47 results on '"Szanto I"'
Search Results
2. TOPOLOGICAL DESCRIPTION OF A NON-DIFFERENTIABLE BIOECONOMICS MODEL
- Author
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GONZÁLEZ-OLIVARES, E., SÁEZ, E., STANGE, E., and SZÁNTÓ, I.
- Published
- 2005
3. A CUBIC SYSTEM WITH AN INVARIANT TRIANGLE SURROUNDING AT LEAST ONE LIMIT CYCLE
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Liu, Zhenhai, Sáez, E., and Szántó, I.
- Published
- 2003
4. The NADPH oxidase NOX5 protects against apoptosis in ALK-positive anaplastic large-cell lymphoma cell lines
- Author
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Carnesecchi, S., Rougemont, L. A., Doroshow, J. H., Nagy, M., Mouche, S., Gumy-Pause, F., and Szanto, I.
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- 2015
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5. Limit cycles and invariant parabola in a kukles system of degree three
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Zhenhai, Liu, Sáez, E., and Szántó, I.
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- 2008
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6. Limit cycles in Kukles systems of arbitrary degree with invariant ellipse
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Chavarriga, J., García, I.A., Sáez, E., and Szántó, I.
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- 2007
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7. Deficiency in the NADPH oxidase 4 predisposes towards diet-induced obesity
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Li, Y, Mouche, S, Sajic, T, Veyrat-Durebex, C, Supale, R, Pierroz, D, Ferrari, S, Negro, F, Hasler, U, Feraille, E, Moll, S, Meda, P, Deffert, C, Montet, Krause, K-H, and Szanto, I
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- 2012
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8. Insulinemia and leptinemia or of undernutrition in geriatric patients: markers of the metabolic syndrome or of undernutrition?
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Bonin-Guillaume, S, Herrmann, FR, Boillat, D, Szanto, I, Michel, JP, Rohner-Jeanrenaud, F, and Vischer, UM
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- 2006
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9. Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease
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Szanto, I, Rubbia-Brandt, L, Kiss, P, Steger, K, Banfi, B, Kovari, E, Herrmann, F, Hadengue, A, and Krause, K-H
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- 2005
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10. Coexistence of limit cycles and invariant algebraic curves for a Kukles system
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Chavarriga, J., Sáez, E., Szántó, I., and Grau, M.
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- 2004
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11. Treatment of bile leak following laparoscopic cholecystectomy: the significance of the bile duct of Luschka
- Author
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Asztalos, I., Gamal, E.M., Metzger, P., Szanto, I., Altorjay, A., Voros, A., Rozsa, I., and Kiss, J.
- Published
- 1998
12. A cubic Kolmogorov system with six limit cycles
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Lloyd, N.G., Pearson, J.M., Saéz, E, and Szántó, I.
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- 2002
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13. Three limit cycles for a first-order exothermic chemical reaction in a continuous stirred-tank reactor
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Saez, E, Szanto, I, and Monsalve, A
- Published
- 2000
14. Expression of an α7 duplicate nicotinic acetylcholine receptor-related protein in human leukocytes
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Villiger, Y., Szanto, I., Jaconi, S., Blanchet, C., Buisson, B., Krause, K.-H., Bertrand, D., and Romand, J.-A.
- Subjects
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CHOLINERGIC receptors , *LEUCOCYTES - Abstract
We examined the potential expression and function of α7 nicotinic acetylcholine receptors (nAChRs) in leukocytes. RT-PCR with α7 specific primers revealed the presence of the receptor mRNA in leukocytes. Immunoblotting and immunofluorescence experiments demonstrated the expression of a protein that is recognized by α7 specific antibodies. However, nicotine and acetylcholine (ACh) failed to elicit current in leukocytes. Binding experiments with α-bungarotoxin rhodamine conjugated were negative, illustrating the absence of a high-affinity binding site. RT-PCR analysis revealed the selective expression of the dupα7 mRNA. These data indicate that leukocytes express in their membrane the dupα7 protein but its physiological role remains to be identified. [Copyright &y& Elsevier]
- Published
- 2002
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15. An existence of inequality on a fine focus.
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Saez, E. and Szanto, I.
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- 1990
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16. Limit cycles of a cubic Kolmogorov system
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Lloyd, N.G., Pearson, J.M., Sáez, E., and Szántó, I.
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- 1996
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17. On the construction of certain Dulac functions.
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Saez, E. and Szanto, I.
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- 1988
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18. Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia
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Vallet, P., Charnay, Y., Steger, K., Ogier-Denis, E., Kovari, E., Herrmann, F., Michel, J.-P., and Szanto, I.
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ISCHEMIA , *BLOOD circulation disorders , *REACTIVE oxygen species , *BRAIN - Abstract
Abstract: Ischemia-induced neuronal damage has been linked to elevated production of reactive oxygen species (ROS) both in animal models and in humans. NADPH oxidase enzymes (NOX-es) are a major enzymatic source of ROS, but their role in brain ischemia has not yet been investigated. The present study was carried out to examine the expression of NOX4, one of the new NADPH oxidase isoforms in a mouse model of focal permanent brain ischemia. We demonstrate that NOX4 is expressed in neurons using in situ hybridization and immunohistochemistry. Ischemia, induced by middle cerebral artery occlusion resulted in a dramatic increase in cortical NOX4 expression. Elevated NOX4 mRNA levels were detectable as early as 24 h after the onset of ischemia and persisted throughout the 30 days of follow-up period, reaching a maximum between days 7 and 15. The early onset suggests neuronal reaction, while the peak period corresponds to the time of neoangiogenesis occurring mainly in the peri-infarct region. The occurrence of NOX4 in the new capillaries was confirmed by immunohistochemical staining. In summary, our paper reports the presence of the ROS producing NADPH oxidase NOX4 in neurons and demonstrates an upregulation of its expression under ischemic conditions. Moreover, a role for NOX4 in ischemia/hypoxia-induced angiogenesis is suggested by its prominent expression in newly formed capillaries. [Copyright &y& Elsevier]
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- 2005
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19. Investigation of calcitonin (CT) binding to its receptors (CTR) in MCF-7 human breast cancer cell line
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Vincze, B., Lőrincz, I., Pályi, I., Kerpel-Fronius, S., Számel, I., Szántó, I., Svastics, E., and Sugár, J.
- Published
- 1987
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20. NADPH oxidases in healthy white adipose tissue and in obesity: function, regulation, and clinical implications.
