A szívizom sztressz-adaptációja: a peroxinitrit, a mátrix metalloproteinázok, és a hiperlipidémia szerepe = Stress adaptation of the myocardium: role of peroxynitrite, matrix metalloproteinases, and hyperlipidemia

A hiperlipidémia talaján kialakuló iszkémiás szívbetegség a leggyakoribb halálokok közé tartozik. A 4 éves project során a szívizom iszkémiának és az iszkémiás stressz adaptációs képességének (iszkémiás pre- és posztkondíció) celluláris mechanizmusait vizsgáltuk állatkísérletekben, különösképpen a peroxinitrit és celluláris targetjének, az MMP2-nek a szerepét. Új eredményeink közül néhányat emelünk ki. Kimutattuk, hogy hiperlipidemiában a szívben a peroxitrit képződés és ezáltal az MMP-2 aktivitása fokozódik, ami különösen hiperlipidmémiában jelentős, és ezt a folyamatot a prékondíció gátolja. DNA-chip vizsgálattal feltérképeztük hiperlipidémia hatására a génkifejeződés változásait a szívizomban. Kimutattuk, hogy az alacsony mértékű peroxinitrit képződés a stessz adaptáció kiváltásában igen fontos szerepet tölt be, hiszen olyan mechanizmusokat aktivál, melyek az iszkémiás stressz során túlzott mértékű peroxinitrit-MMP aktivitást csökkenti. Leírtuk, hogy nemspecifikus MMP gátlókkal az infarktus területe csökkenthető még hiperlipidémiás állatban is. Humán ApoB100 transzgenetikus eger modelleken megfigyeltük, hogy az oxidatív/nitrozatív stressz oka a hiperkoleszterinémia, és nem a hipertrigliceridémia. Kimutattuk továbbá, hogy a fiziológiás peroxinitrit szint, melyet a szívizom kapszaicin-érzékeny neuronjai szabályoznak, a normális szívizom relaxációt tartja fent. A project futamideje alatt az adott témában összesen 16 nemzetközi cikket (impakt faktor >70) közöltünk. | Ischemic heart disease developing due to hyperlipidemia is the number one killer in civilized societies. The present 4-year project was aiming at exploration of cellular mechanisms underlying stress adaptation of the myocardium, i.e. pre- and postconditioning, focusing on the role of peroxynitrite and its cellular target matrix metalloproteinase-2 (MMP2). Here we emphasize only some of the most important results of the project. We have shown that in hyperlipidemia, myocardial peroxynitrite formation and thereby MMP2 activity is increased, which is attenuated by preconditioning. We have mapped the changes in gene expression due to hyperlipidemia by the use of DNA-microarray assay. We have observed that moderate peroxynitrite formation is necessary to trigger the stress adaptation mechanisms, which in turn will decrease the pathological activation of the peroxynitrite-MMP2 signaling. We have shown that nonspecific MMP inhibitors are able to reduce infarct size even in the presence of hyperlipidemia. In human ApoB-100 transgene mice, we have observed that oxidative/nitrosative stress is due to hypercholesterolemia and not hypertriglyceridemia. Furthermore, we have shown that baseline physiological peroxynitrite formation, which is regulated by myocardial capsaicin-sensitive sensory nerves, plays an important role in the maintenance of normal relaxation of the myocardium. The present project yielded altogether 16 peer-reviewed papers (impact factor >70)

Comparison of propagation methods of different moss species used as wall and ground covering ornamental plants

Mosses are traditionally used as ornamental plants, especially in Japan, USA, England (moss gardens) and Germany, French (green roofs). In shadow areas (where the members of Poaceae usually cannot grow well), mosses are potentially use as “grass”. The stocks of moss colonies maintain optimal microclimate and decrease desiccation of soils (like mulch). Additionally, mosses are evergreen, attractive all year, during winter. In our study, 18 moss species were propagated by fragments (as mixture, with the use of 16 species) and transplantation of carpets (with Brachythecium rivulare and Calliergonella cuspidata) in Szentendre. The aim was to find the most durable species and the best way of propagation. In an outdoor, irrigated garden, propagation by fragments was effective (with 63% coveration) and higher values (93% and 76%) were obtained in the cases of non-irrigated stocks of Amblystegium serpens (in trays) and moss carpets. In vertical structures (moss picture-frames with the use of mixtures), protonema of 2 species (Hypnum cupressiforme and Eurhynchium hyans) covered 24 and 33% of the 0.5 x 0.5 m sized area

