63 results on '"Szabo, S."'
Search Results
2. Finance Mechanisms and Incentives for Photovoltaic Technologies in Developing Countries
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Moner-Girona, M., primary, Szabo, S., additional, and Rolland, S., additional
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- 2012
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3. Clinical Toxicology of Common Drugs and Chemicals in Humans: Stomach*
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Szabo, S., primary and Vincze, A., additional
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- 2010
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4. Duodenal Ulcer and Dopamine: New Elements in Pathogenesis and Therapy
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Szabo, S., primary, Gallagher, G.T., additional, Blyzniuk, A., additional, Maull, E.A., additional, and Sandrock, A.W., additional
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- 1982
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5. Dopamine and Dopamine Receptors in the Gut: Their Possible Role in Duodenal Ulceration
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Szabo, S., primary, Sandrock, A.W., additional, Nafradi, J., additional, Maull, E.A., additional, Gallagher, G.T., additional, and Blyzniuk, A., additional
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- 1982
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6. NEUROPHARMACOLOGIC AND BIOCHEMICAL CHARACTERIZATION OF CHEMICALLY-INDUCED DUODENAL ULCER IN THE RAT
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Szabo, S., primary, Horner, H.C., additional, and Bailey, K.A., additional
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- 1978
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7. Obesity amplifies influenza virus-driven disease severity in male and female mice.
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Alarcon PC, Damen MSMA, Ulanowicz CJ, Sawada K, Oates JR, Toth A, Wayland JL, Chung H, Stankiewicz TE, Moreno-Fernandez ME, Szabo S, Zacharias WJ, and Divanovic S
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- Male, Female, Animals, Mice, Humans, Mice, Inbred C57BL, Obesity, Patient Acuity, Influenza, Human, Obesity, Morbid complications, Orthomyxoviridae Infections, Orthomyxoviridae, Metabolic Diseases
- Abstract
Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30 °C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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8. An Epidemiological Model to Estimate the Prevalence of Diffuse Large B-Cell Lymphoma in the United States.
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Chihara D, Johnston K, Bolatova T, Szabo S, Kalsekar A, Mutebi A, Yang H, Liu Y, Attinson D, and Hutchings M
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- United States epidemiology, Humans, SEER Program, Prevalence, Survival Analysis, Epidemiological Models, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse therapy, Lymphoma, Large B-Cell, Diffuse diagnosis
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Background: Prevalence is reflective of disease incidence and survival, and defined as the number of patients living with active disease. In diseases such as diffuse large B-cell lymphoma (DLBCL) with treatments with curative potential, a proportion of patients are cured, leading to a need for accurate, contemporary estimates of DLBCL prevalence to gauge the impact of the rapidly emerging treatment landscape., Methods: Data from Surveillance, Epidemiology, and End Results (SEER) from 2000-2018 were utilized to develop an epidemiological model of incidence, survival, and cure, to estimate the current prevalent DLBCL population requiring active management in the United States (US). A variety of estimates were explored regarding cure rate and timing, based on a companion analysis of MarketScan data for treatment patterns and survival in incident DLBCL patients, and conditional survival analysis of SEER data., Results: Across scenarios, with estimated cure ranging from 52.8% and 68.9%, and timing of cure ranging from 1 and 20 years post diagnosis, the estimated prevalence ranged from 63,883 to 142,889. With an assumption of no cure, estimated prevalence was 179,475., Discussion: Prevalence estimates of DLBCL varied almost 3-fold, depending on specific cure adjustments made. Further understanding of DLBCL prevalence, for newly diagnosed and relapsed and/or refractory disease, is important to characterize the impact of emerging treatment options and related health care burden., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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9. Safety and Efficacy of 7 Days on/7 Days off Versus 14 Days on/7 Days off Schedules of Capecitabine in Patients with Metastatic Colorectal Cancer: A Retrospective Review.
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Bryson E, Sakach E, Patel U, Watson M, Hall K, Draper A, Davis C, Goyal S, Alese O, Akce M, Shaib W, El-Rayes B, Szabo S, and Wu C
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- Adult, Aged, Antimetabolites, Antineoplastic administration & dosage, Capecitabine adverse effects, Colorectal Neoplasms pathology, Deoxycytidine administration & dosage, Drug Administration Schedule, Fluorouracil administration & dosage, Humans, Male, Middle Aged, Neoplasm Staging, Retrospective Studies, Treatment Outcome, Antimetabolites, Antineoplastic adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Capecitabine administration & dosage, Colorectal Neoplasms drug therapy
- Abstract
Introduction/background: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing., Materials and Methods: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies., Results: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS., Conclusion: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2021
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10. Proteomic identification of Placental Protein 1 (PP1), PP8, and PP22 and characterization of their placental expression in healthy pregnancies and in preeclampsia.
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Szabo S, Karaszi K, Romero R, Toth E, Szilagyi A, Gelencser Z, Xu Y, Balogh A, Szalai G, Hupuczi P, Hargitai B, Krenacs T, Hunyadi-Gulyas E, Darula Z, Kekesi KA, Tarca AL, Erez O, Juhasz G, Kovalszky I, Papp Z, and Than NG
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- Adult, Chromatography, Liquid, Female, Humans, Mass Spectrometry, Pregnancy, Proteomics, Placenta metabolism, Pre-Eclampsia metabolism, Pregnancy Proteins metabolism
- Abstract
Introduction: Placental Protein 1 (PP1), PP8, and PP22 were isolated from the placenta. Herein, we aimed to identify PP1, PP8, and PP22 proteins and their placental and trophoblastic expression patterns to reveal potential involvement in pregnancy complications., Methods: We analyzed PP1, PP8, and PP22 proteins with LC-MS. We compared the placental behaviors of PP1, PP8, and PP22 to the predominantly placenta-expressed PP5/TFPI-2. Placenta-specificity scores were generated from microarray data. Trophoblasts were isolated from healthy placentas and differentiated; total RNA was isolated and subjected to microarray analysis. We assigned the placentas to the following groups: preterm controls, early-onset preeclampsia, early-onset preeclampsia with HELLP syndrome, term controls, and late-onset preeclampsia. After histopathologic examination, placentas were used for tissue microarray construction, immunostaining with anti-PP1, anti-PP5, anti-PP8, or anti-PP22 antibodies, and immunoscoring., Results: PP1, PP8, and PP22 were identified as 'nicotinate-nucleotide pyrophosphorylase', 'serpin B6', and 'protein disulfide-isomerase', respectively. Genes encoding PP1, PP8, and PP22 are not predominantly placenta-expressed, in contrast with PP5. PP1, PP8, and PP22 mRNA expression levels did not increase during trophoblast differentiation, in contrast with PP5. PP1, PP8, and PP22 immunostaining were detected primarily in trophoblasts, while PP5 expression was restricted to the syncytiotrophoblast. The PP1 immunoscore was higher in late-onset preeclampsia, while the PP5 immunoscore was higher in early-onset preeclampsia., Discussion: PP1, PP8, and PP22 are expressed primarily in trophoblasts but do not have trophoblast-specific regulation or functions. The distinct dysregulation of PP1 and PP5 expression in either late-onset or early-onset preeclampsia reflects different pathophysiological pathways in these preeclampsia subsets., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2020
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11. Convincing long-term results independent from the postoperative leg alignment following cementless total knee arthroplasty.
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Kaipel M, Klikovics J, Sinz G, Szabo S, Weinoehrl S, and Hausner T
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- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Humans, Knee Joint diagnostic imaging, Knee Joint physiopathology, Male, Middle Aged, Osteoarthritis, Knee diagnosis, Osteoarthritis, Knee physiopathology, Postoperative Period, Radiography, Retrospective Studies, Arthroplasty, Replacement, Knee methods, Forecasting, Knee Joint surgery, Knee Prosthesis, Osteoarthritis, Knee surgery, Range of Motion, Articular physiology
- Abstract
Background: Cementless primary total knee arthroplasty shows numerous advantages compared with cemented implants (e.g., shorter operation time, preservation of the bone stock). Up to now an increasing number of clinical long-term studies exist. Despite this fact, there is no evidence about the influence of the postoperative leg alignment on the results of cementless knee arthroplasty. There is no work on the clinical outcome of the specific implant, which was used in this study (VANGUARD®, ZimmerBiomet). The purpose of this study was to assess the clinical and radiological long-term results after cementless knee arthroplasty in relation to the postoperative mechanical leg alignment., Methods: Clinical and radiological results were retrospectively assessed in 83 patients at 10.3 years (ranging from 9.6 to 11.8 years) after implantation. Hip-knee-ankle angle (HKA) was measured, and the patients were separated into a corrected (HKA between three degrees of varus and three degrees of valgus, n = 60) and a varus/valgus (HKA > 3° of varus and valgus, n = 23) group., Results: Up to the time of the clinical follow-up, three out of 83 patients already underwent a revision surgery due to a deep infection (3.6%). Tegner-Lysholm Knee scale was 89.1 in the corrected group and 88.8 in the varus/valgus group (p = .94). The mean Knee Injury and Osteoarthritis Outcome score (KOOS) was 81.2 in the corrected group and 82.4 in the varus/valgus group (p = .63)., Conclusions: Results of this study showed convincing clinical and radiological results after primary cementless knee arthroplasty. Under- or overcorrected postoperative mechanical leg alignments did not influence the long-term clinical results., Competing Interests: Declaration of competing interest The corresponding author M.K. declares a conflict of interest: The planning, conducting and data analysis of this study was financially supported by ZimmerBiomet, Warsaw, USA. All other authors declare no conflict of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2020
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12. Increased placental expression of Placental Protein 5 (PP5) / Tissue Factor Pathway Inhibitor-2 (TFPI-2) in women with preeclampsia and HELLP syndrome: Relevance to impaired trophoblast invasion?
