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Farkas S.,Debrecen University | Nagy K.,Debrecen University | Palkovits M.,Semmelweis University | Kovacs G.G.,Medical University of Vienna | And 9 more authors.
Neurochemistry International | Year: 2012

The cannabinoid type-1 receptor (CB 1R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB 1Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB 1R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB 1R radioligand to investigate regional variations in CB 1R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer's disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB 1Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB 1R autoradiography with [ 125I]SD-7015 as radioligand. Regional concentration of [ 125I]SD-7015, corresponding to, and thereby representing, regional CB 1R densities, were expressed in fM/g-tissue. The results show that CB 1R density inversely correlates with Braak tau pathology with the following tendency: controls


Koncsos G.,Semmelweis University | Varga Z.V.,Semmelweis University | Varga Z.V.,U.S. National Institutes of Health | Baranyai T.,Semmelweis University | And 29 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2016

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4. High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto-and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca2+/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria. © 2016 the American Physiological Society.


Szigeti K.,Semmelweis University | Horvath I.,Semmelweis University | Veres D.S.,Semmelweis University | Martinecz B.,Institute of Experimental Medicine | And 7 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015

Inflammation that develops in the brain and peripheral organs after stroke contributes profoundly to poor outcome of patients. However, mechanisms through which inflammation impacts on brain injury and overall outcome are improperly understood, in part because the earliest inflammatory events after brain injury are not revealed by current imaging tools. Here, we show that single-photon emission computed tomography (NanoSPECT/CT Plus) allows visualization of blood brain barrier (BBB) injury after experimental stroke well before changes can be detected with magnetic resonance imaging (MRI). Early 99mTc-DTPA (diethylene triamine pentaacetic acid) signal changes predict infarct development and systemic inflammation preceding experimental stroke leads to very early perfusion deficits and increased BBB injury within 2 hours after the onset of ischemia. Acute brain injury also leads to peripheral inflammation and immunosuppression, which contribute to poor outcome of stroke patients. The SPECT imaging revealed early (within 2 hours) changes in perfusion, barrier function and inflammation in the lungs and the gut after experimental stroke, with good predictive value for the development of histopathologic changes at later time points. Collectively, visualization of early inflammatory changes after stroke could open new translational research avenues to elucidate the interactions between central and peripheral inflammation and to evaluate in vivo 'multi-system' effects of putative anti-inflammatory treatments. © 2015 ISCBFM.


Fulop A.,Semmelweis University | Szijarto A.,Semmelweis University | Harsanyi L.,Semmelweis University | Budai A.,Semmelweis University | And 7 more authors.
PLoS ONE | Year: 2014

Objectives: In the early recognition of portal vein ligation (PVL) induced tumor progression, positron emission tomography and magnetic resonance imaging (PET/MRI) could improve diagnostic accuracy of conventionally used methods. It is unknown how PVL affects metabolic patterns of tumor free hepatic tissues. The aim of this preliminary study is to evaluate the effect of PVL on glucose metabolism, using PET/MRI imaging in healthy rat liver. Materials and Methods: Male Wistar rats (n = 30) underwent PVL. 2-deoxy-2-(18F)fluoro-D- glucose (FDG) PET/MRI imaging (nanoScan PET/MRI) and morphological/histological examination were performed before (Day 0) and 1, 2, 3, and 7 days after PVL. Dynamic PET data were collected and the standardized uptake values (SUV) for ligated and non-ligated liver lobes were calculated in relation to cardiac left ventricle (SUVVOI/SUVCLV) and mean liver SUV (SUV VOI/SUVLiver). Results: PVL induced atrophy of ligated lobes, while non-ligated liver tissue showed compensatory hypertrophy. Dynamic PET scan revealed altered FDG kinetics in both ligated and non-ligated liver lobes. SUVVOI/SUVCLV significantly increased in both groups of lobes, with a maximal value at the 2nd postoperative day and returned near to the baseline 7 days after the ligation. After PVL, ligated liver lobes showed significantly higher tracer uptake compared to the non-ligated lobes (significantly higher SUVVOI/SUVLiver values were observed at postoperative day 1, 2 and 3). The homogenous tracer biodistribution observed before PVL reappeared by 7th postoperative day. Conclusion: The observed alterations in FDG uptake dynamics should be taken into account during the assessment of PET data until the PVL induced atrophic and regenerative processes are completed. © 2014 Fülöp et al.


