90 results on '"Grune, Tilman"'
Search Results
2. High glucose leads to redistribution of the proteasomal system.
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Grune, Tilman, Schnell, Vanessa, and Jung, Tobias
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GLUCOSE , *NUCLEAR factor E2 related factor , *CELL lines - Abstract
The impact of high glucose on the cellular redox state, causing both induction of antioxidative systems and also enhanced protein oxidation is discussed for a long time. It is established that elevated glucose levels are disrupting the cellular proteostasis and influencing the proteasomal system. However, it is still unresolved whether this is due to a reaction of the cellular proteasomal system towards the high glucose or whether this is a secondary reaction to inflammatory stimuli. Therefore, we used a dermal fibroblast cell line exposed to high glucose in order to reveal whether a response of the proteasomal system takes place. We investigated the α4 and the inducible iβ5 subunits of the 20S proteasome, as well as the Rpn1‐subunit of the 19S proteasomal regulator complex, measured activity of the 20S, 20S1, and 26S proteasome and detected as well changes in expression as a redistribution into the nucleus. Interestingly, while the activity of the proteasomal forms rather decreased under high glucose treatment; higher expression levels of components of the proteasomal system and higher concentrations of protein‐bound 3‐nitrotyrosine and Nrf2 (nuclear factor [erythroid‐derived 2]‐like 2) were detected. However, no change in the cytosol‐nucleus distribution could be detected for most of the quantified parameters. We concluded that high glucose alone, without additional inflammatory stimuli, provokes a regulatory response on the ubiquitin‐proteasomal system. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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3. Frailty is characterized by biomarker patterns reflecting inflammation or muscle catabolism in multi‐morbid patients.
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Kochlik, Bastian, Franz, Kristina, Henning, Thorsten, Weber, Daniela, Wernitz, Andreas, Herpich, Catrin, Jannasch, Franziska, Aykaç, Volkan, Müller‐Werdan, Ursula, Schulze, Matthias B., Grune, Tilman, and Norman, Kristina
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- 2023
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4. Metabolism and Recovery of Epithionitriles from Glucosinolates--A Human Intervention Study.
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Hoffmann, Holger, Baldermann, Susanne, Wiesner-Reinhold, Melanie, Bergmann, Manuela M., Grune, Tilman, and Hanschen, Franziska S.
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- 2023
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5. High‐fat, sucrose and salt‐rich diet during rat spermatogenesis lead to the development of chronic kidney disease in the female offspring of the F2 generation.
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Zhang, Xiaoli, Hasan, Ahmed A., Wu, Hongwei, Gaballa, Mohamed M. S., Zeng, Suimin, Liu, Liping, Xie, Li, Jung, Tobias, Grune, Tilman, Krämer, Bernhard K., Kleuser, Burkhard, Li, Jian, and Hocher, Berthold
- Published
- 2022
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6. Spontaneous Degenerative Aortic Valve Disease in New Zealand Obese Mice.
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Ott, Christiane, Pappritz, Kathleen, Hegemann, Niklas, John, Cathleen, Jeuthe, Sarah, McAlpine, Cameron S., Yoshiko Iwamoto, Lauryn, Jonathan H., Klages, Jan, Klopfleisch, Robert, Van Linthout, Sophie, Swirski, Fil, Nahrendorf, Matthias, Kintscher, Ulrich, Grune, Tilman, Kuebler, Wolfgang M., Grune, Jana, and Iwamoto, Yoshiko
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- 2021
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7. Altered Adiponectin Response in Older Women Following Dextrose and High‐Fat Dietary Challenges.
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Herpich, Catrin, Kochlik, Bastian, Haß, Ulrike, Weber, Daniela, Grune, Tilman, and Norman, Kristina
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- 2021
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8. High‐protein diet more effectively reduces hepatic fat than low‐protein diet despite lower autophagy and FGF21 levels.
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Xu, Chenchen, Markova, Mariya, Seebeck, Nicole, Loft, Anne, Hornemann, Silke, Gantert, Thomas, Kabisch, Stefan, Herz, Kathleen, Loske, Jennifer, Ost, Mario, Coleman, Verena, Klauschen, Frederick, Rosenthal, Anke, Lange, Volker, Machann, Jürgen, Klaus, Susanne, Grune, Tilman, Herzig, Stephan, Pivovarova‐Ramich, Olga, and Pfeiffer, Andreas F. H.
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HIGH-protein diet ,LOW-protein diet ,FATTY liver ,FAT ,FIBROBLAST growth factors ,AUTOPHAGY - Abstract
Background and aims: Non‐alcoholic fatty liver disease (NAFLD) is becoming increasingly prevalent and nutrition intervention remains the most important therapeutic approach for NAFLD. Our aim was to investigate whether low‐ (LP) or high‐protein (HP) diets are more effective in reducing liver fat and reversing NAFLD and which mechanisms are involved. Methods: 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500‐1600 kcal/day) diet groups, a low protein (10E% protein) and a high protein (30E% protein), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery. Results: IHL levels decreased by 42.6% in the HP group, but were not significantly changed in the LP group despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA‐seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of β‐oxidation genes did not increase in the HP group. Conclusions: HP diet more effectively reduces hepatic fat than LP diet despite of lower autophagy and FGF21. Our data suggest that liver fat reduction upon HP diets result primarily from suppression of fat uptake and lipid biosynthesis. [ABSTRACT FROM AUTHOR]
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- 2020
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9. Punicalagin Attenuates Palmitate‐Induced Lipid Droplet Content by Simultaneously Improving Autophagy in Hepatocytes.
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Korovila, Ioanna, Jung, Tobias, Deubel, Stefanie, Grune, Tilman, and Ott, Christiane
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- 2020
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10. Associations of fat‐soluble micronutrients and redox biomarkers with frailty status in the FRAILOMIC initiative.
