Východiská: Mozgové nádory tvoria rôznorodú skupinu malignít charakterizovaných intertumorálnou aj intratumorálnou heterogenitou. Medzi najagresívnejší z nich radíme glioblastóm, ktorý je napriek pokrokom v súčasnej medicíne stále neliečiteľný. Jedným z dôvodov je vysoký stupeň rekurencie ochorenia a rezistencia na štandardne využívané chemoterapeutikum temozolomid. Preto mapovanie dráh zodpovedných za tumorigenézu na transkripčnej úrovni môže prispieť k determinovaniu príčin a stupňa agresivity medzi jednotlivými typmi gliálnych malignít. Súbor pacientov a metódy: Do súboru vzoriek boli zaradené biopsie od pacientov s astrocytómom (n = 6), glioblastómom (n = 22) a meningiómom (n = 14). Kontrolnú skupinu predstavovali RNA izolované zo zdravého ľudského mozgu (n = 3). Reverznou transkripciou získanú cDNA sme využili na kvantitatívnu analýzu pomocou Human Cancer PathwayFinder™ real-time PCR Array v 96 jamkovom formáte a pre každú vzorku sme stanovili expresiu 84 génov patriacich do 9 regulačných dráh (angiogenéza, apoptóza, bunkový cyklus a starnutie, poškodenie a oprava DNA, epiteliálno-mezenchymálny prechod, hypoxia, celkový metabolizmus a dynamika telomér). Výsledky: Určením relatívnej expresie vybraných génov sme charakterizovali profil jednotlivých mozgových malignít v kontexte signálnych dráh ovplyvňujúcich tumorigenézu. Zo všetkých sledovaných génov jednotlivých dráh sme zaznamenali dereguláciu u glioblastómov v 50 %, u meningiómov v 52,4 % a u astrocytómov v 53,6 %. Celkovo sme najvýraznejšie zmeny so štatistickou signifikanciou oproti kontrole zaznamenali u génov spájaných s epiteliálno-mezenchymálnou tranzíciou (CDH2, FOXC2, GSC, SNAI2 a SOX10), bunkovým starnutím (BMI1, ETS2, MAP2K1 a SOD1), opravou DNA (DDB2, ERCC3, GADD45G a LIG4) a dynamikou telomér (TEP1, TERF2IP, TNKS a TNKS2). Záver: Na základe získaných dát môžeme konštatovať, že jednotlivé diagnózy sa líšia v transkriptomickom profile. Prihliadnúc na tento fakt, je preto nevyhnutná potreba individuálneho molekulového prístupu s cieľom komplexnej a cielenej terapie na viacerých stupňoch nádorového metabolizmu.
Background: Brain tumors are a heterogeneous group of malignancies characterized by inter- and intratumoral heterogeneity. Among them, the most aggressive and, despite advances in medicine, still incurable remains glioblastoma. One of the reasons is the high recurrence rate of the disease and resistance to temozolomide, a golden standard in chemotherapy of brain tumors. Therefore, mapping the pathways responsible for tumorigenesis at the transcriptional level may help to determine the causes and aggressive behavior among different glial tumors. Patients and methods: Biopsies from patients with astrocytoma (N = 6), glioblastoma (N = 22), and meningioma (N = 14) were included in the sample set. A control group consisted of RNA isolated from healthy human brain (N = 3). The reverse-transcribed cDNAs were analyzed using the Human Cancer PathwayFinder™ real-time PCR Array in a 96-well format. The expression of 84 genes belonging to 9 signaling pathways (angiogenesis, apoptosis, cell cycle and senescence, DNA damage and repair, epithelial-to-mesenchymal transition, hypoxia, overall metabolism, and telomere dynamics) was determined for each sample. Results: By determining the relative expression of selected genes, we characterized the transcriptomic profile of individual brain malignancies in the context of signaling pathways involved in tumorigenesis. We observed deregulation in 50, 52.4 and 53.6% % of the genes in glioblastomas, meningiomas and astrocytomas, respectively. The most pronounced changes with statistical significance compared to control were observed in the genes associated with epithelial-to-mesenchymal transition (CDH2, FOXC2, GSC, SNAI2, and SOX10), cellular senescence (BMI1, ETS2, MAP2K1, and SOD1), DNA repair (DDB2, ERCC3, GADD45G, and LIG4), and dynamic of telomeres (TEP1, TERF2IP, TNKS, and TNKS2). Conclusion: Based on the obtained data, we can conclude that individual diagnoses differ in transcriptomic profile. An individual molecular approach is therefore necessary in order to provide comprehensive and targeted therapy on multiple metabolic pathways in the diagnosis of brain tumors.