- Author
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Jornayvaz FR, Gariani K, Somm E, Jaquet V, Bouzakri K, and Szanto I
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- Humans, Animals, Insulin Resistance, Oxidation-Reduction, Mice, Diabetes Mellitus, Type 2 metabolism, Adipocytes metabolism, Obesity metabolism, NADPH Oxidases metabolism, Adipose Tissue, White metabolism, Reactive Oxygen Species metabolism
- Abstract
Reactive oxygen species, when produced in a controlled manner, are physiological modulators of healthy white adipose tissue (WAT) expansion and metabolic function. By contrast, unbridled production of oxidants is associated with pathological WAT expansion and the establishment of metabolic dysfunctions, most notably insulin resistance and type 2 diabetes mellitus. NADPH oxidases (NOXs) produce oxidants in an orderly fashion and are present in adipocytes and in other diverse WAT-constituent cell types. Recent studies have established several links between aberrant NOX-derived oxidant production, adiposity, and metabolic homeostasis. The objective of this review is to highlight the physiological roles attributed to diverse NOX isoforms in healthy WAT and summarize current knowledge of the metabolic consequences related to perturbations in their adequate oxidant production. We detail WAT-related alterations in preclinical investigations conducted in NOX-deficient murine models. In addition, we review clinical studies that have employed NOX inhibitors and currently available data related to human NOX mutations in metabolic disturbances. Future investigations aimed at understanding the integration of NOX-derived oxidants in the regulation of the WAT cellular redox network are essential for designing successful redox-related precision therapies to curb obesity and attenuate obesity-associated metabolic pathologies., (© 2024 The Author(s). Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)
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- 2024
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21. Case report: Initial atypical skeletal symptoms and dental anomalies as first signs of Gardner syndrome: the importance of genetic analysis in the early diagnosis.
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Antal G, Zsigmond A, Till Á, Orsi E, Szanto I, Büki G, Kereskai L, Herbert Z, Hadzsiev K, and Bene J
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- Humans, Female, Adolescent, Tooth Abnormalities genetics, Tooth Abnormalities pathology, Tooth Abnormalities diagnosis, Early Diagnosis, Pedigree, Gardner Syndrome genetics, Gardner Syndrome diagnosis, Gardner Syndrome pathology, Genetic Testing
- Abstract
Background: Gardner syndrome is a rare genetic cancer predisposition disorder characterized by intestinal polyposis, multiple osteomas, and soft and hard tissue tumors. Dental anomalies are present in approximately 30%-70% of patients with Gardner syndrome and can be discovered during routine dental examinations. However, sometimes the diagnosis is challenging due to the high clinical variability and incomplete clinical picture. Herein, we report a family with various dental and bone anomalies, in which the definitive diagnosis was established with the help of a comprehensive genetic analysis based on state-of-the-art next-generation sequencing technology. Case presentation: A 17-year-old female index patient presented with dental (caries, impacted, retained and anteriorly located teeth) and atypical bone anomalies not resembling Gardner syndrome. She was first referred to our Genetic Counselling Unit at the age of 11 due to an atypical bone abnormality identified by a panoramic X-ray. Tooth 3.6 was surgically removed and the histopathology report revealed a Paget's disease-like bone metabolic disorder with mixed osteoblastic and osteoclastic activity of the mandible. A small lumbar subcutaneous tumor was discovered by physical examination. Ultrasound examination of the tumor raised the possibility of a soft tissue propagation of chondromatosis. Her sister, 2 years younger at the age of 14, had some benign tumors (multiple exostoses, odontomas, epidermoid cysts) and impacted teeth. Their mother had also skeletal symptoms. Her lower teeth did not develop, the 9th-10th ribs were fused, and she complained of intermittent jaw pain. A cranial CT scan showed fibrous dysplasia on the cranial bones. Whole exome sequencing identified a heterozygous pathogenic nonsense mutation (c.4700C>G; p.Ser1567*) in the APC gene in the index patient's DNA. Targeted sequencing revealed the same variant in the DNA of the other affected family members (the sister and the mother). Conclusion: Early diagnosis of this rare, genetically determined syndrome is very important, because of the potentially high malignant transformation of intestinal polyps. Dentists should be familiar with the typical maxillofacial features of this disorder, to be able to refer patients to genetic counseling. Dental anomalies often precede the intestinal polyposis and facilitate the early diagnosis, thereby increasing the patients' chances of survival. Genetic analysis may be necessary in patients with atypical phenotypic signs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Antal, Zsigmond, Till, Orsi, Szanto, Büki, Kereskai, Herbert, Hadzsiev and Bene.)
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- 2024
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22. Non-pain-related complaints of paediatric patients after dental treatment under general anaesthesia.
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Radacsi A, Sandor B, Farkas N, Kovesi T, Szanto I, and Katona K
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- Child, Humans, Child Behavior, Dental Care, Anesthesia, General adverse effects, Anesthesia, Dental adverse effects
- Abstract
Aim: To investigate the prevalence, duration, and severity of non-pain-related complaints after dental treatment under general anaesthesia (DTGA) and to identify correlating factors from patient's characteristics and treatment., Methods: Parents/caregivers of children treated under general anaesthesia were asked to fill in a dichotomous questionnaire during hospitalisation and the postoperative week. Several complaints were evaluated in relation to factors associated with dental treatment and general anaesthesia., Conclusion: Postoperative morbidity after DTGA is common. Patients and their parents should be informed about the possibility of experiencing mild to moderate complaints, and adverse events that may last up to 7 days.
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- 2023
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23. Pain-related complaints of paediatric patients after dental treatment under general anaesthesia.
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Radacsi A, Katona K, Farkas N, Kovesi T, Szanto I, and Sandor B
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- Humans, Child, Cross-Sectional Studies, Anesthesia, Local, Dental Care, Pain, Postoperative, Anesthesia, General adverse effects
- Abstract
Aim: To identify factors related to postoperative pain and to recognise strategies to reduce this pain after dental treatment under general anaesthesia., Methods: Cross-sectional observational study. Children treated under general ansesthesia reported pain daily using the Wong Baker FACES® Pain Rating Scale. Their parents/caregivers filled in a related Yes/No questionnaire during hospitalisation and the first postoperative week. The duration and severity of pain were evaluated in relation to various factors., Conclusion: A well-established protocol is indicated to reduce operation time. Patients and their parents should be informed about the possibility of constantly subsiding postoperative pain that may last for a week. As additional local anaesthesia during general anaesthesia (GA) does not provide postoperative pain reduction in deciduous tooth extraction cases, its administration could be omitted.
- Published
- 2023
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24. NADPH Oxidases Connecting Fatty Liver Disease, Insulin Resistance and Type 2 Diabetes: Current Knowledge and Therapeutic Outlook.
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Nascè A, Gariani K, Jornayvaz FR, and Szanto I
- Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by ectopic fat accumulation in hepatocytes, is closely linked to insulin resistance and is the most frequent complication of type 2 diabetes mellitus (T2DM). One of the features connecting NAFLD, insulin resistance and T2DM is cellular oxidative stress. Oxidative stress refers to a redox imbalance due to an inequity between the capacity of production and the elimination of reactive oxygen species (ROS). One of the major cellular ROS sources is NADPH oxidase enzymes (NOX-es). In physiological conditions, NOX-es produce ROS purposefully in a timely and spatially regulated manner and are crucial regulators of various cellular events linked to metabolism, receptor signal transmission, proliferation and apoptosis. In contrast, dysregulated NOX-derived ROS production is related to the onset of diverse pathologies. This review provides a synopsis of current knowledge concerning NOX enzymes as connective elements between NAFLD, insulin resistance and T2DM and weighs their potential relevance as pharmacological targets to alleviate fatty liver disease.