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Karaszi K, Szabo S, Juhasz K, Kiraly P, Kocsis-Deak B, Hargitai B, Krenacs T, Hupuczi P, Erez O, Papp Z, Kovalszky I, and Than NG
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- Adult, Case-Control Studies, Female, HELLP Syndrome pathology, Humans, Placenta pathology, Placentation, Pre-Eclampsia pathology, Pregnancy, Glycoproteins metabolism, HELLP Syndrome metabolism, Placenta metabolism, Pre-Eclampsia metabolism
- Abstract
Introduction: Placental Protein 5 (PP5)/Tissue Factor Pathway Inhibitor-2 (TFPI-2) is an extracellular matrix-associated protein mainly expressed by the syncytiotrophoblast that may regulate trophoblast invasion. Our aim was to study placental PP5/TFPI-2 expression and its relation to placental pathology in various forms of preeclampsia and HELLP syndrome., Methods: Placental and maternal blood specimens were collected at the time of delivery from the same women in the following groups: 1) early controls; 2) early preeclampsia; 3) early preeclampsia with HELLP syndrome; 4) late controls; and 5) late preeclampsia. After histopathological examination, placental specimens were immunostained with polyclonal anti-PP5/TFPI-2 antibody on Western blot and tissue microarray immunohistochemistry. Placental PP5/TFPI-2 immunoscores were assessed manually and with a semi-automated method. Maternal sera were immunoassayed for PP5/TFPI-2., Results: PP5/TFPI-2 was localized to the cytoplasm of syncytiotrophoblast. Manual and semi-automated PP5/TFPI-2 immunoscores were higher in early preeclampsia with or without HELLP syndrome but not in late preeclampsia than in respective controls. In patients with preeclampsia, the correlation of placental PP5/TFPI-2 expression with maternal vascular malperfusion score of the placenta was positive while it was negative with birthweight and placental weight. Maternal serum PP5/TFPI-2 concentration was higher in early preeclampsia and it tended to be higher in early preeclampsia with HELLP syndrome than in early controls., Discussion: Our findings suggest that an increased placental PP5/TFPI-2 expression may be associated with abnormal placentation in early preeclampsia, with or without HELLP syndrome., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2019
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13. Nogo-B receptor deficiency causes cerebral vasculature defects during embryonic development in mice.
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Rana U, Liu Z, Kumar SN, Zhao B, Hu W, Bordas M, Cossette S, Szabo S, Foeckler J, Weiler H, Chrzanowska-Wodnicka M, Holtz ML, Misra RP, Salato V, North PE, Ramchandran R, and Miao QR
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- Animals, Female, Mice, Mice, Knockout, Pregnancy, Blood Vessels embryology, Cerebrovascular Circulation, Receptors, Cell Surface genetics
- Abstract
Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculature development in mouse embryo and primitive blood vessel formation in embryoid body culture systems, respectively. Our results showed that NgBR homozygous knockout mice are embryonically lethal at E7.5 or earlier, and Tie2Cre-mediated endothelial cell-specific NgBR knockout (NgBR ecKO) mice die at E11.5 and have severe blood vessel assembly defects in embryo. In addition, mutant embryos exhibit dilation of cerebral blood vessel, resulting in thin-walled endothelial caverns. The similar vascular defects also were detected in Cdh5(PAC)-CreERT2 NgBR inducible ecKO mice. Murine NgBR gene-targeting embryonic stem cells (ESC) were generated by homologous recombination approaches. Homozygous knockout of NgBR in ESC results in cell apoptosis. Heterozygous knockout of NgBR does not affect ESC cell survival, but reduces the formation and branching of primitive blood vessels in embryoid body culture systems. Mechanistically, NgBR knockdown not only decreases both Nogo-B and VEGF-stimulated endothelial cell migration by abolishing Akt phosphorylation, but also decreases the expression of CCM1 and CCM2 proteins. Furthermore, we performed immunofluorescence (IF) staining of NgBR in human cerebral cavernous malformation patient tissue sections. The quantitative analysis results showed that NgBR expression levels in CD31 positive endothelial cells is significantly decreased in patient tissue sections. These results suggest that NgBR may be one of important genes coordinating the cerebral vasculature development., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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14. Measuring the SDGs: a two-track solution.
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Davis A, Matthews Z, Szabo S, and Fogstad H
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- Goals, Health Status Indicators, Humans, Global Health trends, Health Promotion trends
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- 2015
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15. Epiplakin attenuates experimental mouse liver injury by chaperoning keratin reorganization.
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Szabo S, Wögenstein KL, Österreicher CH, Guldiken N, Chen Y, Doler C, Wiche G, Boor P, Haybaeck J, Strnad P, and Fuchs P
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- Animals, Autoantigens genetics, Chemical and Drug Induced Liver Injury metabolism, Chemical and Drug Induced Liver Injury pathology, Chemical and Drug Induced Liver Injury prevention & control, Female, Hepatocytes drug effects, Hepatocytes metabolism, Hepatocytes pathology, Humans, Keratin-18 metabolism, Keratin-8 genetics, Liver pathology, Male, Methylamines pharmacology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Molecular Chaperones genetics, Molecular Chaperones metabolism, Protein Aggregates, Proteolysis, Stress, Physiological, Up-Regulation, Autoantigens metabolism, Keratin-8 metabolism, Liver injuries, Liver metabolism
- Abstract
Background & Aims: Epiplakin is a member of the plakin protein family and exclusively expressed in epithelial tissues where it binds to keratins. Epiplakin-deficient (Eppk1(-/-)) mice displayed no obvious spontaneous phenotype, but their keratinocytes showed a faster keratin network breakdown in response to stress. The role of epiplakin in the stressed liver remained to be elucidated., Methods: Wild-type (WT) and Eppk1(-/-) mice were subjected to common bile duct ligation (CBDL) or fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing diet. The importance of epiplakin during keratin reorganization was assessed in primary hepatocytes., Results: Our experiments revealed that epiplakin is expressed in hepatocytes and cholangiocytes, and binds to keratin 8 (K8) and K18 via multiple domains. In several liver stress models epiplakin and K8 genes displayed identical expression patterns and transgenic K8 overexpression resulted in elevated hepatic epiplakin levels. After CBDL and DDC treatment, Eppk1(-/-) mice developed a more pronounced liver injury and their livers contained larger amounts of hepatocellular keratin granules, indicating impaired disease-induced keratin network reorganization. In line with these findings, primary Eppk1(-/-) hepatocytes showed increased formation of keratin aggregates after treatment with the phosphatase inhibitor okadaic acid, a phenotype which was rescued by the chemical chaperone trimethylamine N-oxide (TMAO). Finally, transfection experiments revealed that Eppk1(-/-) primary hepatocytes were less able to tolerate forced K8 overexpression and that TMAO treatment rescued this phenotype., Conclusion: Our data indicate that epiplakin plays a protective role during experimental liver injuries by chaperoning disease-induced keratin reorganization., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
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- 2015
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16. Glycemic, Lipid, and Blood Pressure Control Among Individuals with Type 2 Diabetes Mellitus in Saudi Arabia.
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Osenenko KM, Szabo SM, Donato BM, Korol EE, Qatami L, Al Jaser S, Al Saggabi A, El Seid ME, Maclean R, and Levy AR
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- 2014
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17. The Epidemiologic Burden of Hepatitis C Virus Infection in Egypt.
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Szabo SM, Juarez-Garcia A, Levy AR, and Donato BM
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- 2014
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18. Treatment Patterns Among Type 2 Diabetes Mellitus Patients in Saudi Arabia.
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Levy AR, Szabo SM, Osenenko KM, Korol EE, Qatami L, Al JS, Al SA, Al SS, Maclean R, and Donato BM
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- 2014
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19. Aberrant, ectopic expression of VEGF and VEGF receptors 1 and 2 in malignant colonic epithelial cells. Implications for these cells growth via an autocrine mechanism.