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Kochlik, Bastian, Stuetz, Wolfgang, Pérès, Karine, Pilleron, Sophie, Féart, Catherine, García García, Francisco José, Bandinelli, Stefania, Gomez‐Cabrero, David, Rodriguez‐Mañas, Leocadio, Grune, Tilman, and Weber, Daniela
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CAROTENOIDS ,LUTEIN ,BIOMARKERS ,MICRONUTRIENTS ,CHOLECALCIFEROL ,BIOLOGICAL tags ,OXIDATIVE stress - Abstract
Background: A poor fat‐soluble micronutrient (FMN) and a high oxidative stress status are associated with frailty. Our aim was to determine the cross‐sectional association of FMNs and oxidative stress biomarkers [protein carbonyls (PrCarb) and 3‐nitrotyrosine] with the frailty status in participants older than 65 years. Methods: Plasma levels of vitamins A (retinol), D3, E (α‐tocopherol and γ‐tocopherol) and carotenoids (α‐carotene and β‐carotene, lycopene, lutein/zeaxanthin, and β‐cryptoxanthin), PrCarb, and 3‐nitrotyrosine were measured in 1450 individuals of the FRAILOMIC initiative. Participants were classified into robust, pre‐frail, and frail using Fried's frailty criteria. Associations between biomarkers and frailty status were assessed by general linear and logistic regression models, both adjusted for cohort, season of blood sampling, gender, age, height, weight, and smoking. Results: Robust participants had significantly higher vitamin D3 and lutein/zeaxanthin concentrations than pre‐frail and frail subjects; had significantly higher γ‐tocopherol, α‐carotene, β‐carotene, lycopene, and β‐cryptoxanthin concentrations than frail subjects, and had significantly lower PrCarb concentrations than frail participants in multivariate linear models. Frail subjects were more likely to be in the lowest than in the highest tertile for vitamin D3 (adjusted odds ratio: 2.15; 95% confidence interval: 1.42–3.26), α‐tocopherol (2.12; 1.39–3.24), α‐carotene (1.69; 1.00–2.88), β‐carotene (1.84; 1.13–2.99), lycopene (1.94; 1.24–3.05), lutein/zeaxanthin (3.60; 2.34–5.53), and β‐cryptoxanthin (3.02; 1.95–4.69) and were more likely to be in the highest than in the lowest tertile for PrCarb (2.86; 1.82–4.49) than robust subjects in multivariate regression models. Conclusions: Our study indicates that both low FMN and high PrCarb concentrations are associated with pre‐frailty and frailty. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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11. Methionine restriction prevents onset of type 2 diabetes in NZO mice.
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Castaño-Martinez, Teresa, Schumacher, Fabian, Schumacher, Silke, Kochlik, Bastian, Weber, Daniela, Grune, Tilman, Biemann, Ronald, McCann, Adrian, Abraham, Klaus, Weikert, Cornelia, Kleuser, Burkhard, Schürmann, Annette, and Laeger, Thomas
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- 2019
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12. The Influence of Dietary Habits and Meat Consumption on Plasma 3‐Methylhistidine—A Potential Marker for Muscle Protein Turnover.
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Kochlik, Bastian, Gerbracht, Christiana, Grune, Tilman, and Weber, Daniela
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- 2018
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13. “Cyt/Nuc,” a Customizable and Documenting ImageJ Macro for Evaluation of Protein Distributions Between Cytosol and Nucleus.
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Grune, Tilman, Kehm, Richard, Höhn, Annika, and Jung, Tobias
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- 2018
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14. Age-dependent expression of DNMT1 and DNMT3B in PBMCs from a large European population enrolled in the MARK- AGE study.
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Ciccarone, Fabio, Malavolta, Marco, Calabrese, Roberta, Guastafierro, Tiziana, Bacalini, Maria Giulia, Reale, Anna, Franceschi, Claudio, Capri, Miriam, Hervonen, Antti, Hurme, Mikko, Grubeck‐Loebenstein, Beatrix, Koller, Bernhard, Bernhardt, Jürgen, Schӧn, Christiane, Slagboom, P. Eline, Toussaint, Olivier, Sikora, Ewa, Gonos, Efstathios S., Breusing, Nicolle, and Grune, Tilman
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PHYSIOLOGICAL aspects of aging ,DNA methylation ,BLOOD cells ,GENE expression ,HEALTH behavior - Abstract
Aging is associated with alterations in the content and patterns of DNA methylation virtually throughout the entire human lifespan. Reasons for these variations are not well understood. However, several lines of evidence suggest that the epigenetic instability in aging may be traced back to the alteration of the expression of DNA methyltransferases. Here, the association of the expression of DNA methyltransferases DNMT1 and DNMT3B with age has been analysed in the context of the MARK- AGE study, a large-scale cross-sectional study of the European general population. Using peripheral blood mononuclear cells, we assessed the variation of DNMT1 and DNMT3B gene expression in more than two thousand age-stratified women and men (35-75 years) recruited across eight European countries. Significant age-related changes were detected for both transcripts. The level of DNMT1 gradually dropped with aging but this was only observed up to the age of 64 years. By contrast, the expression of DNMT3B decreased linearly with increasing age and this association was particularly evident in females. We next attempted to trace the age-related changes of both transcripts to the influence of different variables that have an impact on changes of their expression in the population, including demographics, dietary and health habits, and clinical parameters. Our results indicate that age affects the expression of DNMT1 and DNMT3B as an almost independent variable in respect of all other variables evaluated. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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15. Quantification of age-related changes of α-tocopherol in lysosomal membranes in murine tissues and human fibroblasts.