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- 2022
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25. NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation.
- Author
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Szanto I
- Subjects
- Humans, Hypoxia, NADPH Oxidase 1 metabolism, NADPH Oxidase 4 genetics, NADPH Oxidase 4 metabolism, Oxidation-Reduction, Reactive Oxygen Species metabolism, NADPH Oxidases metabolism, Neoplasms
- Abstract
Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.
- Published
- 2022
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26. Course induced dexterity development and cerebellar grey matter growth of dentistry students: a randomised trial.
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Siman B, Janszky J, Perlaki G, Fazekas A, Sandor B, Katona K, Marada G, and Szanto I
- Subjects
- Adolescent, Adult, Clinical Competence, Female, Humans, Longitudinal Studies, Male, Students, Young Adult, Dentistry, Gray Matter physiology, Motor Skills, Psychomotor Performance
- Abstract
This study primarily focuses on the assessment of dentistry students' improvement of manual skills resulting from their participation in courses. We aimed to prove that systematic manual skills development significantly improves dexterity. We hypothesized that the dexterity training regimen improves manual dexterity demonstrated by the HAM-Man (Hamburg Assessment Test for Medicine-Manual Dexterity) test scores and CGM (cerebellar grey matter) growth. Thirty volunteers were randomly divided into two equal groups (study and control). Firstly, volunteers were examined by the HAM-Man test and baseline MRI scans. Afterwards, a manual skills development course was launched for the "study group". Secondly, all the manual skills of the students were evaluated longitudinally, by the HAM-Man test. Simultaneously, the follow-up MRI scans were taken to observe morphologic changes in the cerebellum. The Wilcoxon signed-rank test and Student Paired t-test were used for statistical analyses. Value p < 0.05 was considered significant. After the training, significant growth of CGM as well as improvement on manual skill assessment tests, were found in the study group. Training courses are suitable for preparing students with low levels of dexterity for performing demanding tasks. The improvement is demonstrable by a wire bending test and by bilateral CGM enlargement as well.
- Published
- 2021
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27. Beta-Cell-Specific Expression of Nicotinamide Adenine Dinucleotide Phosphate Oxidase 5 Aggravates High-Fat Diet-Induced Impairment of Islet Insulin Secretion in Mice.
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Bouzakri K, Veyrat-Durebex C, Holterman C, Arous C, Barbieux C, Bosco D, Altirriba J, Alibashe M, Tournier BB, Gunton JE, Mouche S, Bietiger W, Forterre A, Berney T, Pinget M, Christofori G, Kennedy C, and Szanto I
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- Animals, Cells, Cultured, Diet, High-Fat adverse effects, Female, Humans, Insulin Secretion drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, NADPH Oxidase 5 metabolism, Islets of Langerhans metabolism, NADPH Oxidase 5 genetics
- Abstract
Aims: Nicotinamide adenine dinucleotide phosphate oxidases (NOX-es) produce reactive oxygen species and modulate β-cell insulin secretion. Islets of type 2 diabetic subjects present elevated expression of NOX5. Here, we sought to characterize regulation of NOX5 expression in human islets in vitro and to uncover the relevance of NOX5 in islet function in vivo using a novel mouse model expressing NOX5 in doxycycline-inducible, β-cell-specific manner (RIP/rtTA/NOX5 mice). Results: In situ hybridization and immunohistochemistry employed on pancreatic sections demonstrated NOX5 messenger ribonucleic acid (mRNA) and protein expressions in human islets. In cultures of dispersed islets, NOX5 protein was observed in somatostatin-positive (δ) cells in basal (2.8 m M glucose) conditions. Small interfering ribonucleic acid (siRNA)-mediated knockdown of NOX5 in human islets cultured in basal glucose concentrations resulted in diminished glucose-induced insulin secretion (GIIS) in vitro . However, when islets were preincubated in high (16.7 m M ) glucose media for 12 h, NOX5 appeared also in insulin-positive (β) cells. In vivo , mice with β-cell NOX5 expression developed aggravated impairment of GIIS compared with control mice when challenged with 14 weeks of high-fat diet. Similarly, in vitro palmitate preincubation resulted in more severe reduction of insulin release in islets of RIP/rtTA/NOX5 mice compared with their control littermates. Decreased insulin secretion was most distinct in response to theophylline stimulation, suggesting impaired cyclic adenosine monophosphate (cAMP)-mediated signaling due to increased phosphodiesterase activation. Innovation and Conclusions: Our data provide the first insight into the complex regulation and function of NOX5 in islets implying an important role for NOX5 in δ-cell-mediated intraislet crosstalk in physiological circumstances but also identifying it as an aggravating factor in β-cell failure in diabetic conditions.
- Published
- 2020
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28. H 2 O 2 Metabolism in Normal Thyroid Cells and in Thyroid Tumorigenesis: Focus on NADPH Oxidases.
- Author
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Szanto I, Pusztaszeri M, and Mavromati M
- Abstract
Thyroid hormone synthesis requires adequate hydrogen peroxide (H
2 O2 ) production that is utilized as an oxidative agent during the synthesis of thyroxin (T4) and triiodothyronine (T3). Thyroid H2 O2 is generated by a member of the family of NADPH oxidase enzymes (NOX-es), termed dual oxidase 2 (DUOX2). NOX/DUOX enzymes produce reactive oxygen species (ROS) as their unique enzymatic activity in a timely and spatially regulated manner and therefore, are important regulators of diverse physiological processes. By contrast, dysfunctional NOX/DUOX-derived ROS production is associated with pathological conditions. Inappropriate DUOX2-generated H2 O2 production results in thyroid hypofunction in rodent models. Recent studies also indicate that ROS improperly released by NOX4, another member of the NOX family, are involved in thyroid carcinogenesis. This review focuses on the current knowledge concerning the redox regulation of thyroid hormonogenesis and cancer development with a specific emphasis on the NOX and DUOX enzymes in these processes.- Published
- 2019
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29. Comparison of fractionation strategies for offline two-dimensional liquid chromatography tandem mass spectrometry analysis of proteins from mouse adipose tissue.