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Ahluwalia A, Jones MK, Szabo S, and Tarnawski AS
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- Cell Line, Tumor, Cell Proliferation, Epithelial Cells metabolism, Humans, Oligonucleotide Array Sequence Analysis, RNA, Messenger metabolism, Colonic Neoplasms metabolism, Gene Expression Regulation, Neoplastic, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor Receptor-1 metabolism, Vascular Endothelial Growth Factor Receptor-2 metabolism
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Unlabelled: Vascular endothelial growth factor A (referred to as VEGF) is implicated in colon cancer growth. Currently, the main accepted mechanism by which VEGF promotes colon cancer growth is via the stimulation of angiogenesis, which was originally postulated by late Judah Folkman. However, the cellular source of VEGF in colon cancer tissue; and, the expression of VEGF and its receptors VEGF-R1 and VEGF-R2 in colon cancer cells are not fully known and are subjects of controversy., Material and Methods: We examined and quantified expression of VEGF, VEGF-R1 and VEGF-R2 in three different human colonic tissue arrays containing sections of adenocarcinoma (n=43) and normal mucosa (n = 41). In human colon cancer cell lines HCT116 and HT29 and normal colon cell lines NCM356 and NCM460, we examined expression of VEGF, VEGF-R1 and VEGF-R2 mRNA and protein, VEGF production and secretion into the culture medium; and, the effect of a potent, selective inhibitor of VEGF receptors, AL-993, on cell proliferation., Results: Human colorectal cancer specimens had strong expression of VEGF in cancer cells and also expressed VEGF-R1 and VEGF-R2.In vitro studies showed that human colon cancer cell lines, HCT116 and HT29, but not normal colonic cell lines, express VEGF, VEGF-R1 and VEGF-R2 and secrete VEGF into the medium up to a concentration 2000 pg/ml within 48 h. Furthermore, we showed that inhibition of VEGF receptors using a specific VEGF-R inhibitor significantly reduced proliferation (by >50%) of cultured colon cancer cell lines., Conclusions: Our findings support the contention that VEGF generated by colon cancer cells stimulates their growth directly through an autocrine mechanism that is independent of its primary function in the induction of angiogenesis., (Published by Elsevier Inc.)
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- 2013
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20. Stable isotope gas chromatography-tandem mass spectrometry determination of aminoethylcysteine ketimine decarboxylated dimer in biological samples.
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Tsikas D, Evans CE, Denton TT, Mitschke A, Gutzki FM, Pinto JT, Khomenko T, Szabo S, and Cooper AJ
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- Animals, Brain drug effects, Brain metabolism, Cysteamine pharmacology, Female, Gas Chromatography-Mass Spectrometry standards, Humans, Male, Mice, Morpholines blood, Morpholines chemistry, Morpholines urine, Rats, Reference Standards, Reproducibility of Results, Tandem Mass Spectrometry standards, Vegetables chemistry, Clinical Chemistry Tests methods, Gas Chromatography-Mass Spectrometry methods, Morpholines analysis, Tandem Mass Spectrometry methods
- Abstract
Aminoethylcysteine ketimine decarboxylated dimer (AECK-DD; systematic name: 1,2-3,4-5,6-7,8-octahydro-1,8a-diaza-4,6-dithiafluoren-9(8aH)-one) is a previously described metabolite of cysteamine that has been reported to be present in mammalian brain, urine, plasma, and cells in culture and vegetables and to possess potent antioxidative properties. Here, we describe a stable isotope gas chromatography-tandem mass spectrometry (GC-MS/MS) method for specific and sensitive determination of AECK-DD in biological samples. (13)C(2)-labeled AECK-DD was synthesized and used as the internal standard. Derivatization was carried out by N-pentafluorobenzylation with pentafluorobenzyl bromide in acetonitrile. Quantification was performed by selected reaction monitoring of the mass transitions m/z 328 to 268 for AECK-DD and m/z 330 to 270 for [(13)C(2)]AECK-DD in the electron capture negative ion chemical ionization mode. The procedure was systematically validated for human plasma and urine samples. AECK-DD was not detectable in human plasma above approximately 4nM but was present in urine samples of healthy humans at a maximal concentration of 46nM. AECK-DD was detectable in rat brain at very low levels of approximately 8pmol/g wet weight. Higher levels of AECK-DD were detected in mouse brain (∼1nmol/g wet weight). Among nine dietary vegetables evaluated, only shallots were found to contain trace amounts of AECK-DD (∼6.8pmol/g fresh tissue)., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
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21. New mechanistic explanation for the localization of ulcers in the rat duodenum: role of iron and selective uptake of cysteamine.
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Khomenko T, Kolodney J, Pinto JT, McLaren GD, Deng X, Chen L, Tolstanova G, Paunovic B, Krasnikov BF, Hoa N, Cooper AJ, and Szabo S
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- Animals, Biological Transport drug effects, Caco-2 Cells, Cystamine metabolism, Cysteamine analogs & derivatives, Cysteamine pharmacology, Deferoxamine pharmacology, Duodenal Ulcer pathology, Duodenum drug effects, Duodenum pathology, Female, Gene Expression Regulation drug effects, Humans, Intestinal Absorption drug effects, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Intracellular Space drug effects, Intracellular Space metabolism, Iron pharmacology, Iron Chelating Agents pharmacology, Mice, Organ Specificity, Organic Cation Transport Proteins antagonists & inhibitors, Organic Cation Transport Proteins deficiency, Organic Cation Transport Proteins genetics, Rats, Reactive Oxygen Species metabolism, Sodium metabolism, Cysteamine metabolism, Duodenal Ulcer metabolism, Duodenum metabolism, Iron metabolism
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Cysteamine, a coenzyme A metabolite, induces duodenal ulcers in rodents. Our recent studies showed that ulcer formation was aggravated by iron overload and diminished in iron deficiency. We hypothesized that cysteamine is selectively taken up in the duodenal mucosa, where iron absorption primarily occurs, and is transported by a carrier-mediated process. Here we report that cysteamine administration in rats leads to cysteamine accumulation in the proximal duodenum, where the highest concentration of iron in the gastrointestinal tract is found. In vitro, iron loading of intestinal epithelial cells (IEC-6) accelerated reactive oxygen species (ROS) production and increased [(14)C]cysteamine uptake. [(14)C]Cysteamine uptake by isolated gastrointestinal mucosal cells and by IEC-6 was pH-dependent and inhibited by unlabeled cysteamine. The uptake of [(14)C]cysteamine by IEC-6 was Na(+)-independent, saturable, inhibited by structural analogs, H(2)-histamine receptor antagonists, and organic cation transporter (OCT) inhibitors. OCT1 mRNA was markedly expressed in the rat duodenum and in IEC-6, and transfection of IEC-6 with OCT1 siRNA decreased OCT1 mRNA expression and inhibited [(14)C]cysteamine uptake. Cysteamine-induced duodenal ulcers were decreased in OCT1/2 knockout mice. These studies provide new insights into the mechanism of cysteamine absorption and demonstrate that intracellular iron plays a critical role in cysteamine uptake and in experimental duodenal ulcerogenesis., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
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22. Association between African American race and outcomes in patients with nonmetastatic triple-negative breast cancer: a retrospective analysis by using results from the Georgia Cancer Specialist Database.
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Christiansen N, Chen L, Gilmore J, Pechar D, and Szabo S
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- Adult, Aged, Antineoplastic Agents therapeutic use, Body Mass Index, Chemotherapy, Adjuvant statistics & numerical data, Disease-Free Survival, Female, Georgia, Humans, Middle Aged, Neoplasm Staging, Obesity ethnology, Outcome and Process Assessment, Health Care, Prevalence, Prognosis, Proportional Hazards Models, Risk Assessment, Risk Factors, Black or African American statistics & numerical data, Breast Neoplasms ethnology, Breast Neoplasms therapy
- Abstract
Introduction: The objective of this study was to evaluate, in a real-world context, the impact of race on disease recurrence and survival in patients with nonmetastatic triple-negative breast cancer (TNBC) treated with adjuvant chemotherapy., Patients and Methods: The study selected patients from the 2003-2008 Georgia Cancer Specialist Database with stage I-III confirmed TNBC who had received adjuvant chemotherapy. These patients were followed-up from initial diagnosis to death, cancer recurrence, or loss to follow-up. The primary outcome was disease-free survival (DFS). Kaplan-Meier curves compared DFS and recurrence between African American and non-African American groups. The impact of African American status was examined further through multivariate Cox models by adjusting for age, comorbidity, body mass index (BMI), smoking status, initial TNBC stage, surgery, and radiation therapy., Results: Among 209 patients with TNBC, 89 (42.6%) were African American. The 2 groups (African American vs. non-African American) were similar in mean age at diagnosis (53.2 vs. 54.4 years; P =.487) and with surgery and radiation rates (98.9% vs. 100%; P = .244; 68.5% vs. 62.5%; P = .365, respectively). Compared with non-African Americans, African American patients had a higher BMI (30.4 vs. 28.6 kg/m(2); P = .0477) and were less likely to be diagnosed at stage I (31.5% vs. 51.7%; P = .0107). The African American patients had a lower 5-year DFS rate (45.2% vs. 79.7%; P = .0005) and a higher 5-year recurrence rate (42.5% vs. 7.0%; P = .0005) compared with the non-African American patients., Conclusions: Among patients with TNBC treated with adjuvant chemotherapy, African American race was associated with a worse outcome irrespective of later stage at presentation or higher BMI., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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23. Gastric mucosal injury activates bFGF gene expression and triggers preferential translation of high molecular weight bFGF isoforms through CUG-initiated, non-canonical codons.
