Peri-infarktus depolarizáció (PID) akut fokális agyi ischemiában = Peri-infarct depolarization (PID) in acute focal cerebral ischemia

Az itt elvégzett kutatás célja az volt, hogy megértsük a stroke során kialakuló peri-infarktus depolarizációk (PID) természetét, és azok szerepét az agyi infarktus kiterjedésének növekedésében. Az előirányzott kísérletek újonnan kifejlesztett képalkotó eljárásokra támaszkodtak, melyeket a stroke különböző patkány modelljeiben alkalmaztunk. A kutatás során három fő célkitűzés teljesült: kifejlesztettünk egy többkomponensű képalkotó eljárást az agyi membránpotenciál-változások és a velük járó hemodinamikai jelenségek direkt megfigyelésére. A laboratóriumunkban kidolgozott módszert egy kísérletes, globális agyi ischemia modellben alkalmaztuk; eredményeink arra engedtek következtetni, hogy az így regisztrált PID-k az agyszövetre káros hatást fejtettek ki, és súlyosbították a stroke kimenetelét. Végül módszerünk segítségével a PID-k tulajdonságait egy kísérletes, fokális agyi ischemia modellben is jellemeztük, amelyben a korai fázisra jellemző PID-k valószínűleg nem növelték az ischemiás károsodás mértékét. Megfigyeléseink árnyalják az eddig érvényben levő hipotézist, mely szerint a PID-k minden esetben károsítják az ischemiás szövetet: azok a PID-k, amelyekkel nem jár repolarizáció és inverz neurovaszkuláris csatolás jellemzi, károsak a sérült agyszövetre, míg azok a PID-k amelyek a mebránpotenciál gyors helyreállásával és tranziens hiperémiával járnak, nem mélyítik at ischemiás károsodást. | Our overall aim was to improve our understanding of the genesis and propagation of stroke-related peri-infarct depolarization (PID), and of their contribution to infarct expansion and maturation. The proposed research relied on novel imaging techniques applied to relevant rat models. The research has obtained 3 goals: First, a multi-modal, live imaging strategy was established to monitor membrane potential variations and associated hemodynamic changes in the brain cortex directly. Second, the technology designed and developed in our lab was applied in a global ischemia model, in which PID proved to be deleterious to the tissue and are proposed to contribute to infarct evolution. Third, our method was used to detect PID in a focal ischemia model, in which early PID appeared to be harmless to the brain, and are suggested not to worsen ischemia outcome. Our observations modify the view held so far, that PID are invariably damaging to the brain tissue. Instead, PID that are not followed by the recovery of membrane potential and involve inverse neurovascular coupling (i.e. decreased CBF) are suggested to be destructive, while PID with repolarization and associated transient functional hyperemia appear not to be harmful to the nervous tissue

Liposomes for topical use: physico-chemical comparison of vesicles prepared from egg or soy lecithin

Developments in nanotechnology and in the formulation of liposomal systems provide the opportunity for cosmetic dermatology to design novel delivery systems. Determination of their physico-chemical parameters has importance when developing a nano-delivery system. The present study highlights some technological aspects/characteristics of liposomes formulated from egg or soy lecithins for topical use. Alterations in the pH, viscosity, surface tension, and microscopic/macroscopic appearance of these vesicular systems were investigated. The chemical composition of the two types of lecithin was checked by mass spectrometry. Caffeine, as a model molecule, was encapsulated into multilamellar vesicles prepared from the two types of lecithin: then zeta potential, membrane fluidity, and encapsulation efficiency were compared. According to our observations, samples prepared from the two lecithins altered the pH in opposite directions: egg lecithin increased it while soy lecithin decreased it with increased lipid concentration. Our EPR spectroscopic results showed that the binding of caffeine did not change the membrane fluidity in the temperature range of possible topical use (measured between 2 and 50 °C). Combining our results on encapsulation efficiency for caffeine (about 30% for both lecithins) with those on membrane fluidity data, we concluded that the interaction of caffeine with the liposomal membrane does not change the rotational motion of the lipid molecules close to the head group region. In conclusion, topical use of egg lecithin for liposomal formulations can be preferred if there are no differences in the physico-chemical properties due to the encapsulated drugs, because the physiological effects of egg lecithin vesicles on skin are significantly better than that of soy lecithin liposomes