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König, Jeannette, Besoke, Fabian, Stuetz, Wolfgang, Malarski, Angelika, Jahreis, Gerhard, Grune, Tilman, and Höhn, Annika
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VITAMIN E ,FIBROBLASTS ,CONNECTIVE tissue cells ,DESMOID tumors ,TISSUES - Abstract
Considering the biological function of α-tocopherol (α-Toc) as a potent protective factor against oxidative stress, this antioxidant is in the focus of aging research. To understand the role of α-Toc during aging we investigated α-Toc concentrations in young and aged primary human fibroblasts after supplementation with RRR-α-Toc. Additionally, α-Toc contents were determined in brain, kidney, and liver tissue of 10 week-, 18 month-, and 24 month-old mice, which were fed a standard diet containing 100 mg/kg dl-α-tocopheryl acetate. α-Toc concentrations in isolated lysosomes and the expression of the α-Toc transport proteins Niemann Pick C1 (NPC1), Niemann Pick C2 (NPC2), and lipoprotein lipase were also analyzed. Obtained data show a significant age-related increase of α-Toc in murine liver, kidney, and brain tissue as well as in human dermal fibroblasts. Also liver and kidney lysosomes are marked by elevated α-Toc contents with aging. NPC1 and NPC2 protein amounts are significantly decreased in adult and aged murine kidney tissue. Also aged human dermal fibroblasts show decreased NPC1 amounts. Supplementation of young and aged fibroblasts led also to decreased NPC1 amounts, suggesting a direct role of this protein in α-Toc distribution. Our results indicate an age-dependent increase of α-Toc in different murine tissues as well as in human fibroblasts. Furthermore saturation and intracellular distribution of α-Toc seem to be strongly dependent on the availability of this vitamin as well as on the presence of the lysosomal protein NPC1. © 2016 BioFactors, 42(3):307-315, 2016 [ABSTRACT FROM AUTHOR]
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- 2016
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16. Actual Isothermal Effects of Water-Filtered Infrared A-Irradiation.
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Höhn, Annika, Hartmann, Petra, Gebhart, Veronika, Sonntag, Johanna, Grune, Tilman, and Jung, Tobias
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IRRADIATION ,PHOTOACTIVATION ,PHOSPHOTRANSFERASES ,PHOTOOXIDATIVE stress ,PHOTOBIOCHEMISTRY ,PHOTOBIOLOGY - Abstract
In this study, the athermal effects of water-filtered infrared A (wIRA)-irradiation (780-1400 nm) on human dermal fibroblasts were investigated. For this purpose, cells were exposed to wIRA-irradiation (178 mW cm
-2 for 1 h), while a sophisticated experimental setup prevented warming of the samples exceeding 0.1°C. The investigated parameters were the formation of reactive oxygen species (ROS), mitochondrial membrane potential and superoxide release, protein oxidation, proliferation rate, as well as intracellular Ca2+ -release in single cells, most of them quantified via fluorescence microscopy and fluorimetric techniques. The existence of actual athermal wIRA-effects is still intensively discussed, since their detection requires a careful experimental setup and both efficient and powerful temperature regulation of the exposed samples. Here, we can definitively show that some of the supposed athermal wIRA-effects may be rather artifacts, since wIRA did not reveal any impact on the above mentioned parameters-- as long as the temperature of the exposed cells was carefully maintained. Though, we were able to identify an athermal DNA-protective wIRA-effect, since the induced DNA damage (quantified via 8-Oxo-G-formation) was significantly decreased after a subsequent UVB-exposure. These results suggest that many of the supposed athermal wIRAeffects can be induced by pure warming of the samples, independent from any wIRA-irradiation. [ABSTRACT FROM AUTHOR]- Published
- 2015
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17. Oxidative Stress and Protein Oxidation.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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18. Removal of Oxidized Proteins.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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19. Protein Oxidation and Aging: Different Model Systems and Affecting Factors.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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20. Protein Oxidation in Some Age-Related Diseases.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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21. Frontmatter.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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22. Index.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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23. Abbreviations.
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Uversky, Vladimir N., Grune, Tilman, Catalgol, Betul, and Jung, Tobias
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- 2012
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24. A comparative study into alterations of coenzyme Q redox status in ageing pigs, mice, and worms.
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Onur, Simone, Niklowitz, Petra, Fischer, Alexandra, Metges, Cornelia C., Grune, Tilman, Menke, Thomas, Rimbach, Gerald, and Döring, Frank
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UBIQUINONES ,OXIDATION-reduction reaction ,ENZYMES ,CHEMICAL synthesis ,SWINE physiology ,ANIMAL species ,CAENORHABDITIS elegans - Abstract
Coenzyme Q derivatives (CoQ) are lipid soluble antioxidants that are synthesized endogenously in almost all species and function as an obligatory cofactor of the respiratory chain. There is evidence that CoQ status is altered by age in several species. Here we determined level and redox-state of CoQ in different age groups of pigs, mice and Caenorhabditis elegans. Since these species are very different with respect to lifespan, reproduction and physiology, our approach could provide some general tendencies of CoQ status in ageing organisms. We found that CoQ level decreases with age in pigs and mice, whereas CoQ content increases in older worms. As observed in all three species, ubiquinone, the oxidized form of CoQ, increases with age. Additionally, we were able to show that supplementation of ubiquinol-10, the reduced form of human CoQ
10 , slightly increases lifespan of post-reproductive worms. In conclusion, the percentage of the oxidized form of CoQ increases with age indicating higher oxidative stress or rather a decreased anti-oxidative capacity of aged animals. © 2014 BioFactors, 40(3):346-354, 2014 [ABSTRACT FROM AUTHOR]- Published
- 2014
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25. Experimental basis for discriminating between thermal and athermal effects of water-filtered infrared A irradiation.
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Jung, Tobias and Grune, Tilman
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INFRARED radiation , *THERMAL analysis , *WATER filtration , *MEDICINE , *COSMETICS , *ELECTROMAGNETISM , *SPECTRUM analysis - Abstract
Considering the widespread application of water-filtered infrared A (wIRA) irradiation in medicine, cosmetics, and wellness, we have conluded that the biological effects of this electromagnetic spectrum, ranging from 780 nm to 1400 nm, have become an important focus of experimental research. Two main effects of wIRA on single cells are discussed: thermal effects, caused by absorption of energy by cellular water and the aqueous medium surrounding the irradiated sample that result in warming, and supposed athermal effects that result from a direct interaction of wIRA with cellular molecules/structures excluding water. In the following, we discuss different experimental setups and highlight some cellular responses to thermal and athermal wIRA effects, as well as the experimental problems in differentiating between them. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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26. An Experimental Setup for the Measurement of Nonthermal Effects During Water-Filtered Infrared A-Irradiation of Mammalian Cell Cultures.