Acute myocardial infarction (AMI) is one of the leading causes of death among adults in older age. Understanding mechanisms how organism responds to ischemia is essential for the ischemic patient's prevention and treatment. Despite the great prevalence and incidence only a small number of studies utilize a metabolomic approach to describe AMI condition. Recent studies have shown the impact of metabolites on epigenetic changes, in these studies plasma metabolites were related to neurological outcome of the patients making metabolomic studies increasingly interesting. The aim of this study was to describe metabolomic response of an organism to ischemic stress through the changes in energetic metabolites and aminoacids in blood plasma in patients overcoming acute myocardial infarction. Blood plasma from patients in the first 12 h after onset of chest pain was collected and compared with volunteers without any history of ischemic diseases via NMR spectroscopy. Lowered plasma levels of pyruvate, alanine, glutamine and neurotransmitter precursors tyrosine and tryptophan were found. Further, we observed increased plasma levels of 3-hydroxybutyrate and acetoacetate in balance with decreased level of lipoproteins fraction, suggesting the ongoing ketonic state of an organism. Discriminatory analysis showed very promising performance where compounds: lipoproteins, alanine, pyruvate, glutamine, tryptophan and 3-hydroxybutyrate were of the highest discriminatory power with feasibility of successful statistical discrimination.
- MeSH
- acetoacetáty krev MeSH
- biologické markery krev MeSH
- bolesti na hrudi krev patofyziologie MeSH
- infarkt myokardu krev diagnóza MeSH
- kyselina 3-hydroxymáselná krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- lipoproteiny krev MeSH
- magnetická rezonanční spektroskopie metody MeSH
- metabolom MeSH
- ROC křivka MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Oxidative stress and decline in cellular redox regulation have been hypothesized to play a key role in cardiovascular aging; however, data on antioxidant and redox regulating systems in the aging heart are controversial. The aim of the present study was to examine the effect of aging on critical antioxidant enzymes and two major redox-regulatory systems glutathione (GSH) and thioredoxin (Trx) system in hearts from adult (6-month-old), old (15-month-old), and senescent (26-month-old) rats. Aging was associated with a non-uniform array of changes, including decline in contents of reduced GSH and total mercaptans in the senescent heart. The activities of Mn-superoxide dismutase (SOD2), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TrxR) exhibited an age-related decline, whereas catalase was unchanged and Cu,Zn-superoxide dismutase (SOD1) displayed only slight decrease in old heart and was unchanged in the senescent heart. GR, Trx, and peroxiredoxin levels were significantly reduced in old and/or senescent hearts, indicating a diminished expression of these proteins. In contrast, SOD2 level was unchanged in the old heart and was slightly elevated in the senescent heart. Decline in GPx activity was accompanied by a loss of GPx level only in old rats, the level in senescent heart was unchanged. These results indicate age-related posttranslational protein modification of SOD2 and GPx. In summary, our data suggest that changes are more pronounced in senescent than in old rat hearts and support the view that aging is associated with disturbed redox balance that could alter cellular signaling and regulation.