NRF2-ome: An integrated web resource to discover protein interaction and regulatory networks of NRF2

NRF2 is the master transcriptional regulator of oxidative and xenobiotic stress responses. NRF2 has important roles in carcinogenesis, inflammation, and neurodegenerative diseases. We developed an online resource, NRF2-ome, to provide an integrated and systems-level database for NRF2. The database contains manually curated and predicted interactions of NRF2 as well as data from external interaction databases. We integrated NRF2 interactome with NRF2 target genes, NRF2 regulating TFs, and miRNAs. We connected NRF2-ome to signaling pathways to allow mapping upstream NRF2 regulatory components that could directly or indirectly influence NRF2 activity totaling 35,967 protein-protein and signaling interactions. The user-friendly website allows researchers without computational background to search, browse, and download the database. The database can be downloaded in SQL, CSV, BioPAX, SBML, PSI-MI, and in a Cytoscape CYS file formats. We illustrated the applicability of the website by suggesting a posttranscriptional negative feedback of NRF2 by MAFG protein and raised the possibility of a connection between NRF2 and the JAK/STAT pathway through STAT1 and STAT3. NRF2-ome can also be used as an evaluation tool to help researchers and drug developers to understand the hidden regulatory mechanisms in the complex network of NRF2. © 2013 Dénes Türei et al

Signalogs: Orthology-Based Identification of Novel Signaling Pathway Components in Three Metazoans

BACKGROUND: Uncovering novel components of signal transduction pathways and their interactions within species is a central task in current biological research. Orthology alignment and functional genomics approaches allow the effective identification of signaling proteins by cross-species data integration. Recently, functional annotation of orthologs was transferred across organisms to predict novel roles for proteins. Despite the wide use of these methods, annotation of complete signaling pathways has not yet been transferred systematically between species. PRINCIPAL FINDINGS: Here we introduce the concept of 'signalog' to describe potential novel signaling function of a protein on the basis of the known signaling role(s) of its ortholog(s). To identify signalogs on genomic scale, we systematically transferred signaling pathway annotations among three animal species, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and humans. Using orthology data from InParanoid and signaling pathway information from the SignaLink database, we predict 88 worm, 92 fly, and 73 human novel signaling components. Furthermore, we developed an on-line tool and an interactive orthology network viewer to allow users to predict and visualize components of orthologous pathways. We verified the novelty of the predicted signalogs by literature search and comparison to known pathway annotations. In C. elegans, 6 out of the predicted novel Notch pathway members were validated experimentally. Our approach predicts signaling roles for 19 human orthodisease proteins and 5 known drug targets, and suggests 14 novel drug target candidates. CONCLUSIONS: Orthology-based pathway membership prediction between species enables the identification of novel signaling pathway components that we referred to as signalogs. Signalogs can be used to build a comprehensive signaling network in a given species. Such networks may increase the biomedical utilization of C. elegans and D. melanogaster. In humans, signalogs may identify novel drug targets and new signaling mechanisms for approved drugs

SignaLink 2 - a signaling pathway resource with multi-layered regulatory networks.

