A gluten-enteropathia kialakulását befolyásoló tényezők vizsgálata = Factors influencing the development of coeliac disease

Kutatásunk során új hajlamosító géneket írtunk le, melyet közrejátszhatnak a gluten-enteropathia (coeliakia) kialakulásában, ezek befolyásolják a T lymphocyták érését és kollaborációját a B sejtekkel, a toll-like receptorokat és a gyulladás során termelődő cytokineket. Megállapítottuk, hogy a coeliakia kialakulása és klinikai megjelenése asszociációt mutat a haptoglobin polimorfizmussal is, melyről a mi közlésünket követően független kutatók igazolták, hogy egyik altípusa azonos vékonybél permeabilitásában kulcsszerepet játszó zonulin molekulával. A kutatás során azonosítottuk a coeliakia-specifikus autoantitestek fő kötőhelyét az autoantigén, a 2-es típusú transzglutamináz enzim felszínén. Megállapítottuk, hogy a coeliakia antitestek betegség-specifikusan ugyanazt a komplex, háromdimenziós epitópot ismerik fel. Sejtkultúrában a coeliakia antitestek gátolják az erek képződését és fokozzák azok permeabilitását, elsősorban a RhoA túlzott aktiválásán keresztül. Megszerveztük és elvégeztük az első reprezentatív coeliakia szűrővizsgálatot Magyarországon. Megállapítottuk, hogy a coeliakia hazai előfordulása 1.3% körül van a magyar gyermekek és fiatal felnőttek körében. A szűrővizsgálatokra egyszerű, helyszíni antitest kimutatáson alapuló szűrő eljárást validáltunk. Kimutattuk, hogy a klinikailag fel nem ismert coeliakia kedvezőtlenül befolyásolja a hepatitis védőoltásra adott immunválaszt és az antitestek szerepet játszanak idegrendszeri szövődmény (ataxia) kialakulásában. | This research identified new susceptibility genes for coeliac disease, a common autoimmune enteropathy triggered by gluten peptides ingested with dietary cereals. The novel genes are mostly related to T-lymphocyte development, collaboration of T and B cells, toll-like receptors and cytokines. We also described association with haptoglobin polymorphism, a master regulator of intestinal permeability also known as zonulin. Predisposing alleles of these genes create a more inflammatory environment in the gut and in multiple copies confer additional risk to HLA-DQ alleles. We identified the main binding epitope of coeliac disease anti-transglutaminase 2 autoantibodies. This epitope has a complex, three-dimensional structure and is disease-specific. Patient antibodies targeting this epitope enhance the enzymatic activity of transglutaminase 2 and cause disturbances in the angiogenesis and vascular permeability in cell culture models via the inappropriate activation of RhoA. We performed the first representative population screening for coeliac disease in Hungary and established that the prevalence is around 1.3% in both children and young adults. The methodology of the screening has been advanced by the application of rapid, onsite antibody detection. Unrecognised coeliac disease was found to predispose to a defective immune response to hepatitis B vaccination (reversible after treatment) and we showed the contribution of coeliac disease antibodies in the late neural complications

Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation

Background: The sodium–glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. Methods: Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure–volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. Results: Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia–reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. Conclusions: Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials

