturated natural aquifer media with varying content of material < 0.063 mm in diameter (silt and clay fraction), background solution chemistry, and flow velocity. Breakthrough curves for Ag-ENPs exhibited blocking behavior that frequently produced a delay in arrival time in comparison to a conservative tracer that was dependent on the physicochemical conditions, and then a rapid increase in the effluent concentration of Ag-ENPs. This breakthrough behavior was accurately described using one or two irreversible retention sites that accounted for Langmuirian blocking on one site. Simulated values for the total retention rate coefficient and the maximum solid phase concentration of Ag-ENPs increased with increasing solution ionic strength, cation valence, clay and silt content, decreasing flow velocity, and for polymer-instead of surfactant-stabilized Ag-ENPs. Increased Ag-ENP retention with ionic strength occurred because of compression of the double layer and lower magnitudes in the zeta potential, whereas lower velocities increased the residence time and decreased the hydrodynamics forces. Enhanced Ag-ENP interactions with cation valence and clay were attributed to the creation of cation bridging in the presence of Ca2+. The delay in breakthrough was always more pronounced for polymer-than surfactant-stabilized Ag-ENPs, because of differences in the properties of the stabilizing agents and the magnitude of their zeta-potential was lower. Our results clearly indicate that the long-term transport behavior of Ag-ENPs in natural, silicate dominated aquifer material will be strongly dependent on blocking behavior that changes with the physicochemical conditions and enhanced Ag-ENP transport may occur when retention sites are filled

Protection of neonatal rat cardiomyocytes from toxicities induced by anthracyclines and hydrogen peroxide (H₂O₂).

<p>Cells were pre-incubated with three concentrations of dexrazoxane for 3 h and then co-incubated with increasing concentrations of anthracyclines daunorubicin (DAU, A) or doxorubicin (DOX, B) for 3 h following a 48-h anthracycline-free period or for 48 h with H₂O₂ (C). Toxicity was assessed as the % of total lactate dehydrogenase (LDH) released from cardiomyocytes into the cell culture medium. Data obtained from ≥4 independent experiments are expressed as the mean ± SD, statistical significance: c – compared with drug-free control (DMSO); d – compared with DAU or DOX; p – compared with H₂O₂ (one-way ANOVA with Dunnett’s post-test, P≤0.05).</p

Chemical structures of the anthracyclines and the topoisomerase II catalytic inhibitors used in this study.

<p>Anthracyclines doxorubicin (DOX) and daunorubicin (DAU) and topoisomerase II catalytic inhibitors dexrazoxane (DEX), sobuzoxane (SOB) and merbarone (MER) were used in this study.</p

Intracellular iron chelation properties.

<p>The intracellular iron (Fe) chelation by dexrazoxane (DEX), sobuzoxane (SOB) and merbarone (MER) was measured as the rate of Fe displacement from the Fe-calcein complex in H9c2 cardiomyoblast cell line. The change of fluorescence of the intracellular-trapped calcein in the H9c2 cells loaded with 100 µM ferric-ammonium citrate was assessed after adding the studied substances (100 µM) as described in Materials and methods section. The experimental strong Fe chelator SIH was used as a positive control. Data from 4 independent experiments are expressed as mean ± SD. Statistical significance: Two-way ANOVA Dunnet’s post-hoc test, P≤0.05; c–compared to control.</p

Cell-cycle analyses.

<p>The human acute promyelocytic leukaemia HL-60 cell line was incubated with dexrazoxane (DEX), sobuzoxane (SOB), merbarone (MER) and doxorubicin (DOX) and combinations thereof in concentrations corresponding to their IC₅₀ values for 72 h and then subjected to flow cytometry cell cycle analysis as described in the materials and methods. Data from 4 independent experiments are expressed as the mean ± SD, statistical significance: c – compared to untreated control cells; d – compared to DOX-treated cells (one-way ANOVA with Dunnett’s post-test, P≤0.05).</p

Elementy prawnonaturalne w stosowaniu Konstytucji RP [Natural-Law Elements in Application of the Constitution of the Republic of Poland]

