Új mechanizmusok azonosítása az oxidatív stressz indukálta mitokondrium-függő nekrotikus sejthalálban = Identification of novel mechanisms in the oxidative stress induced mitochondria-related necrotic cell death

Oxidatív stress körülményei között kimutattuk, hogy a PARP enzim gátlása növeli az MKP-1 expresszióját (ez a foszfatáz felelős elsődlegesen a JNK és p38 MAPK inaktivációjáért), ezért szerepet játszhat a PARP gátlás mediálta mitokondriális védelem folyamatában. LPS indukálta szeptikus shock modell rendszeren vizsgáltuk az Akt kináz mitokondriális targetjeit. Normál állatokban nem, míg a szeptikus shockban az MPT (mitochondrial permeability transition) előfordul, így azonosítani tudtuk a folyamatban részt vevő fehérjéket. Először írtuk le, hogy az Akt foszforilálni tudja a ciklofillin D-t, ezzel csökkentve az MPT folyamatát. Különböző technikákkal igazoltuk, hogy a PARP-1 direkt módon (ADP-ribozilálva) képes befolyásolni transzkripciós faktorokat, melyek az MKP-1, 2 illetve 3 expresszió szabályozásában vesznek részt. | In oxidative stress, we provided evidence that PARP inhibition increase the oxidative stress dependent expression of MKP-1 which is the main phosphatase responsible for the inactivation of JNK and p38 MAP kinase, and so it can play a role in the PARP inhibition mediated mitochondrial protection. Using control mouse liver and liver from LPS induced secptic shock models we isolated mitochondria, and isolated proteins by anti-Akt substrate antibodies. That way we could isolate mitochondrial targets of Akt kinase, and comparing the data we could detect which proteins are phosphorylated in septic shock. Since septic shock model animals mitochondrial permeability transition is taking place while in normal liver it is not, therefore these data may show which protein phosphorylation can contribute to mitochondrial permeability transition. Our data firstly indicated that Akt can phosphorylate cyclophilin D and thereby can prevent cyclophilin D dependent mitochondrial permeability transition. We identified the mechanism by which PARP-1 directly modulated (poly-ADP-ribosylates) nuclear transcription factors involved in the regulation of MKP-1, 2 & 3 expression

Munkahelyi stressz és megküzdési stratégiák vizsgálata földi és légi mentésben dolgozók körében | Examination of work-related stress and coping strategies among ambulance- and air-ambulance workers

Absztrakt Bevezetés: A magyar egészségügyi szférában dolgozók körében köztudott a magas fokú stresszhatás jelenléte, amely kihathat az egyénre. Célkitűzés: A földi és légi mentésben dolgozók körében feltárni a munkahelyi stresszt, annak mértékét, illetve a pozitív és negatív megküzdési stratégiáikat. Módszer: 2015. júniustól októberig vizsgálták Magyarországon a földi és légi mentésben dolgozókat. Az adatgyűjtést saját szerkesztésű, illetve a Rahe-féle, Rövidített Stressz- és Megküzdési Kérdőív segítségével online formában végezték. A kutatás keresztmetszeti típusú, kvantitatív jellegű volt (n = 141). Az adatelemzés SPSS 20.0 statisztikai szoftverrel történt. Szignifikanciahatár p<0,05 volt. Eredmények: Nagyobb a munkahelyi stresszhatás jelenléte a földi mentésben dolgozóknál (p<0,01), nagyobb mértékben jelentkeznek náluk testi és pszichológiai tünetek (p<0,05). A Globális Stressz és Megküzdési Index alapján hatékonyabb copingmechanizmus figyelhető meg a légi mentésben dolgozóknál (p<0,01). Következtetések: Aránytalanság áll fenn a dolgozót ért stresszhatás és az azzal való megküzdési mechanizmus közt. A munkahelyi stressz csökkentésében a munkahelyek humán menedzsmentjének alapvető szerepe és érdeke is kell, hogy legyen. Orv. Hetil., 2016, 157(45), 1802–1808. | Abstract Introduction: Among Hungary’s health sector workers the presence of a high level of stress is known, which can affect the individual. Aim: The aim of the authors was to uncover major risk factors causing work-related stress, as well as its extent, and positive and negative coping strategies among ground and aerial rescue workers. Method: From June until October 2015, a national survey was conducted among Hungarian rescue workers. An own questionnaire and Rahe Stress and coping validated short questionnaire online form were used. A total of 141 persons took part in the survey. Results: As compared to air-ambulance workers, ground rescue workers were exposed to higher work-related stress effects (p<0.01), resulting in a much larger variety of physical and psychological symptoms (p<0.05). Based on Global Stress and Coping Index effective coping mechanisms were observed among air rescue workers (p<0.01). Conclusions: It is important to perform regular professional theoretical and practical training. Human resource management should pay attention on occupational stress reduction. Orv. Hetil., 2016, 157(45), 1802–1808

Olaparib: A Clinically Applied PARP Inhibitor Protects from Experimental Crohn’s Disease and Maintains Barrier Integrity by Improving Bioenergetics through Rescuing Glycolysis in Colonic Epithelial Cells

