Mitokondrium, oxidatív stressz és öregedés

A z ötvenes években látott napvilágot az öregedés szabad gyökös elmélete, amely szerint a metabolikus útvonalak által termelt reaktív oxigénvegyületek lényeges szerepet kapnak az öregedés folyamatában. A teória később, a mitokond - rium reaktív oxigénvegyületek fő forrásaként történő azonosításával, módosításra került és az öregedés mitokondriá - lis elmélete néven vált ismertté. Ezt követően felvetették egy öregedési „ördögi kör” meglétét, amely szerint a mito - kondriális respiráció során képződő reaktív oxigénvegyületek károsítják a mitokondriális DNS-t, a mitokondriális funkciókat. A mitokondriális diszfunkció következtében megnő a termelődő reaktív oxigénvegyületek mennyisége. Ez az „ördögi kör” a mitokondriális DNS- mutációk felszaporodását válthatja ki, amely öregedéshez vezethet. A kö - zelmúltban létrehozott mtDNS-mutátor egerek mitokondriális DNS-replikációjáért felelős DNS-polimeráz γ exo - nukleáz aktivitását elrontották. Ennek következtében a mitokondriális DNS-ben a szomatikus mutációk száma megnövekedett és egy öregedő fenotípus alakult ki. Érdekes módon a mutáns egerekben sem emelkedett reaktívoxi - génvegyület- termelést , sem oxidatív károsodást nem tapasztaltak, amelyek erősen megkérdőjelezték az „ördögi kör” meglétét

Egy előzetes archeomalakológiai vizsgálat eredményei a kora neolit Alsónyék-Bátaszék lelőhelyről

Remnants of several cultures have been found since the mid-2000s on a large-scale archaeological rescue excavation at the borders of Alsónyék - Bátaszék, SW Hungary. Partial processing of the malacological material of Starcevo culture from the so-called Bátaszék-Mémökségi Telep has been carried out in recent years at the Department of Geology and Paleontology, University of Szeged. Following the taxonomic identification, heights and widths of the shells were determined, then the size distribution and the geochemical analysis were implemented. Geochemical results show that specimens were collected in a different hydrodynamic environment compared to the current conditions of the river Danube. Based on the samples, two periods can be separated, one with flood and high water velocity and one with a more stable conditions after the flood events. Similar results can be found at different non-Danubian archaeological sites with the same ages

The environmental history of a former salt town in Transylvania (Sic, Northern Romania)

The medieval market-town of Sic (Szék in Hungarian) was an important Transylvanian settlement due to its remarkable salt mining. The impact of the mining activities on the environment and the history of water management were investigated based on a palaeoecological study, performed on the large Reedbed of Sic (Stufărişurile/Nádas-tó). We found that in the last 3000 years the anthropogenic impact has been continuous in the territory, but the types and intensity of the disturbances changed with time. The most notable environmental transitions took place after 1000 AD, suggesting a significant intensification of salt mining. Forest cover significantly drop, but salt concentration and the frequency of halophytic species in the investigated marshland increased during the Late Middle Ages. The dominance of halophytic marshland species reached their peak in the 17th century. This coincides with the apogee of mining activities and human lake management. The most remarkable deforestation occurred in the 18th century, when the present-day landscape with negligible forest cover was developed

PARP Inhibition Attenuates Acute Kidney Allograft Rejection by Suppressing Cell Death Pathways and Activating PI-3K-Akt Cascade.