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Jung, Tobias, Höhn, Annika, Lau, Anne-Marie, Piazena, Helmut, and Grune, Tilman
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INFRARED radiation ,CELL culture ,MAMMAL cytology ,TEMPERATURE effect ,HOMEOSTASIS ,AQUEOUS solutions - Abstract
In many recent publications, supposed athermal effects of water-filtered infrared A (wIRA) irradiation are discussed. Those effects are mainly attributed to wavelengths in the range from 780 to 1440 nm, and should not result from warming of cellular water or any aqueous medium surrounding the irradiated sample caused by wIRA absorption. Athermal effects are considered to be induced directly by absorption of different wavelengths of the wIRA spectrum by cellular molecules or structures except water. To distinguish between thermal and athermal effects, irradiated samples have to be subjected to a very effective and precise temperature homeostasis. Any experimental effects can only be attributed to pure athermal effects, if the temperature of the irradiated samples is verifiably constant and does not result in hyperthermia. Here, data of temperature distribution in Petri dishes of different types filled with aqueous medium are presented which were estimated by model calculation for different setups of cooling. Additionally, the real temperature development was directly measured. Such a cooling unit enables long-term application of high wIRA irradiances and large doses without any detectable warming of the irradiated samples, in single cell layers. Using such a setup, thermal and athermal effects can be compared and in addition to that quantified. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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27. The contribution of β-carotene to vitamin A supply of humans.
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Weber, Daniela and Grune, Tilman
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- 2012
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28. The outcome of 5-ALA-mediated photodynamic treatment in melanoma cells is influenced by vitamin C and heme oxygenase-1.
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Grimm, Stefanie, Mvondo, Dagmar, Grune, Tilman, and Breusing, Nicolle
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PHOTOCHEMOTHERAPY ,CANCER treatment ,PHOTOSENSITIZERS ,CELL death ,REACTIVE oxygen species ,OXIDATIVE stress ,OXYGENASES ,ANTIOXIDANTS ,CELL-mediated cytotoxicity - Abstract
Photodynamic therapy (PDT) is an important clinical approach for cancer treatment. It involves the administration of a photosensitizer, followed by its activation with light and induction of cell death. The underlying mechanism is an increased production of reactive oxygen species (ROS) leading to oxidative stress, which is followed by cell death. However, effectiveness of PDT is limited due to an initiation of endogenous rescue response systems like heme oxygenase-1 (HO-1) in tumor cells. In recent years, consuming of antioxidant supplements has become widespread, but the effect of exogenously applied antioxidants on cancer therapy outcome remains unclear. Thus, this study was aimed to investigate if exogenous antioxidants might decrease ROS-induced cytotoxicity in photodynamic treatment. Lycopene, β-carotene, vitamin C, N-acetylcysteine, trolox, and N-tert-butyl-α-phenylnitrone in different doses were administered to human melanoma cells prior exposure to photodynamic treatment. Supplementation with vitamin C resulted in a significant decrease of the cell death rate, whereas the other tested antioxidants had no effect on cell viability and oxidative stress markers. The simultaneous application of vitamin C with the HO-1 activity inhibitor zinc protoporphyrine IX (ZnPPIX) caused a considerable decrease of photodynamic treatment-induced cytotoxicity compared to ZnPPIX alone. It can be summarized that exogenously applied antioxidants do not have a leading role in the protective response against photodynamic treatment. However, further studies are necessary to investigate more antioxidants and other substances, which might affect the outcome of photodynamic treatment in cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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29. Proteasomal degradation of β-carotene metabolite—Modified proteins.
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Sommerburg, Olaf, Karius, Nicole, Siems, Werner, Langhans, Claus-Dieter, Leichsenring, Michael, Breusing, Nicolle, and Grune, Tilman
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PROTEINS ,BETA carotene ,OXIDATIVE stress ,CAROTENES ,FERRITIN ,PROTEOLYTIC enzymes - Abstract
Free radical attack on β-carotene results in the formation of high amounts of carotene breakdown products (CBPs) having biological activities. As several of the CBPs are reactive aldehydes, it has to be considered that these compounds are able to modify proteins. Therefore, the aim of the study was to investigate whether CBP-modification of proteins is leading to damaged proteins recognized and degraded by the proteasomal system. We used the model proteins tau and ferritin to test whether CBPs will modify them and whether such modifications lead to enhanced proteasomal degradation. To modify proteins, we used crude CBPs as a mixture obtained after hypochloric acid derived BC degradation, as well as several single compounds, as apo8′-carotenal, retinal, or β-ionone. The majority of the CBPs found in our reaction mixture are well known metabolites as described earlier after BC degradation using different oxidants. CBPs are able to modify proteins, and in in vitro studies, we were able to demonstrate that the 20S proteasome is able to recognize and degrade CBP-modified proteins preferentially. In testing the proteolytic response of HT22 cells toward CBPs, we could demonstrate an enhanced protein turnover, which is sensitive to lactacystin. Interestingly, the proteasomal activity is resistant to treatment with CBP. On the other hand, we were able to demonstrate that supraphysiological levels of CBPs might lead to the formation of protein-CBP-adducts that are able to inhibit the proteasome. Therefore, the removal of CBP-modified proteins seems to be catalyzed by the proteasomal system and is effective, if the formation of CBPs is not overwhelming and leading to protein aggregates. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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30. The proteasome and its role in the degradation of oxidized proteins.
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Jung, Tobias and Grune, Tilman
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FREE radicals , *OXIDATIVE stress , *MAMMALS , *PROTEINS , *BIOMOLECULES - Abstract
The generation of free radicals and the resulting oxidative modification of cell structures are omnipresent in mammalian cells. This includes the permanent oxidation of proteins leading to the disruption of the protein structure and an impaired functionality. In consequence, these oxidized proteins have to be removed in order to prevent serious metabolic disturbances. The most important cellular proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. For normal functioning, the proteasomal system needs the coordinated interaction of numerous components. This review describes the fundamental functions of the 20S “core” proteasome, its regulators, and the roles of the proteasomal system beyond the removal of oxidized proteins in mammalian cells. © 2008 IUBMB IUBMB Life, 60(11): 743–752, 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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31. Modification of Vimentin.