Crohn's disease (CD) is an inflammatory disorder of the intestines characterized by epithelial barrier dysfunction and mucosal damage. The activity of poly(ADP-ribose) polymerase-1 (PARP-1) is deeply involved in the pathomechanism of inflammation since it leads to energy depletion and mitochondrial failure in cells. Focusing on the epithelial barrier integrity and bioenergetics of epithelial cells, we investigated whether the clinically applied PARP inhibitor olaparib might improve experimental CD. We used the oral PARP inhibitor olaparib in the 2,4,6-trinitrobenzene sulfonic acid- (TNBS-) induced mouse colitis model. Inflammatory scoring, cytokine levels, colon histology, hematological analysis, and intestinal permeability were studied. Caco-2 monolayer culture was utilized as an epithelial barrier model, on which we used qPCR and light microscopy imaging, and measured impedance-based barrier integrity, FITC-dextran permeability, apoptosis, mitochondrial oxygen consumption rate, and extracellular acidification rate. Olaparib reduced the inflammation score, the concentration of IL-1β and IL-6, enhanced the level of IL-10, and decreased the intestinal permeability in TNBS-colitis. Blood cell ratios, such as lymphocyte to monocyte ratio, platelet to lymphocyte ratio, and neutrophil to lymphocyte ratio were improved. In H(2)O(2)-treated Caco-2 monolayer, olaparib decreased morphological changes, barrier permeability, and preserved barrier integrity. In oxidative stress, olaparib enhanced glycolysis (extracellular acidification rate), and it improved mitochondrial function (mitochondrial coupling efficiency, maximal respiration, and spare respiratory capacity) in epithelial cells. Olaparib, a PARP inhibitor used in human cancer therapy, improved experimental CD and protected intestinal barrier integrity by preventing its energetic collapse; therefore, it could be repurposed for the therapy of Crohn's disease

Distinct Uptake Routes Participate in Silver Nanoparticle Engulfment by Earthworm and Human Immune Cells

The consequences of engineered silver nanoparticle (AgNP) exposure and cellular interaction with the immune system are poorly understood. The immunocytes of the Eisenia andrei earthworm are frequently applied in ecotoxicological studies and possess functional similarity to vertebrate macrophages. Hence, we characterized and compared the endocytosis mechanisms for the uptake of 75 nm AgNPs by earthworm coelomocytes, human THP-1 monocytes, and differentiated THP-1 (macrophage-like) cells. Our results indicate that microtubule-dependent, scavenger–receptor, and PI3K signaling-mediated macropinocytosis are utilized during AgNP engulfment by human THP-1 and differentiated THP-1 cells. However, earthworm coelomocytes employ actin-dependent phagocytosis during AgNPs uptake. In both human and earthworm immunocytes, AgNPs were located in the cytoplasm, within the endo-/lysosomes. We detected that the internalization of AgNPs is TLR/MyD88-dependent, also involving the bactericidal/permeability-increasing protein (BPI) in the case of human immunocytes. The exposure led to decreased mitochondrial respiration in human immunocytes; however, in coelomocytes, it enhanced respiratory parameters. Our findings provide more data about NP trafficking as nano-carriers in the nanomedicine field, as well as contribute to an understanding of the ecotoxicological consequences of nanoparticle exposure

Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the E-2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF’s active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds (4), (23), (24), (26) and (32), reduced inflammatory macrophage activation. Two of the selected compounds (24) and (26), however, markedly inhibited ROS and nitrite production, NF-κB activation, TNF-α, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound (24) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF’s tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation

Distinct Uptake Routes Participate in Silver Nanoparticle Engulfment by Earthworm and Human Immune Cells

The consequences of engineered silver nanoparticle (AgNP) exposure and cellular interaction with the immune system are poorly understood. The immunocytes of the Eisenia andrei earthworm are frequently applied in ecotoxicological studies and possess functional similarity to vertebrate macrophages. Hence, we characterized and compared the endocytosis mechanisms for the uptake of 75 nm AgNPs by earthworm coelomocytes, human THP-1 monocytes, and differentiated THP-1 (macrophage-like) cells. Our results indicate that microtubule-dependent, scavenger–receptor, and PI3K signaling-mediated macropinocytosis are utilized during AgNP engulfment by human THP-1 and differentiated THP-1 cells. However, earthworm coelomocytes employ actin-dependent phagocytosis during AgNPs uptake. In both human and earthworm immunocytes, AgNPs were located in the cytoplasm, within the endo-/lysosomes. We detected that the internalization of AgNPs is TLR/MyD88-dependent, also involving the bactericidal/permeability-increasing protein (BPI) in the case of human immunocytes. The exposure led to decreased mitochondrial respiration in human immunocytes; however, in coelomocytes, it enhanced respiratory parameters. Our findings provide more data about NP trafficking as nano-carriers in the nanomedicine field, as well as contribute to an understanding of the ecotoxicological consequences of nanoparticle exposure

Measuring and managing liquidity risk in the Hungarian practice

The crisis that unfolded in 2007/2008 turned the attention of the financial world toward liquidity, the lack of which caused substantial losses. As a result, the need arose for the traditional financial models to be extended with liquidity. Our goal is to discover how Hungarian market players relate to liquidity. Our results are obtained through a series of semistructured interviews, and are hoped to be a starting point for extending the existing models in an appropriate way. Our main results show that different investor groups can be identified along their approaches to liquidity, and they rarely use sophisticated models to measure and manage liquidity. We conclude that although market players would have access to complex liquidity measurement and management tools, there is a limited need for these, because the currently available models are unable to use complex liquidity information effectively