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Florkiewicz RZ, Ahluwalia A, Sandor Z, Szabo S, and Tarnawski AS
- Subjects
- Animals, Gastric Mucosa metabolism, Gastric Mucosa physiology, Gene Expression, Male, Molecular Weight, Protein Isoforms biosynthesis, Protein Isoforms genetics, Rats, Rats, Sprague-Dawley, Regeneration genetics, Codon, Initiator genetics, Fibroblast Growth Factor 2 biosynthesis, Fibroblast Growth Factor 2 genetics, Gastric Mucosa injuries, Protein Biosynthesis genetics, Transcriptional Activation
- Abstract
Basic fibroblast growth factor (bFGF or FGF-2) is a pleiotropic growth factor that promotes growth of mesenchymal and epithelial cells, stimulates angiogenesis and neuroprotection. Moreover, exogenous bFGF by stimulating angiogenesis promotes healing of gastroduodenal ulcers and cardiac and brain injury. All these actions were demonstrated in regard to 18kDa bFGF isoform that is secreted by cells via an ER/Golgi-independent pathway and activates FGF receptors. However in some transformed and stressed cells and in some tissues (e.g. brain) the single copy bFGF gene encodes multiple gene products: 18 kDa and also higher molecular weight (HMW) bFGF isoforms: ∼21 and ∼22 kDa in rodents, and ∼22, ∼23 and ∼24 kDa in humans. The biologic roles of these HMW bFGF isoforms in vivo remain unknown. In this study we demonstrated that in normal, uninjured gastric mucosa, bFGF is almost exclusively expressed as 18kDa isoform translated through a classical AUG (methionine) codon. In contrast, in injured gastric mucosa of rat, bFGF gene is preferentially translated to HMW bFGF isoforms through alternative CUG (leucine) initiation codon. Gastric mucosal injury caused in rats a significant increase in bFGF mRNA at 8 and 24h vs. normal mucosa and a significant increase in bFGF protein at 24-72h, mainly due to increased expression of ∼21 and ∼22 kDa HMW bFGF isoforms. This is first demonstration that gastric mucosal injury and repair triggers local activation of bFGF gene with preferential translation of HMW bFGF isoforms through a non-canonical CUG codon. This study uncovered CUG-initiated HMW bFGF translation as a novel regulatory mechanism operating in vivo during gastric injury repair., (Published by Elsevier Inc.)
- Published
- 2011
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24. Essential role of the keratinocyte-specific endonuclease DNase1L2 in the removal of nuclear DNA from hair and nails.
- Author
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Fischer H, Szabo S, Scherz J, Jaeger K, Rossiter H, Buchberger M, Ghannadan M, Hermann M, Theussl HC, Tobin DJ, Wagner EF, Tschachler E, and Eckhart L
- Subjects
- Animals, Apoptosis, DNA, Mitochondrial metabolism, Mice, Stress, Mechanical, Cell Nucleus metabolism, DNA metabolism, Deoxyribonuclease I physiology, Hair metabolism, Hoof and Claw metabolism, Keratinocytes enzymology
- Abstract
Degradation of nuclear DNA is a hallmark of programmed cell death. Epidermal keratinocytes die in the course of cornification to function as the dead building blocks of the cornified layer of the epidermis, nails, and hair. Here, we investigated the mechanism and physiological function of DNA degradation during cornification in vivo. Targeted deletion of the keratinocyte-specific endonuclease DNase1-like 2 (DNase1L2) in the mouse resulted in the aberrant retention of DNA in hair and nails, as well as in epithelia of the tongue and the esophagus. In contrast to our previous studies in human keratinocytes, ablation of DNase1L2 did not compromise the cornified layer of the epidermis. Quantitative PCRs showed that the amount of nuclear DNA was dramatically increased in both hair and nails, and that mitochondrial DNA was increased in the nails of DNase1L2-deficient mice. The presence of nuclear DNA disturbed the normal arrangement of structural proteins in hair corneocytes and caused a significant decrease in the resistance of hair to mechanical stress. These data identify DNase1L2 as an essential and specific regulator of programmed cell death in skin appendages, and demonstrate that the breakdown of nuclear DNA is crucial for establishing the full mechanical stability of hair.
- Published
- 2011
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- View/download PDF
25. Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis.
- Author
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Tolstanova G, Deng X, Khomenko T, Garg P, Paunovic B, Chen L, Sitaraman SV, Shiloach J, Szabo S, and Sandor Z
- Subjects
- Animals, Blotting, Western, Colitis, Ulcerative metabolism, Colitis, Ulcerative physiopathology, Colon drug effects, Colon metabolism, Colon physiopathology, Dextran Sulfate pharmacology, Disease Models, Animal, Endostatins pharmacology, Enzyme-Linked Immunosorbent Assay, Female, Iodoacetamide pharmacology, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase 9 physiology, Mice, Mice, Knockout, Platelet-Derived Growth Factor metabolism, Platelet-Derived Growth Factor physiology, Rats, Up-Regulation drug effects, Vascular Endothelial Growth Factor A metabolism, Vascular Endothelial Growth Factor A physiology, Colitis, Ulcerative etiology, Endostatins physiology
- Abstract
Aims: Vascular endothelial growth factor (VEGF) and pathologic angiogenesis have been demonstrated to play a pathogenic role in the development and progression of inflammatory bowel disease. Thus, we hypothesized that the potent anti-angiogenic factor endostatin might play a beneficial role in experimental ulcerative colitis (UC)., Main Methods: We used three animal models of UC: (1) induced by 6% iodoacetamide (IA) in rats, or (2) by 3% dextran sulfate sodium (DSS) in matrix metalloproteinase-9 (MMP-9) knockout (KO) and wild-type mice, and (3) interleukin-10 (IL-10) KO mice. Groups of MMP-9 KO mice with DSS-induced UC were treated with endostatin or water for 5days., Key Findings: We found concomitant upregulation of VEGF, PDGF, MMP-9 and endostatin in both rat and mouse models of UC. A positive correlation between the levels of endostatin or VEGF and the sizes of colonic lesions was seen in IA-induced UC. The levels and activities of MMP-9 were also significantly increased during UC induced by IA and IL-10 KO. Deletion of MMP-9 decreased the levels of endostatin in both water- and DSS-treated MMP-9 KO mice. Treatment with endostatin significantly improved DSS-induced UC in MMP-9 KO mice., Significance: 1) Concomitantly increased endostatin is a defensive response to the increased VEGF in UC, 2) MMP-9 is a key enzyme to generate endostatin which may modulate the balance between VEGF and endostatin during experimental UC, and 3) endostatin treatment plays a beneficial role in UC. Thus, anti-angiogenesis seems to be a new therapeutic option for UC., (Published by Elsevier Inc.)
- Published
- 2011
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26. New molecular mechanisms of the unexpectedly complex role of VEGF in ulcerative colitis.