Veres D.S.,Semmelweis University | Mathe D.,med Translational Research Centers | Futo I.,Semmelweis University | Horvath I.,Semmelweis University | And 3 more authors.
Molecular Imaging and Biology | Year: 2014

Purpose: The aim of this paper is to present a simple and quantitative data analysis method with a new potential in the application of liver single-photon emission computed tomography (SPECT) imaging. We have established quantitative SPECT/computed tomography (CT) in vivo imaging protocols for determination of liver tumor burden based on the known role of Kupffer cells in cancer of the liver. Procedures: As it is also known that functional Kupffer cells accumulate particulate material contained in the arterial blood of liver supply, we used radiolabeled macro-aggregated albumin particles ([99mTc]-MAA) injected intravenously to image liver disease. Quantification of cold spot liver lesion imaging was also a general objective. Methods: We examined a healthy control group (BALB/C mice, n = 6) and group of induced hepatocellular carcinoma (HCC, matrilin-2 transgenic KO mice, n = 9), where hepatocellular carcinoma was induced by diethylnitrosamine. We used [99mTc]-MAA as radiopharmaceutical for liver SPECT imaging in a small animal SPECT/CT system. A liver radioactivity overview map was generated. Segmentation of the liver was calculated by Otsu thresholding method. Based on the segmentation the radioactivity volume and the summarized liver activity were determined. Results: Tumor burden of the livers was quantitatively determined by creating parametric data from the resulting volumetric maps. Ex vivo liver mass data were applied for the validation of in vivo measurements. An uptake with cold spots as tumors was observed in all diseased animals in SPECT/CT scans. Isotope-labeled particle uptake (standardized uptake concentration) of control (median 0.33) and HCC (median 0.18) groups was significantly different (p = 0.0015, Mann Whitney U test). Conclusion: A new potential application of [99mTc]-MAA was developed and presents a simple and very effective means to quantitatively characterize liver cold spot lesions resulting from Kupffer cell dysfunctions as a consequence of tumor burden. © 2013 World Molecular Imaging Society.


Dios P.,University of Pécs | Nagy S.,University of Pécs | Pal S.,University of Pécs | Pernecker T.,University of Pécs | And 8 more authors.
European Journal of Pharmaceutics and Biopharmaceutics | Year: 2015

Abstract The aim of this study was to design a local, floating, mucoadhesive drug delivery system containing metronidazole for Helicobacter pylori eradication. Face-centered central composite design (with three factors, in three levels) was used for evaluation and optimization of in vitro floating and dissolution studies. Sodium alginate (X1), low substituted hydroxypropyl cellulose (L-HPC B1, X2) and sodium bicarbonate (X3) concentrations were the independent variables in the development of effervescent floating tablets. All tablets showed acceptable physicochemical properties. Statistical analysis revealed that tablets with 5.00% sodium alginate, 38.63% L-HPC B1 and 8.45% sodium bicarbonate content showed promising in vitro floating and dissolution properties for further examinations. Optimized floating tablets expressed remarkable floating force. Their in vitro dissolution studies were compared with two commercially available non-floating metronidazole products and then microbiologically detected dissolution, ex vivo detachment force, rheological mucoadhesion studies and compatibility studies were carried out. Remarkable similarity (f1, f2) between in vitro spectrophotometrically and microbiologically detected dissolutions was found. Studies revealed significant ex vivo mucoadhesion of optimized tablets, which was considerably increased by L-HPC. In vivo X-ray CT studies of optimized tablets showed 8 h gastroretention in rats represented by an animation prepared by special CT technique. © 2015 Elsevier B.V.