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Sajic T, Varesio E, Szanto I, and Hopfgartner G
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- Animals, Male, Mice, Adipose Tissue metabolism, Chromatography, Liquid methods, Proteomics methods, Tandem Mass Spectrometry methods
- Abstract
In the frame of protein identification from mouse adipose tissue, two strategies were compared for the offline elution of peptides from a strong cation exchange (SCX) column in two-dimensional liquid chromatography tandem mass spectrometry (2D-LC-MS/MS) analyses. First, the salt gradient (using K(+) as displacing agent) was evaluated from 25 to 500mM KCl. Then, a less investigated elution mode using a pH gradient (using citric acid and ammonium hydroxide) was carried out from pH 2.5 to 9.0. Equal amounts of peptide digest derived from mouse adipose tissue were loaded onto the SCX column and fractionated according to the two approaches. A total of 15 fractions were collected in two independent experiments for each SCX elution strategy. Then, each fraction was analyzed on a nanoLC-MS/MS platform equipped with a column-switching unit for desalting and enrichment. No substantial differences in peptide quality characteristics (molecular weight, isoelectric point, or GRAVY [grand average of hydropathicity] index distributions) were observed between the two datasets. The pH gradient approach was found to be superior, with 27.5% more unique peptide identifications and 10% more distinct protein identifications compared with the salt-based elution method. In conclusion, our data imply that the pH gradient SCX fractionation is more desirable for proteomics analysis of entire adipose tissue., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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30. NADPH oxidase 4 deficiency reduces aquaporin-2 mRNA expression in cultured renal collecting duct principal cells via increased PDE3 and PDE4 activity.
- Author
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Féraille E, Dizin E, Roth I, Derouette JP, Szanto I, Martin PY, de Seigneux S, and Hasler U
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- 1-Methyl-3-isobutylxanthine, Animals, Aquaporin 2 genetics, Arginine Vasopressin metabolism, Blotting, Western, Cyclic AMP metabolism, Kidney Tubules, Collecting cytology, Mice, NADPH Oxidase 4, Quinolones, RNA, Messenger genetics, RNA, Small Interfering genetics, Real-Time Polymerase Chain Reaction, Rolipram, Signal Transduction physiology, Aquaporin 2 metabolism, Cyclic Nucleotide Phosphodiesterases, Type 3 metabolism, Cyclic Nucleotide Phosphodiesterases, Type 4 metabolism, NADPH Oxidases deficiency, RNA, Messenger metabolism, Reactive Oxygen Species metabolism
- Abstract
The final control of renal water reabsorption occurs in the collecting duct (CD) and relies on regulated expression of aquaporin-2 (AQP2) in principal CD cells. AQP2 transcription is primarily induced by type 2 vasopressin receptor (V2R)-cAMP-protein kinase A (PKA) signaling but also by other factors, including TonEBP and NF-κB. NAPDH oxidase 4 (NOX4) represents a major source of reactive oxygen species (ROS) in the kidney. Because NOX-derived ROS may alter PKA, TonEBP and NF-κB activity, we examined the effects of NOX4 depletion on AQP2 expression. Depleted NOX4 expression by siRNA (siNOX4) in mpkCCDcl4 cells attenuated increased AQP2 mRNA expression by arginine vasopressin (AVP) but not by hypertonicity, which induces both TonEBP and NF-κB activity. AVP-induced AQP2 expression was similarly decreased by the flavoprotein inhibitor diphenyleneiodonium. siNOX4 altered neither TonEBP nor NF-κB activity but attenuated AVP-inducible cellular cAMP concentration, PKA activity and CREB phosphorylation as well as AQP2 mRNA expression induced by forskolin, a potent activator of adenylate cyclase. The repressive effect of siNOX4 on AVP-induced AQP2 mRNA expression was abolished by the non-selective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and was significantly decreased by selective PDE antagonists cilostamide and rolipram, but not vinpocetine, which respectively target PDE3, PDE4 and PDE1. Thus, by inhibiting PDE3 and PDE4 activity NOX4-derived ROS may contribute to V2R-cAMP-PKA signaling and enhance AQP2 transcription.
- Published
- 2014
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31. STAT6 promotes bi-directional modulation of PKM2 in liver and adipose inflammatory cells in rosiglitazone-treated mice.
- Author
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Sajic T, Hainard A, Scherl A, Wohlwend A, Negro F, Sanchez JC, and Szanto I
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- Adipose Tissue cytology, Adipose Tissue drug effects, Animals, Liver cytology, Liver drug effects, Mice, Mice, Knockout, Rosiglitazone, Signal Transduction drug effects, Thyroid Hormone-Binding Proteins, Adipose Tissue metabolism, Carrier Proteins metabolism, Liver metabolism, Membrane Proteins metabolism, Proteome metabolism, STAT6 Transcription Factor metabolism, Signal Transduction physiology, Thiazolidinediones pharmacology, Thyroid Hormones metabolism
- Abstract
STAT6 interacts with PPARγ to elicit macrophage polarization towards an anti-inflammatory, insulin-sensitizing phenotype. Mice deficient in STAT6 display liver lipid accumulation (hepatosteatosis). Rosiglitazone (RSG), a PPARγ agonist, ameliorates hepatosteatosis and enhances insulin sensitivity. To elucidate the role of STAT6 in PPARγ action on hepatosteatosis we compared liver proteomes of RSG-treated wild type and STAT6-deficient mice and we identified pyruvate kinase M2 (PKM2), a glycolysis and proliferation-regulating enzyme that displayed STAT6-dependent expression. RSG induced PKM2 within inflammatory cells in liver but suppressed its expression in adipose tissue. RSG diminished hepatosteatosis and oxidative stress, enhanced fat accumulation and improved insulin sensitivity in STAT6-deficient mice. Our data reveal a complex interaction between STAT6 and PPARγ in the regulation of liver and adipose tissue lipid depot distribution and design STAT6 as a novel link between inflammatory cell metabolism and adipocyte and hepatocyte function.
- Published
- 2013
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32. NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury.
- Author
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Nlandu Khodo S, Dizin E, Sossauer G, Szanto I, Martin PY, Feraille E, Krause KH, and de Seigneux S
- Subjects
- Animals, Antioxidants metabolism, Apoptosis, Atrophy, Capillaries pathology, Fibrosis, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Kidney Diseases genetics, Kidney Diseases pathology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidase 2, NADPH Oxidase 4, NF-E2-Related Factor 2 metabolism, Oxidative Stress, Ureteral Obstruction, Vascular Endothelial Growth Factor A metabolism, Kidney pathology, Kidney Diseases enzymology, Membrane Glycoproteins metabolism, NADPH Oxidases metabolism
- Abstract
NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild-type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1α and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-β1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1α and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions.
- Published
- 2012
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33. High-throughput screening of saliva for early detection of oral cancer: a pilot study.