- Author
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Tolstanova G, Khomenko T, Deng X, Szabo S, and Sandor Z
- Subjects
- Animals, Colitis, Ulcerative chemically induced, Colon drug effects, Interleukin-10 genetics, Iodoacetamide pharmacology, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Rats, Rats, Sprague-Dawley, Signal Transduction, Vascular Endothelial Growth Factor Receptor-2 metabolism, src-Family Kinases metabolism, Capillary Permeability, Colitis, Ulcerative metabolism, Colon metabolism, Vascular Endothelial Growth Factor A metabolism
- Abstract
The effects of VEGF on endothelial cells are mediated by different intracellular signaling cascades (e.g., Erk1/2, Akt, Src). VEGF plays a recently recognized role in ulcerative colitis (UC) pathogenesis, mostly by increasing vascular permeability and promoting the infiltration of inflammatory cells. We hypothesized that the excessive activation of signal transduction pathways, which is responsible for VEGF/VEGFR-2-mediated endothelial permeability (Src, Akt), is a new element in the pathogenesis of chronic UC. We demonstrated increased expression of pro-angiogenic growth factor VEGF and its receptor VEGFR-2 in colonic tissue during acute 6% iodoacetamide-induced UC in rats and chronic spontaneously developed UC in IL-10 knockout mice (IL-10 KO). Development of acute 6% iodoacetamide-induced UC in rats was accompanied by activation of Erk1/2 and Src kinase, while expression of total proteins Erk1/2 and Src was unchanged. During chronic colitis phosphorylation (i.e., activation) of Erk1/2 was significantly decreased in IL-10 KO mice vs. wild-type mice. Levels of total Erk1/2 proteins were unchanged, but the expression of total Src protein as well as its phosphorylated form was significantly increased in IL-10 KO vs. wild-type mice. There were no changes in total Akt proteins, while levels of activated Akt (pAkt) were slightly increased in IL-10 KO vs. wild-type mice. We conclude that VEGF/VEGFR-2-associated signal transduction pathways, that mediate increased vascular permeability (Src, Akt), might play a central role in perpetuation of chronic experimental UC., (Published by Elsevier Inc.)
- Published
- 2010
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27. Measurement of sulfur-containing compounds involved in the metabolism and transport of cysteamine and cystamine. Regional differences in cerebral metabolism.
- Author
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Pinto JT, Khomenko T, Szabo S, McLaren GD, Denton TT, Krasnikov BF, Jeitner TM, and Cooper AJ
- Subjects
- Animals, Biological Transport, Cerebrum chemistry, Chromatography, High Pressure Liquid instrumentation, Male, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Sulfur Compounds blood, Sulfur Compounds metabolism, Cerebrum metabolism, Chromatography, High Pressure Liquid methods, Cystamine metabolism, Cysteamine metabolism, Sulfur Compounds analysis
- Abstract
An HPLC method with coulometric detection is presented for the quantitation of cysteamine, cystamine, thialysine, glutathione, glutathione disulfide and an oxidized metabolite of thialysine [S-(2-aminoethyl)-L-cysteine ketimine decarboxylated dimer (AECK-DD)]. The advantage of coulometric detection is that derivatization is unnecessary if the analyte is redox sensitive. The method was used to quantitate several sulfur-containing compounds in plasma and brain following gavage feeding of cysteamine to rats. Cysteamine, cystamine, thialysine and AECK-DD were detected in the brains of these animals. Interestingly, cysteamine treatment resulted in greatly elevated levels of cerebral methionine, despite the fact that cysteamine is not a precursor of methionine.
- Published
- 2009
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28. Aortic insufficiency due to a partial left-coronary aortic valve prolapse and the detection of two small interatrial jets after blunt thoracic trauma.
- Author
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Szabo S, Oikonomopoulos T, Marx R, and Hoffmeister HM
- Subjects
- Aortic Valve Insufficiency diagnostic imaging, Aortic Valve Insufficiency surgery, Aortic Valve Prolapse diagnostic imaging, Aortic Valve Prolapse surgery, Echocardiography, Heart Valve Prosthesis Implantation, Humans, Male, Middle Aged, Aortic Valve Insufficiency etiology, Aortic Valve Prolapse etiology, Wounds, Nonpenetrating complications
- Abstract
Aortic valve regurgitation due to blunt thoracic trauma is a rare complication. Autopsy studies have been shown that the aortic valve is the most often lacerated one among the heart valves. Actually, we describe a case of a 47 year old man with the signs of heart failure after a blunt thoracic trauma 2 months before caused by aortic insufficiency due to a partial left-coronary aortic valve prolapse. Furthermore, transthoracic and transesophageal echocardiography revealed two small jets between the left and the right atrium.
- Published
- 2007
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29. Altered angiogenic balance in ulcerative colitis: a key to impaired healing?
- Author
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Sandor Z, Deng XM, Khomenko T, Tarnawski AS, and Szabo S
- Subjects
- Angiostatins metabolism, Animals, Endostatins metabolism, Enzyme-Linked Immunosorbent Assay, Female, Rats, Rats, Sprague-Dawley, Vascular Endothelial Growth Factor A metabolism, Colitis, Ulcerative metabolism, Colitis, Ulcerative pathology, Neovascularization, Pathologic, Wound Healing
- Abstract
Angiogenesis is an essential component of ulcer healing since it assures delivery of oxygen and nutrients to the healing site. Previous studies demonstrated increased serum and tissue levels of vascular endothelial growth factor (VEGF, the most potent angiogenic growth factor) in patients with active ulcerative colitis (UC) and animal models of UC. However, there is no explanation why the healing of UC-related mucosal injury is impaired despite increased expression of VEGF. Expression of angiogenesis inhibitors, angiostatin and/or endostatin, in UC has not been determined before. We examined expression of VEGF, angiostatin, and endostatin in two models of experimental UC. The results revealed that in addition to increased VEGF, both endostatin and angiostatin levels were markedly (2-3-folds) increased in colonic mucosa at early stage of experimental UC. This is the first demonstration that colitis triggers increase in angiostatin and endostatin levels. The results may explain why mucosal lesions heal slowly despite increased VEGF levels, and may provide a novel and mechanistic insight into UC.
- Published
- 2006
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30. Cysteamine alters redox state, HIF-1alpha transcriptional interactions and reduces duodenal mucosal oxygenation: novel insight into the mechanisms of duodenal ulceration.
- Author
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Khomenko T, Deng X, Sandor Z, Tarnawski AS, and Szabo S
- Subjects
- Animals, Cell Nucleus metabolism, Cytoplasm metabolism, DNA metabolism, DNA-Binding Proteins metabolism, Duodenum metabolism, Female, Gastric Mucosa metabolism, Hypoxia-Inducible Factor 1, alpha Subunit, Intestinal Mucosa metabolism, Oxidation-Reduction, Oxygen Consumption physiology, Protein Binding, Rats, Rats, Sprague-Dawley, Stomach drug effects, Transcription Factors biosynthesis, Transcription, Genetic, Cysteamine pharmacology, Duodenal Ulcer metabolism, Duodenum drug effects, Intestinal Mucosa drug effects, Oxygen Consumption drug effects, Transcription Factors metabolism
- Abstract
Our recent studies demonstrated a critical role of enhanced transcriptional activity of early growth response factor-1 (Egr-1) in early stages of cysteamine-induced duodenal ulcer in rats. Since cysteamine is also a reducing agent, the aims of this study were to determine the effect of cysteamine on proximal duodenal mucosa: (a) redox status, (b) mucosal oxygenation, (c) expression of hypoxia-inducible factor 1 (HIF-1alpha) and its binding to DNA, and (d) HIF-1alpha interaction with Egr-1 and other redox-sensitive transcription factors. Here we demonstrate for the first time that cysteamine treatment reduced the duodenal oxygenation by 19% (vs. baseline) and markedly increased the redox status in duodenal mucosa (p<0.05). Cysteamine increased HIF-1alpha expression, its binding to DNA, and enhanced the HIF-1alpha interactions with Egr-1 and other transcription factors (e.g., AP-1, AP-2, L-III BP, NF-E1, NF-E2, STAT4, and MRE), their binding to DNA. Thus, these data demonstrate the involvement of the redox-dependent regulatory mechanisms in the early stages of duodenal ulceration.
- Published
- 2004
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- View/download PDF
31. Effect of cysteamine on redox-sensitive thiol-containing proteins in the duodenal mucosa.
- Author
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Khomenko T, Deng X, Jadus MR, and Szabo S
- Subjects
- Animals, Base Sequence, DNA metabolism, DNA Primers, DNA-(Apurinic or Apyrimidinic Site) Lyase chemistry, DNA-Binding Proteins chemistry, Duodenum metabolism, Early Growth Response Protein 1, Female, Intestinal Mucosa metabolism, Oxidation-Reduction, Protein Binding, Protein Transport, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Thioredoxins chemistry, Transcription Factors chemistry, Cysteamine pharmacology, DNA-(Apurinic or Apyrimidinic Site) Lyase metabolism, DNA-Binding Proteins metabolism, Duodenum drug effects, Immediate-Early Proteins, Intestinal Mucosa drug effects, Sulfhydryl Compounds metabolism, Thioredoxins metabolism, Transcription Factors metabolism
- Abstract
Recent studies from our laboratory demonstrated that Egr-1 is upregulated in the rat duodenal mucosa during cysteamine-induced duodenal ulceration and that antisense egr-1 oligonucleotide aggravates the duodenal ulcers. This study was aimed to determine the effects of cysteamine on redox-sensitive Egr-1 transcriptional activity and on other thiol-containing proteins such as redox factor-1 (Ref-1) and thioredoxin (Trx). Here we demonstrate for the first time that cysteamine increases the expression and nuclear translocation of Egr-1, Ref-1, and Trx, and activates binding of Egr-1 to DNA. Moreover, we also show that Egr-1 forms a complex with other redox-sensitive transcription factors (e.g., AP-1, AP-2, NFATc, Sp1, PAX-5, MTF-1, c-Myb, and CREB) in rat duodenal mucosa and that cysteamine enhances the formation of these complexes. The antioxidant ebselen markedly elevated the nuclear Ref-1 expression and Egr-1/DNA binding, and decreased the ulcerogenic effect of cysteamine as did catalase. Thus, redox-sensitive signaling systems seem to play an important role in cysteamine-induced duodenal ulceration.