Comparison of propagation methods of different moss species used as wall and ground covering ornamental plants

Mosses are traditionally used as ornamental plants, especially in Japan, USA, England (moss gardens) and Germany, French (greenroofs). In shadow areas (where the members of Poaceae usually cannot grow well), mosses are potentially use as “grass”. The stocks of mosscolonies maintain optimal microclimate and decrease desiccation of soils (like mulch). Additionally, mosses are evergreen, attractive all year, duringwinter. In our study, 18 moss species were propagated by fragments (as mixture, with the use of 16 species) and transplantation of carpets(with Brachythecium rivulare and Calliergonella cuspidata) in Szentendre. The aim was to find the most durable species and the best wayof propagation. In an outdoor, irrigated garden, propagation by fragments was effective (with 63% coveration) and higher values (93% and76%) were obtained in the cases of non-irrigated stocks of Amblystegium serpens (in trays) and moss carpets. In vertical structures (mosspicture-frames with the use of mixtures), protonema of 2 species (Hypnum cupressiforme and Eurhynchium hyans) covered 24 and 33% ofthe 0.5 x 0.5 m sized area

A posztoperatív keringésváltozások jelentősége a májsebészetben

Absztrakt A máj rendhagyó keringéséért két afferens (arteria hepatica, vena portae) és egy efferens rendszer (venae hepaticae) felelős. Speciális vérellátásának köszönhetően az akut, izolált – szelektíven egy-egy érképletet érintő – vascularis okklúziók eltérő, életet veszélyeztető klinikopatológiai tünetegyütteshez vezethetnek, ezért azonnali felismerésük elengedhetetlen a máj állapota, illetve a beteg túlélésének szempontjából egyaránt. Akut keringészavarok kialakulásával elsősorban májműtétek kapcsán kell számolnunk. Az adekvát terápia mielőbbi megkezdése szempontjából kiemelten fontos a kóros keringési állapotok sajátosságainak pontos ismerete. Jelen tanulmány célja a szelektív posztoperatív keringési anomáliák etiológiájának, illetve tünettanának bemutatása, továbbá javaslat megfogalmazása a diagnosztikai lépések és a lehetséges terápia terén klinikai esetek ismertetése alapján. A szerzők bemutatják a májsebészetben használatos vascularis kirekesztés (Pringle-manőver) okozta ischaemiás-reperfúziós májkárosodást is. Orv. Hetil., 2015, 156(48), 1938–1948

Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling

The role of interleukin-24 in the pathomechanism of IBD-associated tissue remodeling

Abstract: Introduction: Intestinal fibrosis is a serious complication of inflammatory bowel diseases (IBD). Interleukin(IL)-24 is a member of IL-20 cytokine subfamily, which regulatory effect is suspected in connection with inflammation, apoptosis or tissue remodeling in other organs. Increased level of IL-24 was described in the colon of patients with active IBD, however its biological role is still poorly understood. Methods: Colonic presence of IL-24 and its receptor IL-20RB was investigated in the dextran-sodium sulfate (DSS) induced mice model of IBD (n=8; C57BL/6J). Impact of IL-24 on colonic extracellular matrix (ECM) production was investigated in the DSS treated wild type and IL-20RB knockout (KO) mice. Effect of intracolonic injection of IL-24 was also investigated. The role of IL-24 treatment on the expression of fibrosis related genes was investigated in colonic epithelial (HT-29) and fibroblast (CCD-18Co) cells. Results: Expression of IL-24 increased in colonic tissue of DSS-treated mice compared to controls. Lack of IL-24 receptor resulted in reduced ECM deposition in IL-20RB KO mice compared to wild type group. Local administration of IL-24 increased the expression of the fibrosis associated genes in the colon. IL-24 treatment increased the expression of TGF-ß1 and PDGF-B in HT-29, and that of COL1, COL3, FN1, MMP2, -9, TIMP1, -2 in CCD-18Co cells. Discussion: IL-24 may promote tissue remodeling shifted toward an excessive deposition of ECM components directly by acting on fibroblast and indirectly via induction of pro-fibrotic factors on epithelial cells. Our data suggest that inhibition of IL-24 may have a significant anti-fibrotic effect. Support: OTKA-K116928, VKE-2017-00006,EFOP-3.6.3-VEKOP-16-2017-00009,MTA-SE Pediatrics and Nephrology Research Group, János Bolyai Research Scholarship of the Hungarian Academy of Science