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Szanto I, Mark L, Bona A, Maasz G, Sandor B, Gelencser G, Turi Z, and Gallyas F Jr
- Subjects
- Aged, Carcinoma, Mucoepidermoid metabolism, Carcinoma, Squamous Cell metabolism, Case-Control Studies, Early Detection of Cancer, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mouth Neoplasms metabolism, Neoplasm Staging, Pilot Projects, Prognosis, Proteomics methods, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Biomarkers, Tumor metabolism, Carcinoma, Mucoepidermoid diagnosis, Carcinoma, Squamous Cell diagnosis, High-Throughput Screening Assays, Mouth Neoplasms diagnosis, Saliva chemistry
- Abstract
The success of tumour therapy depends considerably on early diagnosis. Therefore, we aimed to develop a widely available, cheap, non-invasive, high-throughput method suitable for screening high-risk populations, at least, for early signs of malignant transformation in the oral cavity. First, in order to identify suitable tumour marker candidates, we compared the protein patterns of five selected saliva samples obtained from healthy controls and tumour patients after electrophoretic separation, excised the bands that were consistently up-regulated in the tumour patients only, and performed matrix-assisted laser-desorption ionisation (MALDI)-time of flight (TOF) tandem mass spectrometry (MS/MS) analysis of the proteins in these bands after in-gel tryptic digestion. From the panel of proteins identified, we chose annexin 1 and peroxiredoxin 2 for further studies based on their presence in the saliva of all five oral cancer patients only. Then, we performed a homology search of protein databases using the primary sequence of each in silico tryptic fragment peptide of these two proteins as bait, and selected a unique peptide for each. Finally, we performed targeted MALDI-TOF MS peptide analysis in a blinded fashion on all samples obtained from 20 healthy controls and 22 tumour patients for the presence of these peptides. We found both peptides present in the saliva samples of all cancer patients only. Even though these tumour markers should be validated in a wider population, our results indicate that targeted MALDI-TOF MS analysis of unique peptides of putative saliva protein tumour biomarkers could be the method of choice for cost-efficient, high-throughput screening for the early detection of oral cancer.
- Published
- 2012
- Full Text
- View/download PDF
34. Comparison of three detergent-free protein extraction protocols for white adipose tissue.
- Author
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Sajic T, Hopfgartner G, Szanto I, and Varesio E
- Subjects
- Animals, Blotting, Western methods, Chloroform chemistry, Detergents chemistry, Male, Methanol chemistry, Mice, Proteins chemistry, Sucrose chemistry, Trifluoroethanol chemistry, Water chemistry, Adipose Tissue, White metabolism, Centrifugation methods, Chemical Fractionation methods, Proteins isolation & purification
- Abstract
A comparative study of three detergent-free protein extraction protocols--a differential centrifugal fractionation, a delipidation protocol based on the Bligh and Dyer method, and the trifluoroethanol addition as cosolvent to an aqueous buffer--was performed on white adipose tissue. The performance of the protocols directly compatible with liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) was evaluated based on the total protein extraction yield and the protein recovery from different functional and cellular compartments. The most suitable method for the extraction of white adipose tissue proteins from a wide range of cellular and structural compartments was the delipidation protocol based on the Bligh and Dyer method., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
35. Differential proteomic analysis of STAT6 knockout mice reveals new regulatory function in liver lipid homeostasis.
- Author
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Iff J, Wang W, Sajic T, Oudry N, Gueneau E, Hopfgartner G, Varesio E, and Szanto I
- Subjects
- Animals, Computer Simulation, Fatty Acid-Binding Proteins genetics, Fatty Acid-Binding Proteins metabolism, Female, Gene Expression, Heat-Shock Proteins, Immunohistochemistry, Isotope Labeling, Male, Mass Spectrometry methods, Mice, Mice, Inbred BALB C, Mice, Knockout, Promoter Regions, Genetic, Proteome metabolism, STAT3 Transcription Factor genetics, STAT3 Transcription Factor metabolism, STAT6 Transcription Factor genetics, Signal Transduction, Suppressor of Cytokine Signaling 3 Protein, Suppressor of Cytokine Signaling Proteins genetics, Suppressor of Cytokine Signaling Proteins metabolism, Lipid Metabolism physiology, Liver metabolism, Proteomics methods, STAT6 Transcription Factor metabolism
- Abstract
Increased inflammatory signaling is a key feature of metabolic disorders. In this context, the role of increased pro-inflammatory signals has been extensively studied. By contrast, no efforts have been dedicated to study the contrasting scenario: the attenuation of anti-inflammatory signals and their role in metabolic homeostasis. IL-4 and IL-13 are anti-inflammatory cytokines signaling through the Signal Transducer and Activator of Transcription 6 (STAT6). Our study was aimed at evaluating the lack of STAT6 signaling on liver homeostasis. To this end we analyzed the liver proteome of wild type and STAT6 knock-out mice using 2D nanoscale LC-MS/MS with iTRAQ labeling technique. The coordinated changes in proteins identified by this quantitative proteome analysis indicated disturbed lipid homeostasis and a state of hepatocellular stress. Most significantly, the expression of the liver fatty acid binding protein (FABP1) was increased in the knock-out mice. In line with the elevated FABP1 expression we found latent liver lipid accumulation in the STAT6-deficient mice which was further aggravated when mice were challenged by a high fat diet. In conclusion, our study revealed a so far uncharacterized role for STAT6 in regulating liver lipid homeostasis and demonstrates the importance of anti-inflammatory signaling in the defense against the development of liver steatosis.
- Published
- 2009
- Full Text
- View/download PDF
36. The central melanocortin system directly controls peripheral lipid metabolism.
- Author
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Nogueiras R, Wiedmer P, Perez-Tilve D, Veyrat-Durebex C, Keogh JM, Sutton GM, Pfluger PT, Castaneda TR, Neschen S, Hofmann SM, Howles PN, Morgan DA, Benoit SC, Szanto I, Schrott B, Schürmann A, Joost HG, Hammond C, Hui DY, Woods SC, Rahmouni K, Butler AA, Farooqi IS, O'Rahilly S, Rohner-Jeanrenaud F, and Tschöp MH
- Subjects
- Adipocytes cytology, Adipocytes metabolism, Adipose Tissue cytology, Adipose Tissue metabolism, Animals, Behavior, Animal physiology, Eating, Glucose metabolism, Humans, Insulin metabolism, Melanocyte-Stimulating Hormones administration & dosage, Melanocyte-Stimulating Hormones metabolism, Mice, Mice, Knockout, Rats, Rats, Sprague-Dawley, Receptor, Melanocortin, Type 4 genetics, Receptor, Melanocortin, Type 4 metabolism, Receptors, Melanocortin, alpha-MSH administration & dosage, alpha-MSH analogs & derivatives, alpha-MSH metabolism, Central Nervous System metabolism, Lipid Metabolism, Melanocortins metabolism, Signal Transduction physiology
- Abstract
Disruptions of the melanocortin signaling system have been linked to obesity. We investigated a possible role of the central nervous melanocortin system (CNS-Mcr) in the control of adiposity through effects on nutrient partitioning and cellular lipid metabolism independent of nutrient intake. We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose tissue (WAT), while increased CNS-Mcr signaling triggered lipid mobilization. These effects were independent of food intake and preceded changes in adiposity. In addition, decreased CNS-Mcr signaling promoted increased insulin sensitivity and glucose uptake in WAT while decreasing glucose utilization in muscle and brown adipose tissue. Such CNS control of peripheral nutrient partitioning depended on sympathetic nervous system function and was enhanced by synergistic effects on liver triglyceride synthesis. Our findings offer an explanation for enhanced adiposity resulting from decreased melanocortin signaling, even in the absence of hyperphagia, and are consistent with feeding-independent changes in substrate utilization as reflected by respiratory quotient, which is increased with chronic Mcr blockade in rodents and in humans with loss-of-function mutations in MC4R. We also reveal molecular underpinnings for direct control of the CNS-Mcr over lipid metabolism. These results suggest ways to design more efficient pharmacological methods for controlling adiposity.