- Published
- 2003
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32. Experimental colitis decreases rat jejunal amino acid absorption: role of capsaicin sensitive primary afferents.
- Author
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Barada KA, Kafrouni MI, Khoury CI, Saade NE, Mourad FH, Szabo SS, and Nassar CF
- Subjects
- Afferent Pathways drug effects, Animals, Animals, Newborn, Capsaicin administration & dosage, Capsaicin pharmacology, Colitis chemically induced, Colitis pathology, Denervation, Disease Models, Animal, Female, In Vitro Techniques, Injections, Subcutaneous, Intestinal Mucosa drug effects, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Iodoacetamide toxicity, Jejunum drug effects, Jejunum innervation, Male, Rats, Rats, Sprague-Dawley, Time Factors, Vagotomy, Vagus Nerve cytology, Vagus Nerve drug effects, Alanine metabolism, Colitis metabolism, Intestinal Absorption, Jejunum metabolism
- Abstract
Ulcerative colitis and experimental colitis are known to be associated with functional and structural abnormalities of the small intestine. The aim of this study was to determine whether experimental colitis in the rat has any effect on jejunal amino acid absorption and to investigate the neural mechanisms involved. In Sprague Dawley rats, colitis was induced by intracolonic administration of 0.1 ml of 6% iodoacetamide. Alanine absorption in the jejunum was measured using the single pass intraluminal perfusion technique in vivo and the three-compartment model in vitro. Experiments were done in normal and sham treated rats, as well as in rats that underwent neonatal capsaicin treatment, adult capsaicin treatment, or subdiaphragmatic vagotomy. Colitis was more severe in rats subjected to neonatal or adult capsaicin treatment, but was not affected by subdiaphragmatic vagotomy. In rats with colitis, jejunal alanine absorption was reduced by 2% (P>0.05), 28%, 40%, and 18% (P<0.001) at 1, 1.5, 2, and 3 days post rectal iodoacetamide administration. A rebound increase of 12% above baseline was noted at 4 days (P<0.05). Similar results were noted in vitro. In rats that received two consecutive injections of iodoacetamide, the decrease in jejunal alanine absorption occurred earlier, was more severe, and persisted for more than 30 days. Neonatal as well as adult capsaicin treatment aggravated both the colitis and the decrease in jejunal alanine absorption. On the other hand, subdiaphragmatic vagotomy attenuated the decrease in jejunal alanine absorption, but had no significant effect on colitis severity. It is concluded that iodoacetamide induced colitis impairs jejunal amino acid absorption and that this effect involves vagal efferents as well as capsaicin sensitive primary afferents.
- Published
- 2001
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33. Effects of chronic antidepressant drug administration and electroconvulsive shock on locus coeruleus electrophysiologic activity.
- Author
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Szabo ST and Blier P
- Subjects
- Animals, Humans, Locus Coeruleus physiopathology, Rats, Synaptic Transmission physiology, Antidepressive Agents pharmacology, Electroconvulsive Therapy, Locus Coeruleus drug effects, Norepinephrine physiology, Synaptic Transmission drug effects
- Published
- 2001
- Full Text
- View/download PDF
34. Characteristics of two cases with dup(15)(q11.2-q12): one of maternal and one of paternal origin.
- Author
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Mao R, Jalal SM, Snow K, Michels VV, Szabo SM, and Babovic-Vuksanovic D
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Karyotyping, Male, Chromosomes, Human, Pair 15, Gene Duplication, Genomic Imprinting
- Abstract
Purpose: The phenotype correlations for interstitial duplications that include the Prader-Willi/Angelman syndrome critical region are not well established. We describe two such duplication cases, one of which was of maternal origin and the other was paternal., Methods: High resolution G-banding, fluorescence in situ hybridization (FISH) for SNRP-N and D15S10 were used for cytogenetic analysis. Southern blot analyses based on parent of origin specific DNA methylation at D15S63 (PW71) locus were utilized for detection of methylated and unmethylated fragments., Results: The duplication was established by the FISH analysis. The molecular pattern suggested a maternal origin of the duplication in patient 1 and a paternal origin in patient 2. Patient 1 (2 years old) had developmental and speech delays with pervasive developmental disorder or mild autism, strabismus, and normal growth parameters with seizures. Patient 2 (16 years old) had global developmental delay, verbal IQ of 94, depression, obesity, food-seeking behavior, and significant behavioral problems that included self-injurious tendencies. Neither patient had significant dysmorphic features or abnormalities of internal organs., Conclusion: The two cases suggest that some patients with 15q11.2q12 duplication may have significant anomalies, and there appear to be phenotypic differences between maternal and paternal transmission of the duplication.
- Published
- 2000
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35. Identification and quantitation of interferon-gamma producing T cells in psoriatic lesions: localization to both CD4+ and CD8+ subsets.
- Author
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Szabo SK, Hammerberg C, Yoshida Y, Bata-Csorgo Z, and Cooper KD
- Subjects
- Adult, CD3 Complex analysis, CD4-Positive T-Lymphocytes chemistry, CD8-Positive T-Lymphocytes chemistry, Epidermal Cells, Female, Flow Cytometry, Humans, Interleukin-4 metabolism, Lymphocyte Count, Male, Microchemistry, Middle Aged, Skin anatomy & histology, Skin cytology, Skin immunology, T-Lymphocytes cytology, Interferon-gamma metabolism, Psoriasis metabolism, Psoriasis pathology, T-Lymphocytes metabolism
- Abstract
Interferon-gamma (IFN-gamma) produced by lesional T cell clones is critical for the induction into G1 of the cell cycle by psoriatic keratinocyte stem cells; however, direct data demonstrating psoriatic lesional T cell subset IFN-gamma expression, and quantitation at a single cell level to calculate in vivo proportions, are lacking. In this study, using flow cytometry of freshly isolated normal and psoriatic lesional T cells from keratome biopsies, we found elevated CD3+, CD4+, and CD8+ T cells in all compartments of psoriatic skin, compared with normals. Using Brefeldin A to induce short-term intracellular accumulation of IFN-gamma in T cells capable of IFN-gamma production, we found that 90% of psoriatic patients have IFN-gamma-producing T cells at a greater proportion of their CD3+ cells than normals, with a mean of 16%+/-3%, as compared with 4%+/-2% in normal epidermis (p = 0.01). Expressed as density in the tissue, the IFN-gamma+ CD3+ cell number in psoriatic epidermis was 97+/-22 per mm2 surface area, as compared with 4.4+/-1.8 per mm2 of normal epidermis (p = 0.002). Thus, the total number of IFN-gamma+CD3+ T cells in the skin of a patient with 20% involvement is estimated to be 3.9 x 10(8). CD4+ and CD8+ IFN-gamma+ T cells were both elevated in psoriatic epidermis (p = 0.04 and p = 0.008, respectively) relative to normal skin. In the dermis, only 44% of patients demonstrated a higher percentage of IFN-gamma-producing T cells than did normals (p = 0.1), possibly indicating dilution, in some patients, by fresh infiltrating T cells. Interleukin-4 was not found by a combination of flow cytometry, reverse transcriptase-polymerase chain reaction, western blot, and immunoprecipitation. In conclusion, a significant portion of lesional T cells in psoriasis are IFN-gamma producing, without interleukin-4. The increased numbers of both IFN-gamma+CD4+ and IFN-gamma+CD8+ T cells indicate that both CD4+ and CD8+ IFN-gamma+ T cells are present in appropriate anatomic locations to sustain the lesional pathology.
- Published
- 1998
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36. Genes that regulate interleukin-4 expression in T cells.
- Author
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Szabo SJ, Glimcher LH, and Ho IC
- Subjects
- Animals, Humans, Interleukin-4 immunology, STAT6 Transcription Factor, Trans-Activators genetics, Transcription Factors genetics, Gene Expression Regulation immunology, Interleukin-4 genetics, T-Lymphocytes immunology
- Abstract
Interleukin-4 is an immunomodulatory cytokine which plays a central role in the regulation of allergic and atopic immune responses. Significant progress has been made in gaining a detailed understanding of the transcriptional regulation of the interleukin-4 gene. The recent identification and characterization of several key transcription factors has helped to elucidate the molecular mechanisms of T helper cell cytokine gene expression.