BACKGROUND Signaling networks in eukaryotes are made up of upstream and downstream subnetworks. The upstream subnetwork contains the intertwined network of signaling pathways, while the downstream regulatory part contains transcription factors and their binding sites on the DNA as well as microRNAs and their mRNA targets. Currently, most signaling and regulatory databases contain only a subsection of this network, making comprehensive analyses highly time-consuming and dependent on specific data handling expertise. The need for detailed mapping of signaling systems is also supported by the fact that several drug development failures were caused by undiscovered cross-talk or regulatory effects of drug targets. We previously created a uniformly curated signaling pathway resource, SignaLink, to facilitate the analysis of pathway cross-talks. Here, we present SignaLink 2, which significantly extends the coverage and applications of its predecessor. DESCRIPTION We developed a novel concept to integrate and utilize different subsections (i.e., layers) of the signaling network. The multi-layered (onion-like) database structure is made up of signaling pathways, their pathway regulators (e.g., scaffold and endocytotic proteins) and modifier enzymes (e.g., phosphatases, ubiquitin ligases), as well as transcriptional and post-transcriptional regulators of all of these components. The user-friendly website allows the interactive exploration of how each signaling protein is regulated. The customizable download page enables the analysis of any user-specified part of the signaling network. Compared to other signaling resources, distinctive features of SignaLink 2 are the following: 1) it involves experimental data not only from humans but from two invertebrate model organisms, C. elegans and D. melanogaster; 2) combines manual curation with large-scale datasets; 3) provides confidence scores for each interaction; 4) operates a customizable download page with multiple file formats (e.g., BioPAX, Cytoscape, SBML). Non-profit users can access SignaLink 2 free of charge at http://SignaLink.org. CONCLUSIONS With SignaLink 2 as a single resource, users can effectively analyze signaling pathways, scaffold proteins, modifier enzymes, transcription factors and miRNAs that are important in the regulation of signaling processes. This integrated resource allows the systems-level examination of how cross-talks and signaling flow are regulated, as well as provide data for cross-species comparisons and drug discovery analyses

SignaLink 2 - a signaling pathway resource with multi-layered regulatory networks

ABSTRACT: BACKGROUND: Signaling networks in eukaryotes are made up of upstream and downstream subnetworks. The upstream subnetwork contains the intertwined network of signaling pathways, while the downstream regulatory part contains transcription factors and their binding sites on the DNA as well as microRNAs and their mRNA targets. Currently, most signaling and regulatory databases contain only a subsection of this network, making comprehensive analyses highly time-consuming and dependent on specific data handling expertise. The need for detailed mapping of signaling systems is also supported by the fact that several drug development failures were caused by undiscovered cross-talk or regulatory effects of drug targets. We previously created a uniformly curated signaling pathway resource, SignaLink, to facilitate the analysis of pathway cross-talks. Here, we present SignaLink 2, which significantly extends the coverage and applications of its predecessor.Description: We developed a novel concept to integrate and utilize different subsections (i.e., layers) of the signaling network. The multi-layered (onion-like) database structure is made up of signaling pathways, their pathway regulators (e.g., scaffold and endocytotic proteins) and modifier enzymes (e.g., phosphatases, ubiquitin ligases), as well as transcriptional and post-transcriptional regulators of all of these components. The user-friendly website allows the interactive exploration of how each signaling protein is regulated. The customizable download page enables the analysis of any user-specified part of the signaling network. Compared to other signaling resources, distinctive features of SignaLink 2 are the following: 1) it involves experimental data not only from humans but from two invertebrate model organisms, C. elegans and D. melanogaster; 2) combines manual curation with large-scale datasets; 3) provides confidence scores for each interaction; 4) operates a customizable download page with multiple file formats (e.g., BioPAX, Cytoscape, SBML). Non-profit users can access SignaLink 2 free of charge at http://SignaLink.org CONCLUSIONS: With SignaLink 2 as a single resource, users can effectively analyze signaling pathways, scaffold proteins, modifier enzymes, transcription factors and miRNAs that are important in the regulation of signaling processes. This integrated resource allows the systems-level examination of how cross-talks and signaling flow are regulated, as well as provide data for cross-species comparisons and drug discovery analyses

A De Quervain-féle tendinopathia kezelése konzervatív módszerekkel = Treatment of De Quervain’s tendinopathy with conservative methods