Recognizing inherent and inalienable nature of dignity and universality of certain values, the Constitution of the Republic of Poland, introduces to the foundations of Polish legal system some elements of natural law which may be used for application of the Basic Law. Constitutional recognition of these elements only makes sense on the assumption of their cognizability. Therefore, as an important element of constitutional concept of natural law is taken the recognition of the argument of cognitivism according to which moral assessments may have the nature of judgments and truth qualification (they may be true or false). In the course of application of the constitution, norms of natural-law character and natural-law justification. Since dignity and the essence of freedoms and rights based on dignity are the only inviolable values recognized by the constitution, the arguments of natural law lead to a far-going reinterpretation of constitutional norms. The norm of natural law protecting inviolable values will have precedence in the event of collision with norms protecting other values, also with constitutional norms. Even if such a norm is formulated on the basis of the provisions of the constitution, in fact natural law is given higher rank than elements based only on enacted law. Despite that, reliability of a legally established order does not seem to be radically endangered. Konstytucja RP uznając przyrodzoność i niezbywalność godności oraz uniwersalność niektórych wartości, wprowadza do podstaw całego polskiego systemu prawnego elementy prawnonaturalne, które mogą być wykorzystane w stosowaniu konstytucji. Konstytucyjne uznanie takich elementów ma sens przy założeniu ich poznawalności, stąd istotnym elementem konstytucyjnej koncepcji prawa naturalnego jest uznanie tezy kognitywizmu głoszącej, że oceny moralne mogą mieć charakter sądów i kwalifikację prawdziwościową – mogą być prawdziwe lub fałszywe. W procesie stosowania konstytucji mogą być formułowane normy o charakterze prawnonaturalnym oraz uzasadnienia prawnonaturalne. Ponieważ jedynymi wartościami uznanymi w konstytucji za nienaruszalne jest godność oraz istota wolności i praw, których godność jest źródłem, argumentacja prawnonaturalna może prowadzić do daleko idącej reinterpretacji norm konstytucyjnych. Norma prawnonaturalna chroniąca warunki konieczne poszanowania godności lub istoty wolności i praw będzie miała pierwszeństwo w razie kolizji z normami chroniącymi inne wartości, także z normami konstytucyjnymi. Choć norma taka będzie formułowana na podstawie przepisów konstytucji, to jednak faktycznie prawo naturalne uzyskuje wyższą rangę od elementów opartych jedynie na stanowieniu. Mimo tego bezpieczeństwo prawne nie wydaje się być radykalnie zagrożone. O prawnonaturalnym charakterze normy i uzasadnienia decyduje oparcie w ocenach moralnych, które pretendują do bycia sądami, do bycia prawdziwymi lub fałszywymi. Z punktu widzenia stosowania konstytucji i wymogu intersubiektywnej komunikowalności i kontrolowalności dookreślania treści prawnonaturalnych, dla nadania ocenom charakteru sądów istotny jest kształt procedur i argumentacji prowadzących do tego dookreślenia. Powinny to być procedury i argumentacja typowe dla dyskursu mającego na celu sformułowanie prawdziwych sądów. Maksymalizowana powinna być dyskursywność takich procedur, a podstawą rozstrzygnięcia powinien być, jeśli to tylko możliwe, konsens. Nie mogą być uważane za rozstrzygające argumenty odwołujące się do woli indywidualnej lub zbiorowej, reakcji emocjonalnych, stopnia rozpowszechnienia danej oceny czy do tradycji kulturowej

Far-Red-Absorbing Cationic Phthalocyanine Photosensitizers: Synthesis and Evaluation of the Photodynamic Anticancer Activity and the Mode of Cell Death Induction

Novel zinc, magnesium, and metal-free octasubstituted phthalocyanine photosensitizers bearing [(triethylammonio)­ethyl]­sulfanyl substituents in the peripheral or nonperipheral positions were synthesized and investigated for their photophysical properties (Φ_Δ value up to 0.91, λ_max up to 750 nm) and photodynamic anticancer activity. The photodynamic treatment of 3T3, HeLa, SK-MEL-28, and HCT 116 cancer cells revealed that the magnesium complexes were not active (IC₅₀ > 100 μM), whereas the IC₅₀ values of the zinc complexes typically reached values in the submicromolar range with low toxicity in the dark (TC₅₀ ≈ 1500 μM). The subcellular changes upon photodynamic treatment of the HeLa cells indicated that the studied photosensitizers induced damage primarily to the lysosomes, which was followed by a relocalization and damage to other organelles. The time-lapse morphological changes along with the flow cytometry and caspase activity measurements indicated a predominant involvement of necrosis-like cell death