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Kueper, Thomas, Grune, Tilman, Muhr, Gesa‐Meike, Lenz, Holger, Wittern, Klaus‐Peter, Wenck, Horst, Stäb, Franz, and Blatt, Thomas
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MAILLARD reaction , *FIBROBLASTS , *BIODEGRADATION , *PROPERTIES of matter , *HEART failure , *PROTEINS , *BLOOD plasma , *GLUCOSE , *LYSINE , *SKIN - Abstract
In a recent study, we were able to show that the intermediate filament protein vimentin aggregates in human dermal fibroblasts because of modification by the advanced glycation endproduct carboxymethyllysine (CML). In this work, we investigated the formation of intracellular CML in relation to the concentration of glucose in the culture medium. The natural degradation product of glucose, methylglyoxal, was able to induce the aggregation of vimentin. This dicarbonyl leads to the formation of the modifications MG-H1 and carboxyethyllysine (CEL) as a result of the reaction with arginine and lysine residues of proteins. Furthermore, we found that the protein vimentin was modified, not only by CML and CEL, but also by pentosidine and pyrraline. These findings underline the special position of vimentin as a preferential target of the Maillard reaction in human skin. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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32. Oxidative stress related changes in the brain of hypercholesterolemic rabbits.
- Author
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Aytan, Nurgül, Jung, Tobias, Tamtürk, Faruk, Grune, Tilman, and Kartal-Özer, Nesrin
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OXIDATIVE stress ,HYPERCHOLESTEREMIA ,ALZHEIMER'S disease ,REACTIVE oxygen species ,CHOLESTEROL ,NEURODEGENERATION - Abstract
In recent years, there has been increasing evidence that cholesterol plays a role in the pathology of Alzheimer disease. Since hypercholesterolemia was reported to increase the levels of reactive oxygen species and Alzheimer disease has clearly involved an oxidative component, it is possible that hypercholesterolemia is via increased oxidant production facilitating the disease development of the neurodegenerative disease. Therefore, we tested in an established model of enhanced cholesterol feed in rabbits the effects of serum cholesterol increase on oxidative stress parameters as well in serum as in the brain. In addition to that we tested the effects of vitamin E on the cholesterol-induced oxidative stress. Since Alzheimer disease is largely connected with increased protein oxidation whereas cholesterol is rather connected with lipid peroxidation processes, we tested both protein carbonyl levels and the formation of malondialdehyde, a marker of lipid peroxidation. We could clearly demonstrate an increase in serum malondialdehyde due to high cholesterol feeding, which is accompanied by an increase in protein oxidation parameters in the brain, especially in the hippocampus. Therefore, we suggest that specific neuropathological changes occur during the feeding of hypercholesterolemic diet. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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33. Report of Society for Free Radical Research Europe Summer School.
- Author
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Griffiths, Helen R., Grune, Tilman, Gonos, Efstathios, and Kartal-Ozer, Nesrin
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CONFERENCES & conventions , *LIPIDS , *PEROXIDATION , *PATHOLOGICAL physiology - Abstract
The article reports on the 3rd Summer School of the Society for Free Radical Research Europe (SFRR-E) held at Hotel Spetses in Greece between August 30 and September 5, 2008. The event was opened by the principal organiser, Professor Nesrin Kartal-Ozer, who highlighted the quality of the applicants who had expressed an interest in attending the school. The programme for each day of the event focused on one specific theme within the broader scope of the theme, "Lipid Peroxidation and Free Radical-Signalling: Role in Pathophysiology."
- Published
- 2008
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34. Lipofuscin.
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JUNG, TOBIAS, BADER, NICOLLE, and GRUNE, TILMAN
- Subjects
LIPOFUSCINS ,ANIMAL pigments ,PROTEINS ,LYSOSOMAL storage diseases ,LIFE spans ,MITOCHONDRIA ,OXIDATION-reduction reaction - Abstract
One of the highlights of postmitotic aging is the intracellular accumulation of highly oxidized and cross-linked proteins, known as lipofuscin. Lipofuscin is insoluble and not degradable by lysosomal enzymes or the proteasomal system, which is responsible for the recognition and degradation of misfolded and oxidatively damaged proteins. These aggregates have been found in various cell types, including heart, liver, kidney, neuronal tissue, and dermal tissue, and are associated with the life span of a single postmitotic cell and, consequently, of the whole organism. Lipofuscin formation appears to depend on the rate of oxidative damage to proteins, the functionality of mitochondrial repair systems, the proteasomal system, and the functionality and effectiveness of the lysosomes. This review highlights the current knowledge of the formation, distribution, and effects of lipofuscin in mammalian cells. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
35. Reversible inhibition of mammalian glutamine synthetase by tyrosine nitration
- Author
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Görg, Boris, Qvartskhava, Natalia, Voss, Peter, Grune, Tilman, Häussinger, Dieter, and Schliess, Freimut
- Subjects
TYROSINE ,AMINO acids ,MAMMALS ,GLUTAMINE synthetase - Abstract
Abstract: The effect of tyrosine nitration on mammalian GS activity and stability was studied in vitro. Peroxynitrite at a concentration of 5μmol/l produced tyrosine nitration and inactivation of GS, whereas 50μmol/l peroxynitrite additionally increased S-nitrosylation and carbonylation and degradation of GS by the 20S proteasome. (−)Epicatechin completely prevented both, tyrosine nitration and inactivation of GS by peroxynitrite (5μmol/l). Further, a putative “denitrase” activity restored the activity of peroxynitrite (5μmol/l)-treated GS. The data point to a potential regulation of GS activity by a reversible tyrosine nitration. High levels of oxidative stress may irreversibly damage and predispose the enzyme to proteasomal degradation. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
36. Osmotic regulation of STAT3 stability in H4IIE rat hepatoma cells
- Author
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Lornejad-Schäfer, Mohammad Reza, Albrecht, Ute, Poppek, Diana, Gehrmann, Thor, Grune, Tilman, Bode, Johannes G., Häussinger, Dieter, and Schliess, Freimut
- Subjects
LIVER tumors ,FIBRINOGEN ,PHOSPHORYLATION ,CHEMICAL reactions - Abstract
Abstract: Little is known about the regulation of signal transducer and activator of transcription (STAT) stability. Here the osmolarity-dependence of STAT3 stability, ubiquitination, Tyr
705 phosphorylation, STAT3 transactivation and γ-fibrinogen (γ-FBG) expression was studied in hepatoma cells. Hyper-osmolarity accelerated STAT3 degradation which was prevented by proteasome inhibitors. Hypo-osmolarity stabilized STAT3, most likely due to a decrease in STAT3 ubiquitination. Accordingly, STAT3 Tyr705 phosphorylation, α2 -macroglobulin promoter activity and γ-FBG expression were osmosensitive. Modulation of STAT3 stability may contribute to a hydration dependence of acute phase protein expression. [Copyright &y& Elsevier]- Published