Absztrakt: Bevezetés: A De Quervain-féle tendinopathia a csukló-kéz régióját érintő betegség. A hüvelykujj mozgatása fájdalmassá válik, a kéz funkciója jelentősen romlik. A betegség a legújabb kutatások szerint inkább degeneratív, semmint gyulladásos eredetű. Első lépésként a kéz sínezése, nemszteroid gyulladáscsökkentő szerek és különböző fizikoterápiás kezelések alkalmazása javasolt. Hatástalanságuk esetén további lehetőség az ínhüvelybe fecskendezett szteroidinjekció és a műtéti úton végzett ínhüvelybemetszés. Célkitűzés: Kutatásunkban megvizsgáltuk, hogy az excentrikus tréninggel kibővített konzervatív kezelés megfelelő alternatíváját nyújthatja-e a jelenleg elfogadott kezelési lehetőségeknek. Módszer: Az excentrikus tréning 8 hétig tartott, melyet indokolt esetben 12 hetesre bővítettünk. A betegek (n = 9) a betanítást követően naponta többször végezték a tréninget, amit a heti találkozók alkalmával kontrolláltunk. Az 1., a 8., valamint a 12. heti találkozó során az inspekciót követően mértük az ízületi mozgástartományt, az izomerőt, a fájdalmas régiók számát, illetve elvégeztük a ’Numeric Pain Rating Scale’, a ’Quick Disabilities of the Arm, Shoulder and Hand’, valamint a ’Patient-Rated Wrist Evaluation’ kérdőívek felvételét. A méréseket páros mintás t-teszttel és ismételt méréses varianciaanalízissel elemeztük. Az elemzéseket IBM SPSS Statistics 25.0 és Microsoft Office Excel Professional Plus 2016 programmal végeztük; p<0,05 esetén tekintettük statisztikailag szignifikánsnak eredményeinket. Eredmények: Szignifikáns javulást mértünk a fájdalom intenzitása (’Numeric Pain Rating Scale’ p = 0,005, n = 9) és a kéz, valamint a csukló funkciója terén (’Quick Disabilities of the Arm, Shoulder and Hand Outcome Measure’ kérdőív 1. rész p<0,001, 2. rész p<0,001, ’Patient-Rated Wrist Evaluation’ kérdőív p<0,001; n = 9). Következtetés: Eredményeink alapján megfelelő betegbeválasztás mellett az excentrikus tréninggel kibővített konzervatív kezelés valós alternatívája lehet a jelenleg alkalmazott kezeléseknek. Orv Hetil. 2020; 161(11): 419–424. | Abstract: Introduction: De Quervain’s tendinopathy affects the region of the wrist and the hand. Thumb motion becomes painful. This illness is caused by a degenerative process rather than inflammation. Primary treatment methods are splinting, taking non-steroid anti-inflammatory drugs and different physical therapeutic modalities, administration of a steroid injection into the tendon sheath or surgical release of the tendon sheath may be performed. Aim: The aim of the present study was to investigate whether conservative treatment complemented by eccentric training could provide an adequate alternative to the currently accepted treatment options. Method: The eccentric training lasted for 8 weeks (if necessary for 12 weeks). Following the introduction to exercises, patients (n = 9) repeated the training several times a day, which was controlled during weekly meetings. At the 1st, 8th and 12th meetings, inspection and the following measurements were performed: range of motion, muscle strength, evaluation and number of painful regions including the completion of patient questionnaires. Data were analysed with paired samples t-tests and repeated measures ANOVA. IBM SPSS Statistics 25.0 and Microsoft Office Excel Professional Plus 2016 programs were used. Results were regarded significant at level of p<0.05. Results: Significant improvements were found in the intensity of pain (Numeric Pain Rating Scale p = 0.005, n = 9) and in the functionality of the hand and wrist (Quick Disabilities of the Arm, Shoulder and Hand questionnaire part 1. p<0.001, part 2. p<0.001, Patient-Rated Wrist Evaluation questionnaire p<0.001; n = 9). Conclusion: With careful patient selection, conservative treatment complemented by eccentric training could be an alternative to current treatment options. Orv Hetil. 2020; 161(11): 419–424