High Dose Fish Oil Added to Various Lipid Emulsions Normalizes Superoxide Dismutase 1 Activity in Home Parenteral Nutrition Patients

(1) Objectives: Intestinal failure in home parenteral nutrition patients (HPNPs) results in oxidative stress and liver damage. This study investigated how a high dose of fish oil (FO) added to various lipid emulsions influences antioxidant status and liver function markers in HPNPs. (2) Methods: Twelve HPNPs receiving Smoflipid for at least 3 months were given FO (Omegaven) for a further 4 weeks. Then, the patients were randomized to subsequently receive Lipoplus and ClinOleic for 6 weeks or vice versa plus 4 weeks of Omegaven after each cycle in a crossover design. Twelve age- and sex-matched healthy controls (HCs) were included. (3) Results: Superoxide dismutase (SOD1) activity and oxidized-low-density lipoprotein concentration were higher in all baseline HPN regimens compared to HCs. The Omegaven lowered SOD1 compared to baseline regimens and thus normalized it toward HCs. Lower paraoxonase 1 activity and fibroblast growth factor 19 (FGF19) concentration and, on the converse, higher alkaline phosphatase activity and cholesten concentration were observed in all baseline regimens compared to HCs. A close correlation was observed between FGF19 and SOD1 in baseline regimens. (4) Conclusions: An escalated dose of FO normalized SOD1 activity in HPNPs toward that of HCs. Bile acid metabolism was altered in HPNPs without signs of significant cholestasis and not affected by Omegaven

Porovnání cytotoxicity chelidoninu a homochelidoninu, dimethoxy analoga izolovaného z Chelidonium majus L. (Papaveraceae), vůči lidským leukemickým a plicním nádorovým buňkám

In this study the effects of naturally occurring homochelidonine in comparison to chelidonine on cell cycle progression and cell death in leukemic T-cells with different p53 status are described. We found that homochelidonine and chelidonine displayed significant cytotoxicity in examined blood cancer cells with the exception of HEL 92.1.7 and U-937 exposed to homochelidonine. Unexpectedly, homochelidonine and chelidonine-induced cytotoxicity was more pronounced in Jurkat cells contrary to MOLT-4 cells. Homochelidonine showed an antiproliferative effect on A549 cells but it was less effective compared to chelidonine. Biphasic dose-depended G1 and G2/M cell cycle arrest along with the population of sub-G1 was found after treatment with homochelidonine in MOLT-4 cells. In variance thereto, an increase in G2/M cells was detected after treatment with homochelidonine in Jurkat cells. Treatment with chelidonine induced cell cycle arrest in the G2/M cell cycle in both MOLT-4 and Jurkat cells. MOLT-4 and Jurkat cells treated with homochelidonine and chelidonine showed features of apoptosis such as phosphatidylserine exposure, a loss of mitochondrial membrane potential and an increase in the caspases -3/7, -8 and -9. Western blots indicate that homochelidonine and chelidonine exposure activates Chk1 and Chk2. Studies conducted with fluorescence microscopy demonstrated that chelidonine and homochelidonine inhibit tubulin polymerization in A549 cells. Collectively, the data indicate that chelidonine and homochelidonine are potent inducers of cell death in cancer cell lines, highlighting their potential relevance in leukemic cells.Tato práce porovnává cytotoxicitu chelidoninu a homochelidoninu vůči lidským leukemickým a plicním nádorovým buňkám. Výsledky studie naznačují, že chelidonin a homochelidonin jsou účinnými aktivátory apoptózy u nádorových buněčných linií

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

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

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

Quantitative Analysis of the Anti-Proliferative Activity of Combinations of Selected Iron-Chelating Agents and Clinically Used Anti-Neoplastic Drugs

<div><p>Recent studies have demonstrated that several chelators possess marked potential as potent anti-neoplastic drugs and as agents that can ameliorate some of the adverse effects associated with standard chemotherapy. Anti-cancer treatment employs combinations of several drugs that have different mechanisms of action. However, data regarding the potential interactions between iron chelators and established chemotherapeutics are lacking. Using estrogen receptor-positive MCF-7 breast cancer cells, we explored the combined anti-proliferative potential of four iron chelators, namely: desferrioxamine (DFO), salicylaldehyde isonicotinoyl hydrazone (SIH), (<i>E</i>)-<i>N′</i>-[1-(2-hydroxy-5-nitrophenyl)ethyliden] isonicotinoyl hydrazone (NHAPI), and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT), plus six selected anti-neoplastic drugs. These six agents are used for breast cancer treatment and include: paclitaxel, 5-fluorouracil, doxorubicin, methotrexate, tamoxifen and 4-hydroperoxycyclophosphamide (an active metabolite of cyclophosphamide). Our quantitative chelator-drug analyses were designed according to the Chou-Talalay method for drug combination assessment. All combinations of these agents yielded concentration-dependent, anti-proliferative effects. The hydrophilic siderophore, DFO, imposed antagonism when used in combination with all six anti-tumor agents and this antagonistic effect increased with increasing dose. Conversely, synergistic interactions were observed with combinations of the lipophilic chelators, NHAPI or Dp44mT, with doxorubicin and also the combinations of SIH, NHAPI or Dp44mT with tamoxifen. The combination of Dp44mT with anti-neoplastic agents was further enhanced following formation of its redox-active iron and especially copper complexes. The most potent combinations of Dp44mT and NHAPI with tamoxifen were confirmed as synergistic using another estrogen receptor-expressing breast cancer cell line, T47D, but not estrogen receptor-negative MDA-MB-231 cells. Furthermore, the synergy of NHAPI and tamoxifen was confirmed using MCF-7 cells by electrical impedance data, a mitochondrial inner membrane potential assay and cell cycle analyses. This is the first systematic investigation to quantitatively assess interactions between Fe chelators and standard chemotherapies using breast cancer cells. These studies are vital for their future clinical development.</p></div