- MeSH
- antioxidancia analýza metabolismus MeSH
- glutathionperoxidasa analýza metabolismus MeSH
- krysa rodu rattus MeSH
- myokard chemie enzymologie MeSH
- oxidace-redukce MeSH
- potkani Wistar MeSH
- stárnutí metabolismus MeSH
- superoxiddismutasa metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Bielkoviny tepelného šoku (heat shock proteins – HSPs) HSP27, HSP70 a HSP90 sú molekulárne šaperóny, ktorých expresia sa zvyšuje ovplyvnením buniek po pôsobení enviromentálneho stresu, akými sú tepelný šok, ťažké kovy, oxidačný stres alebo pri patologických podmienkach ako napr. ischémia, infekcia a zápal. Ich protektívna úloha pomáha bunke vyrovnať sa s letálnymi podmienkami. HSPs sú skupina bielkovín, ktoré v zdravých bunkách zodpovedajú za udržanie homeostázy, za interakciu s rôznymi bielkovinovými substrátmi na zabezpečenie ich správneho zbalenia, zabraňujú zbaľovaniu intermediátorov, ktoré vedú ku tvorbe chybne zbalených alebo poškodených molekúl. Ukázalo sa, že interagujú s rôznymi kľúčovými bielkovinami a zohrávajú úlohu v regulácii apoptózy. Viaceré bielkoviny tepelného šoku preukázali priamu interakciu s rozličnými zložkami úzko regulovanej kaspázovo-závislej programovanej bunkovej smrti. Tieto bielkoviny rovnako ovplyvňujú kaspázovo-nezávislú dráhu apoptózy väzbou s apoptickými faktormi. Bielkoviny tepelného šoku sú odlišne exprimované v hematologických malignitách. Z dôvodu ich asociácie a úlohy v leukémiách, HSPs predstavujú zaujímavý cieľ v antileukemickej terapii. Tento prehľadový článok opisuje rôzne molekuly intaragujúce s antiapoptotickými bielkovinami HSP70 a HSP90, ktoré by mohli byť využité v nádorovej terapii na základe ich inhibície. Klúčové slová:bielkoviny tepelného šoku – inhibítory – leukémia – apoptóza Táto práca bola podporená grantom „Zvýšenie možností kariérneho rastu vo výskume a vývoji v oblasti lekárskych vied“ (IMTS 26110230067), operačný program Vzdelávanie, doc. MUDr. Ján Staško, PhD., mim. prof., 2012–2015. Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy. Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do biomedicínských časopisů. Obdržané: 7. 8. 2015 Prijaté: 11. 10. 2015
Heat shock proteins (HSPs) HSP27, HSP70 and HSP90 are molecular chaperones; their expression is increased after exposure of cells to conditions of environmental stress, including heat shock, heavy metals, oxidative stress, or pathologic conditions, such as ischemia, infection, and inflammation. Their protective function is to help the cell cope with lethal conditions. The HSPs are a class of proteins which, in normal cells, are responsible for maintaining homeostasis, interacting with diverse protein substrates to assist in their folding, and preventing the appearance of folding intermediates that lead to misfolded or damaged molecules. They have been shown to interact with different key apoptotic proteins and play a crucial role in regulating apoptosis. Several HSPs have been demonstrated to directly interact with various components of tightly regulated caspase-dependent programmed cell death. These proteins also affect caspase-independent apoptosis by interacting with apoptogenic factors. Heat shock proteins are aberrantly expressed in hematological malignancies. Because of their prognostic implications and functional role in leukemias, HSPs represent an interesting target for antileukemic therapy. This review will describe different molecules interacting with anti-apoptotic proteins HSP70 and HSP90, which can be used in cancer therapy based on their inhibition.
- MeSH
- apoptóza fyziologie MeSH
- klinické zkoušky jako téma MeSH
- klinické zkoušky, fáze I jako téma MeSH
- klinické zkoušky, fáze II jako téma MeSH
- leukemie farmakoterapie MeSH
- lidé MeSH
- proteiny tepelného šoku HSP27 fyziologie metabolismus MeSH
- proteiny tepelného šoku HSP70 antagonisté a inhibitory fyziologie metabolismus účinky léků MeSH
- proteiny tepelného šoku HSP90 antagonisté a inhibitory fyziologie metabolismus účinky léků MeSH
- proteiny tepelného šoku * fyziologie metabolismus účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Altered Ca(2+) handling may be responsible for the development of cardiac contractile dysfunctions with advanced age. In the present study, we investigated the roles of oxidative damage to sarcoplasmic reticulum (SR) and expression of Ca(2+)-ATPase (SERCA 2a) and phospholamban in age-associated dysfunction of cardiac SR. SR vesicles were prepared from hearts of 2-, 6-, 15-, and 26-month-old Wistar rats. Although activity of Ca(2+)-ATPase decreased with advancing age, no differences in relative amounts of SERCA 2a and phospholamban protein were observed. On the other hand, significant accumulation of protein oxidative damage occurred with aging. The results of this study suggest that age-related alteration in Ca(2+)-ATPase activity in the rat heart is not a consequence of decreased protein levels of SERCA 2a and phospholamban, but could arise from oxidative modifications of SR proteins. Cellular oxidative damage caused by reactive oxygen species could contribute to age-related alternations in myocardial relaxation.
- MeSH
- Ca2+-ATPasy metabolismus MeSH
- krysa rodu rattus MeSH
- kultivované buňky MeSH
- myokard enzymologie patologie MeSH
- oxidace-redukce MeSH
- oxidační stres fyziologie MeSH
- potkani Wistar MeSH
- sarkoplazmatické retikulum enzymologie MeSH
- stárnutí patologie fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