Könyvszemle

1. Carole Hough (szerk.): The Oxford Handbook of Names and Naming = Oxford kézikönyv a nevekről és a névadásról 2. Oliviu Felecan (szerk.): Name and Naming. Sacred and Profane in Onomastics. Proceedings of the Fourth „Name and Naming” International Conference on Onomastics. September 5–7, 2017. = Név és névadás. Szent és profán a nevekben. A IV. „Név és Névadás” Nemzetközi Névtani Konferencia előadásai. 2017. szeptember 5–7. 3. Terhi Ainiala - Jan-Ola Östman (szerk.): Socio-onomastics. The pragmatics of names = Szocioonomasztika. A nevek pragmatikája 4. Star Medzerian Vanguri (szerk.): Rhetorics of Names and Naming = A nevek és a névadás retorikája 5. Bölcskei Andrea - Farkas Tamás - Slíz Mariann (szerk.): Magyar és nemzetközi névtani terminológia = Hungarian and International Onomastic Terminology 6. Újabb kötetek a magyar névkutatásról – angol nyelven 7. Vörös Ferenc (szerk.): A nyelvföldrajztól a névföldrajzig VIII. A nyelvterület keleti peremén. A 2017. május 30–31-i kolozsvári névföldrajzi tanácskozás előadásai 8. Patrick Hanks – Kate Hardcastle – Flavia Hodges: A Dictionary of First Names = Egyénnevek szótára 9. Fercsik Erzsébet – Raátz Judit: Örök névnaptár. A mai magyar keresztnevek legteljesebb gyűjteménye 10. Vörös Ferenc: Kárpát-medencei történeti családnévatlasz 11. Két kiadvány a magyarországi szlovákok családneveiről 12. Kanizsai Mária: Nevek, nyelvek, sorsok. Személynévvizsgálatok a Mura menti horvátok körében 1794-től 1998-ig 13. Szoták Szilvia (szerk.): Őrvidéki házinevek 14. Gabriele Rodríguez: Namen machen Leute. Wie Vornamen unser Leben beeinflussen = A név teszi az embert. Hogyan befolyásolják az egyénnevek az életünket? 15. Nikoletta Kanavou: The Names of Homeric Heroes. Problems and Interpretations = A homéroszi hősök nevei. Problémák és interpretációk 16. Marcienne Martin: A Name to Exist. The Example of the Pseudonym on the Internet = Egy név a létezésért. Az internetes álnév példája 17. Tóth Valéria: Személynévi helynévadás az ómagyar korban 18. Ditrói Eszter: Helynévrendszerek modellalapú vizsgálata. A helynévminták összevető analízise statisztikai megközelítésben 19. Kocán Béla: Helynévtörténeti vizsgálatok a régi Ugocsa megyében 20. Sebestyén Zsolt: A Felső-Tisza-vidék folyóvíznevei 21. Harald Bichlmeier (szerk.): Germanen, Mars und Schotter. Das Geheimnis des Namens Merseburg = Germánok, Mars és sóder. Merseburg nevének titka 22. Peter Jordan - Paul Woodman (szerk.): Place-Name Changes. Proceedings of the Symposion in Rome, 17–18 November 2014. = Helynévváltozások. A 2014. november 17–18-án Rómában tartott szimpózium előadásai 23. Jonas Löfström - Betina Schnabel-Le Corre (szerk.): Challenges in Synchronic Toponymy. Structure, Context and Use = Défis de la toponymie synchronique. Structures, contextes et usages = A szinkrón névföldrajz kihívásai. Rendszer, kontextus és használat 24. Gwilym Lucas Eades: The Geography of Names. Indigenous to post-foundational = A nevek földrajza. Ősi és kése

Influence of the Drug Position on Bioactivity in Angiopep-2—Daunomycin Conjugates

The blood–brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug–peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure–activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness

Influence of the Drug Position on Bioactivity in Angiopep-2—Daunomycin Conjugates

The blood–brain barrier (BBB) is a semipermeable system, and, therefore, most of the active substances are poorly transported through this barrier, resulting in decreased therapeutic effects. Angiopep-2 (TFFYGGSRGKRNNFKTEEY) is a peptide ligand of low-density lipoprotein receptor-related protein-1 (LRP1), which can cross the BBB via receptor-mediated transcytosis and simultaneously target glioblastomas. Angiopep-2 contains three amino groups that have previously been used to produce drug–peptide conjugates, although the role and importance of each position have not yet been investigated. Thus, we studied the number and position of drug molecules in Angiopep-2 based conjugates. Conjugates containing one, two, and three daunomycin molecules conjugated via oxime linkage in all possible variations were prepared. The in vitro cytostatic effect and cellular uptake of the conjugates were investigated on U87 human glioblastoma cells. Degradation studies in the presence of rat liver lysosomal homogenates were also performed in order for us to better understand the structure–activity relationship and to determine the smallest metabolites. Conjugates with the best cytostatic effects had a drug molecule at the N-terminus. We demonstrated that the increasing number of drug molecules does not necessarily increase the efficacy of the conjugates, and proved that modification of the different conjugation sites results in differing biological effectiveness

Synthesis and SAR Analysis of Novel 4-Hydroxytamoxifen Analogues Based on Their Cytotoxic Activity and Electron-Donor Character

Utilizing McMurry reactions of 4,4′-dihydroxybenzophenone with appropriate carbonyl compounds, a series of 4-Hydroxytamoxifen analogues were synthesized. Their cytotoxic activity was evaluated in vitro on four human malignant cell lines (MCF-7, MDA-MB 231, A2058, HT-29). It was found that some of these novel Tamoxifen analogues show marked cytotoxicity in a dose-dependent manner. The relative ROS-generating capability of the synthetized analogues was evaluated by cyclic voltammetry (CV) and DFT modeling studies. The results of cell-viability assays, CV measurements and DFT calculations suggest that the cytotoxicity of the majority of the novel compounds is mainly elicited by their interactions with cellular targets including estrogen receptors rather than triggered by redox processes. However, three novel compounds could be involved in ROS-production and subsequent formation of quinone-methide preventing proliferation and disrupting the redox balance of the treated cells. Among the cell lines studied, HT-29 proved to be the most susceptible to the treatment with compounds having ROS-generating potency