- 2005
- Full Text
- View/download PDF
37. Anti-fibrosclerotic effects of shock wave therapy in lipedema and cellulite.
- Author
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Siems, Werner, Grune, Tilman, Voss, Peter, and Brenke, Rainer
- Subjects
- *
LIPIDS , *PEROXIDATION , *MALONDIALDEHYDE , *MULTIPLE sclerosis , *CELLULITE , *EXTRACORPOREAL shock wave therapy - Abstract
In vivo measurements in 26 female patients with lipedema and cellulite parameters were carried out before and after therapy by means of complex physical decongestive therapy (CPDT) including manual lymph drainage and compression as main components and/or shock wave therapy (SWT). Oxidative stress parameters of blood serum and biomechanic skin properties/smoothening of dermis and hypodermis surface were evaluated. Oxidative stress in lipedema and cellulite was demonstrated by increased serum concentrations of malondialdehyde (MDA) and plasma protein carbonyls compared with healthy control persons. Both MDA and protein carbonyls in blood plasma decreased after serial shock wave application and CPDT. The SWT itself and CPDT itself lead to MDA release from edematous tissue into the plasma. Obviously both therapy types, SWT and CPDT, mitigate oxidative stress in lipedema and cellulite. In parallel SWT improved significantly the biomechanic skin properties leading to smoothening of dermis and hypodermis surface. Significant correlation between MDA depletion of edematous and lipid enriched dermis and improvement of mechanic skin properties was demonstrated. From these findings it is concluded, that a release of lipid peroxidation (LPO) products from edematous dermis is an important sclerosis-preventing effect of SWT and/or CPDT in lipedema and cellulite. Expression of factors stimulating angiogenesis and lymphangiogenesis such as VEGF was not induced by SWT and/or CPDT and, therefore, not involved in beneficial effects by SWT and/or CPDT. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
38. Iron uptake of the normoxic, anoxic and postanoxic microglial cell line RAW 264.7.
- Author
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Widmer, Rebecca and Grune, Tilman
- Subjects
- *
IRON in the body , *HYPOXEMIA , *INFLUENCE of altitude , *HEMOGLOBINS , *PHYSIOLOGICAL effects of oxygen , *MICROGLIA , *HOMEOSTASIS - Abstract
Iron is one of the trace elements playing a key role in the normal brain metabolism. An excess of free iron on the other hand is catalyzing the iron-mediated oxygen radical production. Such a condition might be a harmful event leading perhaps to serious tissue damage and degeneration. Therefore, during evolution a complex iron sequestering apparatus developed, minimizing the amount of redox-reactive free iron. However, this system might be severely disturbed under pathophysiological conditions including hypoxia or anoxia. Since little is known about the non-transferrin-mediated iron metabolism of the brain during anoxia/reoxygenation, we tested the ability of the microglial cell line RAW 264.7 to take up iron independently of transferrin under various oxygen concentrations. Microglial cells are thought to be the major player in the maintenance of the extracellular homeostasis in the brain. Therefore, we investigated the iron metabolism of microglial cells employing radiolabeled ferric chloride. We tested the uptake of iron under normoxic, anoxic and postanoxic conditions. Furthermore, the amount of ferritin was measured by immunoblotting. We were able to show that iron enters the microglial cell line in the absence of extracellular transferrin under normoxic, anoxic and postanoxic conditions. Interestingly, the amount of ferritin is decreasing in the early reoxygenation phase. Therefore, we concluded that microglia is able to contribute to the brain iron homeostasis under anoxic and postanoxic conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
39. HNE and Further Lipid Peroxidation Products.
- Author
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Siems, Werner, Grune, Tilman, Sommerburg, Olaf, Flohé, Leopold, and Cadenas, Enrique
- Subjects
- *
BIOLOGY , *LIPIDS , *PEROXIDATION , *MEDICAL conferences , *MEETINGS , *CONFERENCE attendance - Abstract
The article presents updates concerning the field of biology as of May 2005. According to research, assessment oxidative stress by measurement of lipid peroxidation products is of biological and clinical importance when considering the multiple functions of lipids. Another news is about the Berlin Meeting HNE and Further Lipid Peroxidation Products: From Basic Science to Medicine in Germany held from July 6 to 9, 2004. The meeting was attended by more than 150 participants from 35 countries. The last item reports on the death of Alex Sevanian, Professor of Molecular Pharmacology and Toxicology at the University of Southern California in Los Angeles, because of complications related to the cancer.
- Published
- 2005
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40. Distribution of oxidized and HNE-modified proteins in U87 cells.