- Published
- 1997
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37. Regulation of interleukin-12 signal transduction during T helper phenotype development.
- Author
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Jacobson NG, Szabo SJ, Güler ML, Gorham JD, and Murphy KM
- Subjects
- Animals, Cell Differentiation immunology, Humans, Immunophenotyping, Interleukin-12 metabolism, Lymphocyte Activation, Signal Transduction immunology, T-Lymphocytes, Helper-Inducer immunology
- Published
- 1995
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38. Current understanding of IL4 gene regulation in T cells.
- Author
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Murphy KM, Murphy TL, Gold JS, and Szabo SJ
- Subjects
- Animals, Base Sequence, Gene Expression Regulation, Humans, Molecular Sequence Data, Interleukin-4 genetics, T-Lymphocytes immunology
- Published
- 1993
- Full Text
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39. Glutathione, protein sulfhydryls and cysteine proteases in gastric mucosal injury and protection.
- Author
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Szabo S, Nagy L, and Plebani M
- Subjects
- Animals, Cysteine Proteinase Inhibitors metabolism, Gastric Mucosa enzymology, Rats, Cysteine Endopeptidases metabolism, Gastric Mucosa drug effects, Glutathione metabolism, Sulfhydryl Compounds metabolism
- Abstract
Glutathione is one of the endogenous protective chemicals, like prostaglandins, in the gastric mucosa. Depletion of these agents aggravate the chemical- or stress-induced gastric erosions and ulcers. However, gastroprotection can be achieved even in the presence of low mucosal concentration of glutathione and prostaglandins, indicating the presence of other protective chemicals (e.g. polyamines, growth factors, neurotransmitters, steroids) in the stomach. Protein sulfhydryls were also implicated in the mechanism of action of gastroprotective drugs. We recently tested the hypothesis that cysteine proteases might be a target of gastroprotective and antiulcer agents, and decided to look for the presence of proteases and protease inhibitors (PI) in the gastric mucosa and juice. Protease activity and PI were measured with general substrates hemoglobin, azocasein and albumin at optimal pH (2.0, 5.6, 7.4) of aspartic, cysteine and serine proteases. Homogenates of glandular stomach mucosa and gastric juice from fasted rats were incubated in the presence or absence of specific inhibitors and gastroprotective SH alkylators such as NEM or iodoacetate. PI was measured after acid and heat inactivation of endogenous proteinases and addition of pepsin, cysteine proteinase papain, or trypsin. Our results indicate that of the proteases found in the stomach 98% was pepsin at pH 2.0, and up to 56% or 24% was SH-sensitive at pH 5.6 or 7.4, respectively. Intragastric administration of SH alkylators such as NEM or iodoacetate exerted a dose- and time-dependent gastroprotection against chemically induced acute erosions and ulcers. Thus, in addition to glutathione, proteinases and their specific endogenous inhibitors may also be involved in gastric mucosal injury and protection.
- Published
- 1992
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40. Thioguanine-induced adrenocortical necrosis and its prevention by hypophysectomy in the rat. Light and electron microscopic study.
- Author
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Szabo S, Kovacs K, Horvath E, Szabo D, Hüttner I, Garg BD, and Tuchweber B
- Subjects
- Adrenal Cortex Diseases pathology, Adrenal Cortex Diseases prevention & control, Animals, Capillary Permeability, Dose-Response Relationship, Drug, Endothelium pathology, Female, Hemorrhage chemically induced, Horseradish Peroxidase metabolism, Microscopy, Electron, Necrosis, Rats, Adrenal Cortex Diseases chemically induced, Adrenal Gland Diseases chemically induced, Hypophysectomy, Thioguanine toxicity
- Published
- 1977
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- View/download PDF
41. The influence of cysteamine and propionitrile on duodenal phosphoprotein phosphatase in rats.
- Author
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Japundzić I, Japundzić M, Levi E, and Szabo S
- Subjects
- Acid Phosphatase metabolism, Alkaline Phosphatase metabolism, Animals, Dose-Response Relationship, Drug, Duodenal Ulcer chemically induced, Duodenal Ulcer enzymology, Ethanolamine, Ethanolamines pharmacology, Female, Kinetics, Phosphoprotein Phosphatases metabolism, Rats, Rats, Inbred Strains, Somatostatin pharmacology, Cysteamine pharmacology, Duodenum enzymology, Intestinal Mucosa enzymology, Nitriles pharmacology, Phosphoprotein Phosphatases antagonists & inhibitors
- Abstract
Cysteamine and propionitrile cause severe duodenal ulcers with perforation within 24-48 h after a single injection in rats. These animal models were used to gain insight into the early, preulcerogenic biochemical changes in the duodenal mucosa. The results indicate that a single sc injection of cysteamine and propionitrile induced dose- and time-dependent decreases in the activity of phosphoprotein phosphatase (PPPase) in homogenate and particulate fractions of rat duodenal mucosa. The decrease in enzyme activity was detectable 4 h after the injection of the ulcerogens, it was maximal at 12 h, and hardly detectable at 24 h. No effect on the enzyme activity was found under in vitro conditions. PPPase activity in the liver was not influenced by either cysteamine or propionitrile. Furthermore, the toxic but nonulcerogenic derivative of cysteamine ethanolamine had no effect on PPPase in the duodenum. Thus, the effect of the duodenal ulcerogens on PPPase activity was indirect and organ specific, related only to the target organ (i.e., duodenal mucosa). The effect of the drugs was also selective at the level of mucosal cells: both duodenal ulcerogens depleted protein and alkaline phosphatase but not lysosomal acid phosphatase. The decrease of PPPase activity could be a general property of the duodenal ulcerogens since it is independent of their effect on endogenous somatostatin.
- Published
- 1988
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42. Animal model of human disease. Waterhouse-Friderichsen syndrome. Animal model: Acrylonitrile-induced adrenal apoplexy.
- Author
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Szabo S, Reynolds ES, and Kovacs K
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Rats, Vinyl Compounds, Adrenal Gland Diseases chemically induced, Nitriles, Waterhouse-Friderichsen Syndrome pathology
- Published
- 1976
43. Morphologic effects of cysteamine on the rat adenohypophysis.
- Author
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Cairns PD, McComb DJ, Horvath E, Kovacs K, Milligan JV, and Szabo S
- Subjects
- Animals, Castration, Estradiol pharmacology, Female, Luteinizing Hormone blood, Microscopy, Electron, Organ Size drug effects, Prolactin blood, Rats, Rats, Inbred Strains, Cysteamine pharmacology, Pituitary Gland, Anterior drug effects
- Abstract
In pituitary lactotrophs of female Sprague-Dawley rats given cysteamine (300 mg/kg, per os/day) for 7 days, forming granules were increased in number and contained many separate electron-dense structures suggesting crinophagy. Compared to control values, cysteamine treatment caused no change in blood prolactin (PRL) levels, measured by radioimmunoassay (RIA). 17 beta-Estradiol (50 micrograms, sc/day) for 7 days, induced lactotroph hyperplasia and increased blood PRL levels which were unaffected by simultaneous cysteamine administration. The ultrastructural changes did not reflect those due to bromocriptine suppression of secretory activity, and supported the concept that cysteamine altered lactotroph morphology by an unknown mechanism. In pituitary gonadotrophs following cysteamine treatment, increased electron lucency of luminal contents of dilated rough endoplasmic reticulum was noted; however, blood luteinizing hormone (LH) levels did not differ from those of control values. In ovariectomized rats, cysteamine suppressed castration cell formation and reduced blood LH levels, suggesting an interference with the cell's ability to respond to GnRH stimulation. The morphologic effects of cysteamine appeared to be selective to lactotrophs and gonadotrophs, and were not secondary to vascular impairment, as capillary endothelial cells were undamaged.
- Published
- 1984
- Full Text
- View/download PDF
44. The effect of the duodenal ulcerogen cysteamine on somatostatin and gastrin cells in the rat.
- Author
-
Seiler M, Szabo S, Ourieff S, McComb DJ, Kovacs K, and Reichlin S
- Subjects
- Animals, Cytoplasm ultrastructure, Female, Gastric Mucosa drug effects, Immunoenzyme Techniques, Microscopy, Electron, Pancreas drug effects, Rats, Rats, Inbred Strains, Cysteamine pharmacology, Gastric Mucosa ultrastructure, Gastrins metabolism, Pancreas ultrastructure, Somatostatin metabolism
- Abstract
Previous studies showed a rapid decrease of somatostatin concentration in the gut and an increase in serum gastrin levels after a single dose of the duodenal ulcerogen cysteamine. An attempt was made to identify morphologic changes that would correlate with these functional changes. Rats were killed 1, 4, 8, or 24 hr after a single dose of cysteamine and sections of gastric mucosa and pancreas were processed for electron and light microscopy. Subtle ultrastructural alterations were seen in D cells of the stomach (e.g., dilation of mitochondrial cristae and endoplasmic reticulum, and apparent increase in electron density of secretory granules) after cysteamine administration. The number of somatostatin-positive cells visualized by the immunoperoxidase technique using light microscopy was decreased in 1-4 hr but returned to normal by 24 hr. The alterations observed in the G cells after cysteamine administration are consistent with release of gastrin from mature granules and increased synthesis of the hormone. The lack of major morphologic changes in the D cells suggests that cysteamine affects somatostatin without causing cell necrosis or alteration in lysosome formation. The effect of the drug may thus be mediated at the biochemical level without marked morphologic alterations.