Varga Z.,Hungarian Academy of Sciences | Gyurko I.,Hungarian Academy of Sciences | Paloczi K.,Semmelweis University | Buzas E.I.,Semmelweis University | And 5 more authors.
Cancer Biotherapy and Radiopharmaceuticals | Year: 2016

The biodistribution of extracellular vesicles (EVs) is a fundamental question in the field of circulating biomarkers, which has recently gained attention. Despite the capabilities of nuclear imaging methods, such as single-photon emission computed tomography, radioisotope labeling of EVs and the use of the aforementioned methods for in vivo studies hardly can be found in the literature. In this article, the authors describe a novel method for the radioisotope labeling of erythrocyte-derived EVs using the 99mTc-tricarbonyl complex. Moreover, the capability of the developed labeling method for in vivo biodistribution studies is demonstrated in a mouse model. The authors found that the intravenously administered 99mTc-labeled EVs mostly accumulated in the liver and spleen. The in vivo stability of the labeled EVs was assessed by the comparison of the obtained biodistribution of EVs with that of the free 99mTc-tricarbonyl. According to the authors' data, only a minor fraction of the radioactive label became detached from the EVs. © Copyright 2016, Mary Ann Liebert, Inc. 2016.


PubMed | Institute of Experimental Medicine, med Translational Research Centers and Semmelweis University
Type: Journal Article | Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism | Year: 2015

Inflammation that develops in the brain and peripheral organs after stroke contributes profoundly to poor outcome of patients. However, mechanisms through which inflammation impacts on brain injury and overall outcome are improperly understood, in part because the earliest inflammatory events after brain injury are not revealed by current imaging tools. Here, we show that single-photon emission computed tomography (NanoSPECT/CT Plus) allows visualization of blood brain barrier (BBB) injury after experimental stroke well before changes can be detected with magnetic resonance imaging (MRI). Early 99mTc-DTPA (diethylene triamine pentaacetic acid) signal changes predict infarct development and systemic inflammation preceding experimental stroke leads to very early perfusion deficits and increased BBB injury within 2hours after the onset of ischemia. Acute brain injury also leads to peripheral inflammation and immunosuppression, which contribute to poor outcome of stroke patients. The SPECT imaging revealed early (within 2hours) changes in perfusion, barrier function and inflammation in the lungs and the gut after experimental stroke, with good predictive value for the development of histopathologic changes at later time points. Collectively, visualization of early inflammatory changes after stroke could open new translational research avenues to elucidate the interactions between central and peripheral inflammation and to evaluate in vivo multi-system effects of putative anti-inflammatory treatments.


PubMed | University of Pécs and med Translational Research Centers
Type: | Journal: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V | Year: 2015

The aim of this study was to design a local, floating, mucoadhesive drug delivery system containing metronidazole for Helicobacter pylori eradication. Face-centered central composite design (with three factors, in three levels) was used for evaluation and optimization of in vitro floating and dissolution studies. Sodium alginate (X1), low substituted hydroxypropyl cellulose (L-HPC B1, X2) and sodium bicarbonate (X3) concentrations were the independent variables in the development of effervescent floating tablets. All tablets showed acceptable physicochemical properties. Statistical analysis revealed that tablets with 5.00% sodium alginate, 38.63% L-HPC B1 and 8.45% sodium bicarbonate content showed promising in vitro floating and dissolution properties for further examinations. Optimized floating tablets expressed remarkable floating force. Their in vitro dissolution studies were compared with two commercially available non-floating metronidazole products and then microbiologically detected dissolution, ex vivo detachment force, rheological mucoadhesion studies and compatibility studies were carried out. Remarkable similarity (f1, f2) between in vitro spectrophotometrically and microbiologically detected dissolutions was found. Studies revealed significant ex vivo mucoadhesion of optimized tablets, which was considerably increased by L-HPC. In vivo X-ray CT studies of optimized tablets showed 8h gastroretention in rats represented by an animation prepared by special CT technique.


PubMed | University of Pécs, med Translational Research Centers and Semmelweis University
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

The objective of the study was to reveal the influence of necessarily added barium sulfate (BaSO

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