- Author
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Jung, Tobias, Engels, Martina, Kaiser, Barbara, and Grune, Tilman
- Subjects
OXIDATIVE stress ,OXIDATION-reduction reaction ,PROTEINS ,OXIDIZING agents ,ASTROCYTOMAS ,HYDROGEN peroxide - Abstract
Protein modification is one of the important processes during oxidative stress. This modification of proteins is either due to direct oxidation of proteins by various oxidants or due to secondary modification by lipid peroxidation products, e.g. 4-hydroxynonenal. In the here presented work we compare the intracellular distribution of protein modification products after treatment of human U87 astrocytoma cells with hydrogen peroxide or HNE. The treatment with hydrogen peroxide leads mainly to a cytosolic formation of oxidized proteins whereas HNE treatment is forming HNE-adducts throughout the cell. Therefore, we concluded that HNE diffusion distance in cells enables this lipid peroxidation product to act as a second messenger within the cell and on the other hand is the reason for the genotoxic properties of this compound. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
41. Copper related toxic effects on cellular protein metabolism in human astrocytes.
- Author
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Merkera, Katrin, Hapke, Doreen, Reckzeh, Kristian, Schmidt, Hartmut, Lochs, Herbert, and Grune, Tilman
- Subjects
OXIDATIVE stress ,PROTEIN metabolism ,LIVER cells ,THERAPEUTIC use of copper ,HEPATOLENTICULAR degeneration ,BRAIN diseases - Abstract
Introduction: Copper overload due to a defect in the ATPase 7B mediated copper excretion within hepatocytes produces the phenotype of Wilson disease. The overload of hepatocytes with copper results in necrotic liver cells and is accompanied by a high concentration of blood copper levels. That occurs to be the reason for increasing neurological copper concentration. Although copper is linked to oxidation, there are no data on the direct copper related effects in human brain cells. Aim: To test the copper induced changes in protein oxidation in human astrocyte like cells. Methods: We used U87 cells as model for human astrocytes. Cells were treated with increasing concentrations of copper(II)-chloride in Dulbeccos minimal essential medium. Subsequently, at different time points we investigated: cellular growth, cellular survival under copper treatment, the concentration of oxidized tryptophane in GADPH in vitro as well as the carbonyl concentration and the concentration of oxidized proteins in vivo in U87 glial cells. Results: The viability of cells decreased with both increasing copper concentration and duration of treatment. The concentration of oxidized proteins was directly correlated to the increase of copper concentration and duration of exposure. Conclusion: These observations demonstrate the similarities between copper treatment and treatment with other commonly used oxidants, including hydrogen peroxide. Furthermore, the vulnerability of astrocytes towards copper exposure could be demonstrated. Therefore, these data give further insights into understanding of copper metabolism, which in turn is important to reveal the exact pathological mechanism in copper related diseases such as Wilson disease. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
42. Role of 4-hydroxynonenal in the hemozoin-mediated inhibition of differentiation of human monocytes to dendritic cells induced by GM-CSF/IL-4.
- Author
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Skorokhod, Oleksii, Schwarzer, Evelin, Grune, Tilman, and Arese, Paolo
- Subjects
MALARIA ,MONOCYTES ,LEUCOCYTES ,ANTIGENS ,IMMUNOSUPPRESSION - Abstract
In falciparum malaria, rupture of parasitized RBC liberates hemozoin (HZ), polymerized heme that contains and generates lipoperoxidation products. In HZ and HZ-loaded monocytes 4-HNE attained approx. 50 and 15 μM, respectively. In malaria, HZ-loaded monocytes are precursors of dendritic cells (DC). Here, the role of 4-HNE as inhibitor of DC differentiation was examined. 4-HNE in HZ was quantified after derivatization by HPLC. DC were differentiated in vitro from human monocytes supplemented with GM-CSF/IL-4 and analyzed for surface antigens and 4-HNE-adducts by FACScan after labelling with specific antibodies. HZ-loading, or treatment with 4-HNE induced large numbers of 4-HNE-protein-adducts on the monocyte membrane. As low as 10 nM 4-HNE inhibited up-regulation of functionally important DC differentiation markers. 1 μM 4-HNE elicited inhibition of up-regulation of DC differentiation markers as follows: MHC-class I and II, -29% and -40%; CD1a, -16%; CD40, -25%; CD54, -27%; and CD83 (the most important DC differentiation marker), -45%, with no signs of apoptosis. The sequence of additions was important, as the inhibitory effect was reduced when 4-HNE was added after GM-CSF/IL-4, indicating that GM-CSF/IL-4 receptors could be modified by 4-HNE. In conclusion, inhibition of DC differentiation by 4-HNE may play a role in malaria immunodepression. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
43. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease.
- Author
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Keck, Susi, Nitsch, Robert, Grune, Tilman, and Ullrich, Oliver
- Subjects
PROTEASE inhibitors ,ALZHEIMER'S disease - Abstract
Abstract Alzheimer's disease (AD) is characterized neuropathologically by intracellular neurofibrillary tangles (NFTs) formed of tau-based paired helical filaments (PHFs) and extracellular β-amyloid plaques. The degree of Alzheimer dementia correlates with the severity of PHFs and NFTs. As an intraneuronal accumulation of oxidatively damaged proteins has been found in the brains of patients with AD, a dysfunction of the proteasomal system, which degrades damaged proteins, has been assumed to cause protein aggregation and therefore neurodegeneration in AD. In this study, we revealed that such proteasome dysfunction in AD brain results from the inhibitory binding of PHF-tau to proteasomes. We analysed the proteasome activity in brains from patients with AD and age-matched controls, and observed a significant decrease to 56% of the control level in the straight gyrus of patients with AD. This loss of activity was not associated with a decrease in the proteasome protein. PHF-tau co-precipitated during proteasome immunoprecipitation and proteasome subunits could be co-isolated during isolation of PHFs from AD brain. Furthermore, the proteasome activity in human brains strongly correlated with the amount of co-precipitated PHF-tau during immunoprecipitation of proteasome. Incubation of isolated proteasomes with PHF-tau isolated from AD brain, and with PHFs after in vitro assembly from human recombinant tau protein, resulted in a distinct inhibition of proteasome activity by PHF-tau. As this inhibition of proteasome activity was sufficient to induce neuronal degeneration and death, we suggest that PHF-tau is able directly to induce neuronal damage in the AD brain. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
44. PARP-mediated proteasome activation: a co-ordination of DNA repair and protein degradation?
- Author
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Arnold, Jenny and Grune, Tilman
- Subjects
- *
MOLECULAR biology , *DNA repair , *NUCLEOPROTEINS - Abstract
Proposes that mechanisms of DNA repair and selective proteolysis of oxidatively damaged nucleoproteins are coordinated by the poly(ADP-ribose) polymerase-1 (PARP-1). Implications for DNA and nucleoproteins of exidative damage in the nucleus; Role of the nuclear proteasome in oxidative stress response; Activation of the nuclear 20S proteasome by automodified PARP-1 following oxidative challenge.