- Published
- 1983
- Full Text
- View/download PDF
45. Ethanol-induced acute gastric injury in mast cell-deficient and congenic normal mice. Evidence that mast cells can augment the area of damage.
- Author
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Galli SJ, Wershil BK, Bose R, Walker PA, and Szabo S
- Subjects
- Animals, Histocytochemistry, Male, Mice, Mice, Inbred Strains, Alcoholic Intoxication pathology, Mast Cells physiology, Stomach pathology
- Abstract
The authors used stereomicroscopy and planimetry to measure the area of glandular stomach mucosa acutely injured by oral ethanol in mast cell-deficient and congenic normal (+/+) mice, and examined the damaged areas in 1-mu sections. Ethanol caused degranulation and/or disruption of gastric mucosal mast cells, and, at certain concentrations of ethanol, mast cell-deficient WBB6F1-W/Wv or WCB6F1-Sl/Sld mice developed significantly less (43-90% less) acute gastric injury than either congenic +/+ mice or WBB6F1-W/Wv mice whose mast cells were restored by bone marrow transplantation from WBB6F1-+/+ mice. Nevertheless, ethanol produced detectable, and in some cases substantial, gastric injury even in the complete absence of mast cells. Thus, ethanol can produce some damage to the gastric mucosa independently of mast cells. But these data suggest that under certain circumstances mast cells can augment the area of acute gastric injury induced by ethanol.
- Published
- 1987
46. New spectrophotometric and radiochemical assays for acetyl-CoA: arylamine N-acetyltransferase applicable to a variety of arylamines.
- Author
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Andres HH, Klem AJ, Szabo SM, and Weber WW
- Subjects
- Animals, Catalysis, Fluorenes, Liver enzymology, Mice, Mice, Inbred C57BL, Rabbits, Spectrophotometry methods, Tritium, Acetyltransferases analysis, Arylamine N-Acetyltransferase analysis
- Abstract
Simple and sensitive spectrophotometric and radiochemical procedures are described for the assay of acetyl-CoA:arylamine N-acetyltransferase (NAT; EC 2.3.1.5), which catalyzes the reaction acetyl-CoA + arylamine----N-acetylated arylamine + CoASH. The methods are applicable to crude tissue homogenates and blood lysates. The spectrophotometric assay is characterized by two features: (i) NAT activity is measured by quantifying the disappearance of the arylamine substrate as reflected by decreasing Schiff's base formation with dimethylaminobenzaldehyde. (ii) During the enzymatic reaction, the inhibitory product CoASH is recycled by the system acetyl phosphate/phosphotransacetylase to the substrate acetyl-CoA. The radiochemical procedure depends on enzymatic synthesis of [3H]acetyl-CoA in the assay using [3H]acetate, ATP, CoASH, and acetyl-CoA synthetase. NAT activity is measured by quantifying N-[3H]acetylarylamine after separation from [3H]acetate by extraction. Product inhibition by CoASH is prevented in this system by the use of acetyl-CoA synthetase.
- Published
- 1985
- Full Text
- View/download PDF
47. Dopamine disorder in duodenal ulceration.
- Author
-
Szabo S
- Subjects
- Animals, Anti-Ulcer Agents, Apomorphine therapeutic use, Bromocriptine therapeutic use, Chemical Phenomena, Chemistry, Cysteamine adverse effects, Cysteamine antagonists & inhibitors, Drug Synergism, Duodenal Ulcer chemically induced, Ergolines therapeutic use, Female, Gastric Juice drug effects, Haloperidol adverse effects, Pimozide adverse effects, Rats, Receptors, Dopamine drug effects, Dopamine deficiency, Duodenal Ulcer etiology
- Abstract
Cysteamine-induced duodenal ulcers in rats were prevented by the dopamine agonists bromocriptine, lergotrile, and apomorphine, whereas both the severity of duodenal ulcers and the mortality among cysteamine-treated rats were raised by the dopamine receptor antagonist, haloperiodol. Bromocriptine and lergotrile greatly reduced gastric-acid output in cysteamine-treated rats. A review of the literature shows a high incidence of duodenal ulcers in patients with Parkinson's disease (associated with dopamine deficiency) and a low occurrence in schizophrenics (associated with dopamine excess and/or hyperactivity). Thus, changes in peripheral and/or central dopamine concentrations and/or receptor activity may have a role in the pathogenesis of duodenal ulceration.
- Published
- 1979
- Full Text
- View/download PDF
48. Somatostatin stimulates clearance and hepatic uptake of colloidal carbon in the rat.
- Author
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Szabo S
- Subjects
- Animals, Colloids, Dose-Response Relationship, Drug, Female, Gadolinium pharmacology, Kupffer Cells drug effects, Rats, Rats, Inbred Strains, Zymosan pharmacology, Carbon metabolism, Kupffer Cells metabolism, Somatostatin pharmacology
- Abstract
Somatostatin exerts hormonal and neuroendocrine effects. Since it prevents several organ injuries and systemic intoxications, we tested the hypothesis that activation of Kupffer cells might be one mechanism of the beneficial actions of this peptide. The data presented here demonstrate that somatostatin given i.v. in rats dose- and time-dependently accelerated the clearance of colloidal carbon from the blood and enhanced the uptake of carbon in the liver. On a weight basis, somatostatin was more potent than the RES stimulant zymosan or RES blocker gadolinium chloride. Thus, somatostatin might modulate Kupffer cells and possibly other macrophages, and these effects may have a role in the physiologic or pharmacologic actions of this peptide.
- Published
- 1983
- Full Text
- View/download PDF
49. Effect of various steroids and ACTH on distribution of zoxazolamine in rats.
- Author
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Kourounakis P, Szabo S, and Selye H
- Subjects
- Adipose Tissue analysis, Animals, Brain Chemistry drug effects, Corticosterone pharmacology, Drug Interactions, Estradiol pharmacology, Female, Fludrocortisone pharmacology, In Vitro Techniques, Kidney abnormalities, Kidney analysis, Liver analysis, Muscles analysis, Myocardium analysis, Paralysis chemically induced, Pregnenolone Carbonitrile pharmacology, Rats, Spleen analysis, Steroids pharmacology, Triamcinolone pharmacology, Zoxazolamine analysis, Zoxazolamine pharmacology, Adrenocorticotropic Hormone pharmacology, Glucocorticoids pharmacology, Zoxazolamine metabolism
- Published
- 1973
- Full Text
- View/download PDF
50. Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene. Role of mixed function oxidase system.
- Author
-
Reynolds ES, Moslen MT, Szabo S, Jaeger RJ, and Murphy SD
- Subjects
- Animals, Aroclors pharmacology, Carcinogens, Cell Membrane drug effects, Cytochrome P-450 Enzyme System pharmacology, Endoplasmic Reticulum drug effects, Enzyme Induction, Glutathione metabolism, Hexachlorobenzene pharmacology, Liver enzymology, Liver Neoplasms chemically induced, Male, Methylcholanthrene pharmacology, Mitochondria, Liver drug effects, NADP, Phenobarbital pharmacology, Pregnenolone Carbonitrile pharmacology, Rats, Spironolactone pharmacology, Dichloroethylenes pharmacology, Hydrocarbons, Chlorinated pharmacology, Liver drug effects, Mixed Function Oxygenases metabolism, Oxidoreductases metabolism, Vinyl Chloride pharmacology, Vinyl Compounds pharmacology
- Abstract
Vinyl chloride, an occupational carcinogen, produces acute liver injury in rats pretreated with phenobarbital or Aroclor 1254. Injury appears related to morphologic changes in the endoplasmic reticulum. The degree of injury, as indicated by elevation of serum enzymes derived from the liver, correlates with the magnitude of induction of cytochrome P-450 and its reduction by NADPH. Hepatic injury following 1,1-dichloroethylene exposure differs strikingly from that caused by vinyl chloride and appears to involve plasma membranes, mitochondria, and chromatin and spares endoplasmic reticulum. Induction of cytochrome P-450 appears to protect against 1,1-dichloroethylene but not vinyl chloride.
- Published
- 1975
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