- Published
- 2007
- Full Text
- View/download PDF
37. Reduced expression of the NADPH oxidase NOX4 is a hallmark of adipocyte differentiation.
- Author
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Mouche S, Mkaddem SB, Wang W, Katic M, Tseng YH, Carnesecchi S, Steger K, Foti M, Meier CA, Muzzin P, Kahn CR, Ogier-Denis E, and Szanto I
- Subjects
- 3T3 Cells, Adipocytes cytology, Adipose Tissue, Brown cytology, Adipose Tissue, Brown enzymology, Animals, Catalase metabolism, Cells, Cultured, Dietary Fats, Fibroblast Growth Factor 1 metabolism, Fibroblast Growth Factor 2 metabolism, Humans, Insulin metabolism, Insulin Resistance physiology, Insulin-Like Growth Factor I metabolism, Mice, Mice, Knockout, Mice, Obese, NADP metabolism, NADPH Oxidase 4, NADPH Oxidases genetics, RNA, Small Interfering metabolism, Reactive Oxygen Species metabolism, Receptor, Insulin genetics, Receptor, Insulin metabolism, Signal Transduction physiology, Superoxide Dismutase metabolism, Adipocytes enzymology, Adipocytes physiology, Cell Differentiation, Gene Expression Regulation, Enzymologic, NADPH Oxidases metabolism
- Abstract
Adipocyte differentiation is a complex process regulated among other factors by insulin and the production of reactive oxygen species (ROS). NOX4 is a ROS generating NADPH oxidase enzyme mediating insulin's action in 3T3L1 adipocytes. In the present paper we show that NOX4 is expressed at high levels both in white and brown preadipocytes and that differentiation into adipocytes results in a decrease in their NOX4 mRNA content. These in vitro results were confirmed in vivo by demonstrating that in intact adipose tissue the majority of NOX4 expressing cells are localized within the preadipocyte containing stromal/vascular fraction, rather than in the portion consisting of mature adipocytes. In line with these observations, quantification of NOX4 mRNA in fat derived from different rodent models of insulin resistance indicated that alteration in NOX4 expression reflects changes in the ratio of adipocyte/interstitial fractions. In conclusion, we reveal that decreased NOX4 mRNA content is a hallmark of adipocyte differentiation and that NOX4 expression measured in whole adipose tissue is not an unequivocal indicator of intact or impaired insulin action.
- Published
- 2007
- Full Text
- View/download PDF
38. Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3.
- Author
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Carnesecchi S, Carpentier JL, Foti M, and Szanto I
- Subjects
- Acetophenones pharmacology, Cell Line, Tumor, Enzyme Inhibitors pharmacokinetics, Humans, Hydrogen Peroxide metabolism, Membrane Proteins genetics, Mitogen-Activated Protein Kinases metabolism, NADPH Oxidases genetics, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, RNA, Small Interfering genetics, Transcription, Genetic, Transfection, Up-Regulation drug effects, Vascular Endothelial Growth Factor A genetics, Insulin metabolism, Membrane Proteins metabolism, NADPH Oxidases metabolism, Signal Transduction, Vascular Endothelial Growth Factor A biosynthesis
- Abstract
Vascular endothelial growth factor (VEGF) is the most potent stimulatory factor of angiogenesis. Its expression is induced by reactive oxygen species (ROS) in hypoxic conditions and by insulin in normoxic cells. Both ROS and insulin can activate mitogen-activated protein kinases (MAPKs) and induce the transcriptional factor Sp1, components that are essential for VEGF gene expression. The aim of this study was to investigate the role of ROS producing NADPH oxidase enzymes (NOX-es) in insulin-regulated VEGF gene activation. To achieve this goal we chose HepG2 cells as our model system as these cells express the NADPH oxidase isoform NOX3 and respond to insulin stimulation with enhanced ROS production and mRNA transcription and production of VEGF. We demonstrate that in control cells insulin stimulation leads to H2O2 generation, a biphasic activation of p42/44 MAPK and the induction of both Sp1 and HIF-1alpha. Transfection of NOX3-specific siRNA abrogates H2O2 production and inhibits exclusively the second phase of p42/44 MAPK phosphorylation and Sp1 DNA binding and thus prevents upregulation of VEGF-A mRNA expression. In conclusion, our results demonstrate that NOX3, a ROS generating NADPH oxidase, plays an integral role in insulin-induced p42/44 MAPK signal transmission and VEGF-A production.
- Published
- 2006
- Full Text
- View/download PDF
39. Ghrelin action in the brain controls adipocyte metabolism.
- Author
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Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schürmann A, Szanto I, Tschöp MH, and Rohner-Jeanrenaud F
- Subjects
- Acetyl-CoA Carboxylase genetics, Acetyl-CoA Carboxylase metabolism, Adipocytes cytology, Adipose Tissue cytology, Adipose Tissue metabolism, Animals, Brain anatomy & histology, Carrier Proteins genetics, Carrier Proteins metabolism, Eating drug effects, Energy Metabolism drug effects, Fatty Acid Synthases genetics, Fatty Acid Synthases metabolism, Ghrelin, Glucose metabolism, Homeostasis, Ion Channels, Lipoprotein Lipase genetics, Lipoprotein Lipase metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Knockout, Mitochondrial Proteins, Neuropeptide Y genetics, Neuropeptide Y metabolism, Peptide Hormones administration & dosage, Peptide Hormones genetics, Rats, Rats, Wistar, Stearoyl-CoA Desaturase genetics, Stearoyl-CoA Desaturase metabolism, Uncoupling Protein 1, Uncoupling Protein 3, Adipocytes metabolism, Brain metabolism, Peptide Hormones metabolism
- Abstract
Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the CNS. The CNS also directly regulates adipocyte metabolism, as we have shown here by examining central action of the orexigenic hormone ghrelin. Chronic central ghrelin infusion resulted in increases in the glucose utilization rate of white and brown adipose tissue without affecting skeletal muscle. In white adipocytes, mRNA expression of various fat storage-promoting enzymes such as lipoprotein lipase, acetyl-CoA carboxylase alpha, fatty acid synthase, and stearoyl-CoA desaturase-1 was markedly increased, while that of the rate-limiting step in fat oxidation, carnitine palmitoyl transferase-1alpha, was decreased. In brown adipocytes, central ghrelin infusion resulted in lowered expression of the thermogenesis-related mitochondrial uncoupling proteins 1 and 3. These ghrelin effects were dose dependent, occurred independently from ghrelin-induced hyperphagia, and seemed to be mediated by the sympathetic nervous system. Additionally, the expression of some fat storage enzymes was decreased in ghrelin-deficient mice, which led us to conclude that central ghrelin is of physiological relevance in the control of cell metabolism in adipose tissue. These results unravel the existence of what we believe to be a new CNS-based neuroendocrine circuit regulating metabolic homeostasis of adipose tissue.