- Published
- 2002
- Full Text
- View/download PDF
45. Ezrin turnover and cell shape changes catalyzed by proteasome in oxidatively stressed cells.
- Author
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Grune, Tilman, Reinheckel, Thomas, North, James A., Li, Rui, Bescos, Paloma B., Shringarpure, Reshma, and Davies, Kelvin J. A.
- Published
- 2002
- Full Text
- View/download PDF
46. Enrichment of eggs with n−3 polyunsaturated fatty acids: Effects of vitamin E supplementation.
- Author
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Grune, Tilman, Krämer, Klaus, Hoppe, Peter, and Siems, Werner
- Abstract
Eggs enriched with n−3 polyunsaturated fatty acids (PUFA) could contribute to dietary intake of these healthful fatty acids (FA). Because n−3 PUFA are highly susceptible to peroxidation, a first part of the study with Leghorn laying hens was carried out to investigate the influence of different levels of fish oil (0, 0.7, 1.4, 2.8, or 5.6%, respectively) in the diet on n−3 PUFA, cholesterol, vitamin E, and lipid peroxidation product contents in eggs. Addition of fish oil to a complete diet based on wheat, rye, tapioca, and soybean constituents containing 11 IU vitamin E/kg resulted in increased n−3 PUFA content in egg yolk, mainly due to accumulation of docosahexaenoic acid. Cholesterol was not altered up to 2.8% fish oil in the diet. The vitamin E content of the yolk was insufficient for the protection of PUFA from peroxidation. Addition of up to 2.8% fish oil to laying hen diets increased the n−3 PUFA content of yolks with a concomitant imbalance between vitamin E and PUFA, leading to increased levels of cytotoxic aldehydic lipid peroxidation products such as malondialdehyde (MDA). In a second part of the studies, the balance between vitamin E, PUFA, and lipid peroxidation was analyzed during the period of storage of n−3 PUFA-enriched eggs produced after feeding the laying hens with 1.5% fish oil diets with different concentrations of vitamin E (0, 5, 10, 20, 40, 80, 160 IU/kg). Storage of eggs resulted in a marked loss of vitamin E in yolk. In stored eggs, the cytotoxic lipid peroxidation products MDA, 4-hydroxynonenal, and 4-hydroxyhexenal were reduced in response to vitamin E supplementation. To prevent the increase of cytotoxic aldehydic lipid peroxidation during production and storage of n−3 PUFA-enriched eggs, a high vitamin E supplementation with at least 80 IU vitamin E/kg is needed. [ABSTRACT FROM AUTHOR]
- Published
- 2001
- Full Text
- View/download PDF
47. LPS-Induced Protein Oxidation and Proteolysis in BV-2 Microglial Cells.
- Author
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Mehlhase, Jana, Gieche, Jeanette, Ullrich, Oliver, Sitte, Nicolle, and Grune, Tilman
- Subjects
OXIDATION ,PROTEINS ,MICROGLIA - Abstract
Exposure of proteins to oxidants leads to increased oxidation followed by preferential degradation by the proteasomal system. The role of the biological oxidant production in microglial BV-2 cells in the oxidation and turnover of endogenous proteins was measured. It could be demonstrated, that BV-2 cells are relatively resistant to fluxes of oxidants, but nevertheless protein oxidation occurs due to activation by LPS. This protein oxidation is followed by an enhanced degradation of endogenous proteins. Using PBN, a free radical scavenger and antioxidant, we could demonstrate the involvement of free radicals in the increased proteolysis in BV-2 cells after LPS-treatment. A slight but significant up-regulation of the proteasomal system after LPS activation takes place, indicating the importance of his proteolytic system in the maintenance of the protein pool of microglial cells. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
48. Telomere Length As a Marker of Oxidative Stress in Primary Human Fibroblast Cultures.
- Author
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SERRA, VIOLETA, GRUNE, TILMAN, SITTE, NICOLLE, SARETZKI, GABRIELE, and VON ZGLINICKI, THOMAS
- Published
- 2000
- Full Text
- View/download PDF
49. Estimation of metabolic flux rates in liver purine catabolism of tumour-bearing mice by computer simulation of radioactive tracer experiments.
- Author
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Siems, Werner G., Schwendel, Anke, Grune, Tilman, Holzhütter, Hermann-Georg, and Uhlig, Rolf
- Published
- 1994
- Full Text
- View/download PDF
50. Lysosomal, cytoskeletal, and metabolic alterations in cardiomyopathy of cathepsin L knockout mice.
- Author
-
Petermann, Ivonne, Mayer, Christian, Stypmann, Jörg, Biniossek, Martin L., Tobin, Desmond J., Engelen, Markus A., Dandekar, Thomas, Grune, Tilman, Schild, Lorenz, Peters, Christoph, and Reinheckel, Thomas
- Subjects
CARDIOMYOPATHIES ,HEART fibrosis ,LABORATORY mice ,CELL death ,CELL proliferation - Abstract
Presents the summary of a research on the lysosomal, cytoskeletal and metabolic alterations in cardiomyopathy of cathepsin L (CTSL) knockout mice. Findings on the morphology and functional impairment of CTSL-deficient hearts; Development of fibrosis and ultrastructural alterations in CTSL-deficient myocardium; Observations on the alterations of the acidic cellular compartment of CTSL-deficient myocardium and cell death, cell proliferation and its vascular structure.
- Published
- 2006
- Full Text
- View/download PDF
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