BACKGROUND Novel immunosuppressive therapy facilitates long term allograft survival, but acute tubular necrosis and ischemia-reperfusion during transplantation can compromise allograft function. These processes are related to oxidative stress which activates poly- (ADP-ribose) polymerase (PARP) contributing to the activation of cell death pathways. Here we raised the possibility that PARP inhibition curbs cell death pathways and shifts kinase signaling to improved graft survival. METHODS FINDINGS In an acute rat kidney rejection model, we provided evidence that the PARP inhibitor 4-hydroxy-quinazoline (4OHQ) attenuates rejection processes initiated oxidative/nitrosative stress, nuclear poly-ADP-ribosylation and the disintegration of the tubulo-interstitial structures. The PARP inhibitor attenuated rejection processes induced pro-apoptotic pathways by increasing Bcl-2/Bax ratio and suppressing pro-apoptotic t-Bid levels. In transplanted kidneys, the cell death inducing JNK1/2 is normally activated, but PARP inhibition suppressed this activation with having only modest effects on ERK1/2 and p38 MAP kinases. In untreated transplanted kidneys, no significant alterations were detected in the cytoprotective PI-3K-Akt pathway, but the PARP inhibitor significantly activated Akt (by S473 phosphorylation) and suppressed GSK-3β, as well as activated acute NF-kappaB activation contributing to graft protection. CONCLUSION These data show the protective role of PARP inhibition on graft survival by attenuating poly-ADP-ribosylation, oxidative stress, suppressing pro-apoptotic and increasing anti-apoptotic protein level, and by shifting MAP kinases and PI-3-K-Akt pathways to cytoprotective direction. Thus, addition of PARP inhibitors to standard immunosuppressive therapies during kidney transplantation may provide increased protection to prolong graft survival

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

Antioxidant and anti-inflammatory effects in RAW264.7 macrophages of malvidin, a major red wine polyphenol.

Background Red wine polyphenols can prevent cardiovascular and inflammatory diseases. Resveratrol, the most extensively studied constituent, is unlikely to solely account for these beneficial effects because of its rather low abundance and bioavailability. Malvidin is far the most abundant polyphenol in red wine; however, very limited data are available about its effect on inflammatory processes and kinase signaling pathways. METHODS FINDINGS: The present study was carried out by using RAW 264.7 macrophages stimulated by bacterial lipopolysaccharide in the presence and absence of malvidin. From the cells, activation of nuclear factor-kappaB, mitogen-activated protein kinase, protein kinase B/Akt and poly ADP-ribose polymerase, reactive oxygen species production, mitogen-activated protein kinase phosphatase-1 expression and mitochondrial depolarization were determined. We found that malvidin attenuated lipopolysaccharide-induced nuclear factor-kappaB, poly ADP-ribose polymerase and mitogen-activated protein kinase activation, reactive oxygen species production and mitochondrial depolarization, while upregulated the compensatory processes; mitogen-activated protein kinase phosphatase-1 expression and Akt activation. CONCLUSIONS These effects of malvidin may explain the previous findings and at least partially account for the positive effects of moderate red wine consumption on inflammation-mediated chronic maladies such as obesity, diabetes, hypertension and cardiovascular disease

Ice Age Terrestrial and Freshwater Gastropod Refugia in the Carpathian Basin, Central Europe

Thanks to its unique microclimatic, geomorphological , hydrological conditions forming a mosaic-like environment present at all scales, numerous Late Tertiary and Pleistocene warmth-loving gastropod taxa managed to find refugee within the Carpathian Basin during the major-minor cold spells of the Ice Age. This complex system of refugia have been continuously functioning and evolving since the Late Tertiary through the entire Pleistocene and the Holocene. To understand the spatial and temporal evolution of refugia, detailed paleoecological investigations have been implemented, results of which are summed here. The high-grade fractal-like complexity of the environment led to the emergence of a so-called dual refugia, which is a unique feature of the Carpathian Basin. This temporally parallel but spatially differing presence of habitats for taxa of contrasting ecological needs was noted for paleotemperature gradients and temperate woodland and steppe habitat types as well. Furthermore, detailed geological and paleoecological analysis of a small Pleistocene hot-spring fed pond revealed information about the evolution of endemic thermophylous freshwater gastropod taxa within this microrefugia. This chapter is aimed to give an overview of the nature, evolution of temperate terrestrial and freshwater gastropod refugia present in the Carpathian Basin during the Ice Age