- Published
- 2006
- Full Text
- View/download PDF
40. Significance and prognostic value of lysosomal enzyme activities measured in surgically operated adenocarcinomas of the gastroesophageal junction and squamous cell carcinomas of the lower third of esophagus.
- Author
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Altorjay A, Paal B, Sohar N, Kiss J, Szanto I, and Sohar I
- Subjects
- Female, Humans, Male, Middle Aged, Neoplasm Staging, Prognosis, Retrospective Studies, Tripeptidyl-Peptidase 1, Adenocarcinoma diagnosis, Adenocarcinoma enzymology, Adenocarcinoma pathology, Adenocarcinoma surgery, Carcinoma, Squamous Cell diagnosis, Carcinoma, Squamous Cell enzymology, Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell surgery, Esophageal Neoplasms diagnosis, Esophageal Neoplasms enzymology, Esophageal Neoplasms pathology, Esophageal Neoplasms surgery, Gastrointestinal Neoplasms diagnosis, Gastrointestinal Neoplasms enzymology, Gastrointestinal Neoplasms pathology, Gastrointestinal Neoplasms surgery, Lysosomes enzymology
- Abstract
Aim: To establish whether there are fundamental differences in the biochemistries of adenocarcinomas of the gastroesophageal junction (GEJ) and the squamous cell carcinomas of the lower third of the esophagus (LTE)., Methods: Between February 1, 1997 and February 1, 2000, we obtained tissue samples at the moment of resection from 54 patients for biochemical analysis. The full set of data could be comprehensively analyzed in 47 of 54 patients samples (81%). Of these, 29 were adenocarcinomas of the GEJ Siewert type I (n = 8), type II (n = 12), type III (n = 9), and 18 presented as squamous cell carcinomas of the LTE. We evaluated the mean values of 11-lysosomal enzyme and 1-cytosol protease activities of the tumorous and surrounding mucosae as well as their relative activities, measured as the ratio of activity in tumor and normal tissues from the same patient. These data were further analyzed to establish the correlation with tumor localization, TNM stage (lymph-node involvement), histological type (papillary, signet-ring cell, tubular), state of differentiation (good, moderate, poor), and survival (
or=24 mo)., Results: In adenocarcinomas, the activity of alpha-mannosidase (AMAN), cathepsin B (CB) and dipeptidyl-peptidase I (DPP I) increased significantly as compared to the normal gastric mucosa. In squamous cell carcinomas of the esophagus, we also found a significant difference in the activity of cathepsin L and tripeptidyl-peptidase I in addition to these three. There was a statistical correlation of AMAN, CB, and DPP I activity between the level of differentiation of adenocarcinomas of the GEJ and lymph node involvement, because tumors with no lymph node metastases histologically confirmed as well-differentiated, showed a significantly lower activity. The differences in CB and DPP I activity correlated well with the differences in survival rates, since the CB and DPP I values of those who died within 24 mo following surgical intervention were significantly higher than of those who survived for 2 years or more., Conclusion: Adenocarcinomas of the GEJ form a homogenous group from a tumor-biochemical aspect, and differ from the biochemical characteristics of squamous cell carcinomas of the LTE on many points. When adenocarcinomas of the GEJs are examined at the preoperative phase, the ratio of the performed AMAN, CB, and DPP I enzymatic activity of the tissue sample from the tumor and adjacent intact mucosa within 2 cm of the tumor may have a prognostic value even in the preoperative examination period, and may indicate that ranking of these patients into the neo-adjuvant treatment group should be considered. - Published
- 2005
- Full Text
- View/download PDF
41. Expression of mRNA for ROS-generating NADPH oxidases in the aging stomach.
- Author
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Salles N, Szanto I, Herrmann F, Armenian B, Stumm M, Stauffer E, Michel JP, and Krause KH
- Subjects
- Aged, Aged, 80 and over, Biopsy, Chronic Disease, Female, Gastritis enzymology, Gene Expression, Humans, Male, Membrane Glycoproteins biosynthesis, Membrane Glycoproteins genetics, Membrane Proteins biosynthesis, Membrane Proteins genetics, NADPH Oxidase 1, NADPH Oxidase 2, NADPH Oxidase 5, NADPH Oxidases biosynthesis, Polymerase Chain Reaction methods, RNA, Messenger genetics, Severity of Illness Index, Stomach pathology, Aging metabolism, NADPH Oxidases genetics, Reactive Oxygen Species metabolism, Stomach enzymology
- Abstract
Oxidative damage is thought to play a key role in the aging of various organ systems. In this study, we have therefore analyzed mRNA expression of ROS-generating NADPH oxidases in the aging stomach. Gastric biopsies of hospitalized geriatric patients were analyzed for histology (Sidney classification), and real-time PCR was used to quantify mRNA expression of the superoxide-generating NADPH oxidases NOX1, NOX2, and NOX5. We found that stomach biopsies of elderly patients expressed NOX5 and NOX2 mRNA, but not NOX1. The mRNA expression of NOX5 (a lymphocyte NADPH oxidase) neither depended on age nor on the results of the stomach histology. In contrast, mRNA expression of NOX2 (phagocyte NADPH oxidase) was a function of two variables. Increased NOX2 mRNA levels were observed in biopsies with signs of chronic inflammation (p=0.01). Interestingly, however, there was also an age-dependent increase in NOX2 mRNA levels (p=0.01). We conclude that in elderly patients the gastric mRNA expression of the ROS-generating enzyme NOX2 increases as a function of age, possibly contributing to stomach aging and gastric vulnerability of the elderly.
- Published
- 2005
- Full Text
- View/download PDF
42. Mechanisms of HIV receptor and co-receptor down-regulation by prostratin: role of conventional and novel PKC isoforms.
- Author
-
Hezareh M, Moukil MA, Szanto I, Pondarzewski M, Mouche S, Cherix N, Brown SJ, Carpentier JL, and Foti M
- Subjects
- CD4 Antigens metabolism, Cell Line, Endocytosis drug effects, Enzyme Inhibitors pharmacology, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes metabolism, Protein Kinase C antagonists & inhibitors, Protein Transport drug effects, Receptors, CCR5 metabolism, T-Lymphocytes drug effects, T-Lymphocytes metabolism, Tetradecanoylphorbol Acetate pharmacology, Down-Regulation drug effects, Phorbol Esters pharmacology, Protein Kinase C metabolism, Receptors, CXCR4 metabolism, Receptors, HIV metabolism
- Abstract
Prostratin is an unusual non-tumour promoting phorbol ester with potential as an inductive adjuvant therapy for highly active antiretroviral therapy (HAART) due to its ability to up-regulate viral expression from latent provirus. In addition, prostratin is also able to inhibit de novo HIV infection most probably because it induces down-regulation of HIV receptors from the surface of target cells. In this study, we investigate the mechanisms by which prostratin down-regulates HIV receptor and co-receptor surface expression in lymphocytic and monocytic cell lines. Our results indicate that prostratin induces down-regulation of surface expression of CD4 and CXCR4, but not CCR5, in various cell lines. Down-regulation of CD4 and CXCR4 by prostratin is achieved by internalization through receptor-mediated endocytosis and/or macropinocytosis, which is then followed by degradation of these molecules. Because prostratin is a protein kinase C (PKC) activator, we next examined the potential contribution of distinct PKC isoforms to down-regulate CD4 and CXCR4 in response to prostratin stimulation. Although exposure of cells to prostratin or phorbol-myristate-acetate (PMA) induces the translocation of several PKC isoforms to the plasma membrane, the use of specific PKC inhibitors revealed that novel PKCs are the main mediators of the prostratin-induced CD4 down-regulation, whereas both conventional and novel PKCs contribute to CXCR4 down-regulation. Altogether these results showed that prostratin, through the activation of conventional and/or novel PKC isoforms, rapidly reduces cell surface expression of CD4 and CXCR4, but not CCR5, by inducing their internalization and degradation.
- Published
- 2004
- Full Text
- View/download PDF
43. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones.
- Author
-
Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, and Kahn CR
- Subjects
- Alleles, Animals, Deoxyglucose metabolism, Fatty Acids metabolism, Genotype, Glucose metabolism, Glucose Tolerance Test, Insulin metabolism, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Mice, Transgenic, Models, Genetic, Muscle, Skeletal metabolism, Oligonucleotide Array Sequence Analysis, Recombination, Genetic, Time Factors, Triglycerides metabolism, Adipose Tissue metabolism, Insulin Resistance, Muscles metabolism, Receptors, Cytoplasmic and Nuclear genetics, Receptors, Cytoplasmic and Nuclear physiology, Thiazoles metabolism, Thiazolidinediones, Transcription Factors genetics, Transcription Factors physiology
- Abstract
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/loxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.
- Published
- 2003
- Full Text
- View/download PDF
44. Selective interaction between leptin and insulin signaling pathways in a hepatic cell line.
- Author
-
Szanto I and Kahn CR
- Subjects
- Animals, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Carrier Proteins biosynthesis, Glycogen Synthase Kinase 3, Glycogen Synthase Kinases, Humans, Insulin pharmacology, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Leptin pharmacology, Liver cytology, Phosphatidylinositol 3-Kinases metabolism, Phosphoproteins metabolism, Phosphorylation, Protein Isoforms biosynthesis, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-fos genetics, Receptors, Leptin, Serine metabolism, Tumor Cells, Cultured, Tyrosine metabolism, Insulin metabolism, Leptin metabolism, Receptors, Cell Surface, Signal Transduction
- Abstract
Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulin-induced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate.
- Published
- 2000
- Full Text
- View/download PDF
45. Metastasis of an esophageal carcinoma to a giant gastric ulcer.
- Author
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Altorjay A, Gonda G, Ereifej S, Szanto I, Farsang Z, and Kiss J
- Subjects
- Carcinoma, Squamous Cell pathology, Carcinoma, Squamous Cell surgery, Cell Division, Esophageal Neoplasms pathology, Esophagectomy, Gastrectomy, Gastric Fundus pathology, Humans, Male, Middle Aged, Stomach Neoplasms pathology, Stomach Neoplasms surgery, Stomach Ulcer pathology, Carcinoma, Squamous Cell secondary, Esophageal Neoplasms surgery, Stomach Neoplasms secondary, Stomach Ulcer surgery
- Abstract
In patients with esophageal carcinoma it is considered that stomach metastasis is induced mainly via the lymphatic route rather than via the bloodstream route that is common in other types of distant organ metastasis. A 56 year-old patient is reported who underwent synchronous subtotal esophagectomy and total gastrectomy for a middle third esophageal carcinoma and a giant peptic ulcer within the gastric fundus. The final histopathologic examination revealed a squamous cell carcinoma of the esophagus with concomitant squamous tumor implantation within the gastric ulcer. The increased cell proliferation in the ulcer margin can serve as a "biological background or base" for implantation.
- Published
- 1999
46. Malignant tumor developed in colon-esophagus.
- Author
-
Altorjay A, Kiss J, Vörös A, Szanto I, and Bohak A
- Subjects
- Adenocarcinoma diagnosis, Adenocarcinoma surgery, Adenomatous Polyps diagnosis, Adenomatous Polyps surgery, Aged, Anastomosis, Roux-en-Y, Esophageal Neoplasms diagnosis, Esophageal Neoplasms surgery, Esophageal Stenosis surgery, Humans, Male, Postoperative Complications diagnosis, Postoperative Complications surgery, Time Factors, Adenocarcinoma etiology, Adenomatous Polyps etiology, Colon transplantation, Esophageal Neoplasms etiology, Postoperative Complications etiology
- Abstract
This case report describes a very rare late complication developed in the colon-esophagus. An adenomatoid polypus malignant tumor appeared in a colonic interposition graft, five years after resection of the esophageal stricture. The continuity of intestinal tract was repaired with a Roux-en-Y esophago-jejunostomy. Based on a literature review, the authors detail late complications of operations which replace the esophagus with colon.
- Published
- 1995
47. CONTROL OF PROLONGED CONVULSIVE SEIZURES IN CHILDHOOD BY ADMINISTRATION OF INHALATION ANAESTHESIA WITH NITROUS OXIDE (N2O).
- Author
-
KEMENY P, HODOSI J, and SZANTO I
- Subjects
- Child, Humans, Infant, Anesthesia, Anesthesia, Inhalation, Asthma, Barbiturates, Bronchopneumonia, Chloral Hydrate, Drug Therapy, Enterocolitis, Epilepsy, Heart Failure, Intussusception, Muscle Relaxants, Central, Nitrous Oxide, Paraldehyde, Poisoning, Postoperative Complications, Respiration, Artificial, Seizures, Toxicology
- Published
- 1964
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