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51. Trail (TNF-related apoptosis-inducing ligand) induces an inflammatory response in human adipocytes

Author

Zoller, V. (Verena), Funcke, J.-B. (Jan-Bernd), Roos, J. (Julian), Dahlhaus, M. (Meike), Abd El Hay, M. (Muad), Holzmann, K. (Karlheinz), Marienfeld, R. (Ralf), Kietzmann, T. (Thomas), Debatin, K.-M. (Klaus-Michael), Wabitsch, M. (Martin), Fischer-Posovszky, P. (Pamela), Zoller, V. (Verena), Funcke, J.-B. (Jan-Bernd), Roos, J. (Julian), Dahlhaus, M. (Meike), Abd El Hay, M. (Muad), Holzmann, K. (Karlheinz), Marienfeld, R. (Ralf), Kietzmann, T. (Thomas), Debatin, K.-M. (Klaus-Michael), Wabitsch, M. (Martin), and Fischer-Posovszky, P. (Pamela)

Abstract

High serum concentrations of TNF-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor protein family, are found in patients with increased BMI and serum lipid levels. In a model of murine obesity, both the expression of TRAIL and its receptor (TRAIL-R) is elevated in adipose tissue. Accordingly, TRAIL has been proposed as an important mediator of adipose tissue inflammation and obesity-associated diseases. The aim of this study was to investigate if TRAIL regulates inflammatory processes at the level of the adipocyte. Using human Simpson-Golabi-Behmel syndrome (SGBS) cells as a model system, we found that TRAIL induces an inflammatory response in both preadipocytes and adipocytes. It stimulates the expression of interleukin 6 (IL-6), interleukin 8 (IL-8) as well as the chemokines monocyte chemoattractant protein-1 (MCP-1) and chemokine C-C motif ligand 20 (CCL-20) in a time- and dose-dependent manner. By using small molecule inhibitors, we found that both the NFκB and the ERK1/2 pathway are crucial for mediating the effect of TRAIL. Taken together, we identified a novel pro-inflammatory function of TRAIL in human adipocytes. Our findings suggest that targeting the TRAIL/TRAIL-R system might be a useful strategy to tackle obesity-associated adipose tissue inflammation.

Published
2017

52. European contribution to the study of ROS:a summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

Author

Egea, J. (Javier), Fabregat, I. (Isabel), Frapart, Y. M. (Yves M.), Ghezzi, P. (Pietro), Görlach, A. (Agnes), Kietzmann, T. (Thomas), Kubaichuk, K. (Kateryna), Knaus, U. G. (Ulla G.), Lopez, M. G. (Manuela G.), Olaso-Gonzalez, G. (Gloria), Petry, A. (Andreas), Schulz, R. (Rainer), Vina, J. (Jose), Winyard, P. (Paul), Abbas, K. (Kahina), Ademowo, O. S. (Opeyemi S.), Afonso, C. B. (Catarina B.), Andreadou, I. (Ioanna), Antelmann, H. (Haike), Antunes, F. (Fernando), Aslan, M. (Mutay), Bachschmid, M. M. (Markus M.), Barbosa, R. M. (Rui M.), Belousov, V. (Vsevolod), Berndt, C. (Carsten), Bernlohr, D. (David), Bertrán, E. (Esther), Bindoli, A. (Alberto), Bottari, S. P. (Serge P.), Brito, P. M. (Paula M.), Carrara, G. (Guia), Casas, A. I. (Ana I.), Chatzi, A. (Afroditi), Chondrogianni, N. (Niki), Conrad, M. (Marcus), Cooke, M. S. (Marcus S.), Costa, J. G. (João G.), Cuadrado, A. (Antonio), My-Chan Dang, P. (Pham), De Smet, B. (Barbara), Debelec-Butuner, B. (Bilge), Dias, I. H. (Irundika H. K.), Dunn, J. D. (Joe D.an), Edson, A. J. (Amanda J.), El Assar, M. (Mariam), El-Benna, J. (Jamel), Ferdinandy, P. (Péter), Fernandes, A. S. (Ana S.), Fladmark, K. E. (Kari E.), Förstermann, U. (Ulrich), Giniatullin, R. (Rashid), Giricz, Z. (Zoltán), Görbe, A. (Anikó), Griffiths, H. (Helen), Hampl, V. (Vaclav), Hanf, A. (Alina), Herget, J. (Jan), Hernansanz-Agustín, P. (Pablo), Hillion, M. (Melanie), Huang, J. (Jingjing), Ilikay, S. (Serap), Jansen-Dürr, P. (Pidder), Jaquet, V. (Vincent), Joles, J. A. (Jaap A.), Kalyanaraman, B. (Balaraman), Kaminskyy, D. (Danylo), Karbaschi, M. (Mahsa), Kleanthous, M. (Marina), Klotz, L.-O. (Lars-Oliver), Korac, B. (Bato), Korkmaz, K. S. (Kemal S.ami), Koziel, R. (Rafal), Kračun, D. (Damir), Krause, K.-H. (Karl-Heinz), Křen, V. (Vladimír), Krieg, T. (Thomas), Laranjinha, J. (João), Lazou, A. (Antigone), Li, H. (Huige), Martínez-Ruiz, A. (Antonio), Matsui, R. (Reiko), McBean, G. J. (Gethin J.), Meredith, S. P. (Stuart P.), Messens, J. (Joris), Miguel, V. (Verónica), Mikhed, Y. (Yuliya), Milisav, I. (Irina), Milković, L. (Lidija), Miranda-Vizuete, A. (Antonio), Mojović, M. (Miloš), Monsalve, M. (María), Mouthuy, P.-A. (Pierre-Alexis), Mulvey, J. (John), Münzel, T. (Thomas), Muzykantov, V. (Vladimir), Nguyen, I. T. (Isabel T. N.), Oelze, M. (Matthias), Oliveira, N. G. (Nuno G.), Palmeira, C. M. (Carlos M.), Papaevgeniou, N. (Nikoletta), Pavićević, A. (Aleksandra), Pedre, B. (Brandán), Peyrot, F. (Fabienne), Phylactides, M. (Marios), Pircalabioru, G. G. (Gratiela G.), Pitt, A. R. (Andrew R.), Poulsen, H. E. (Henrik E.), Prieto, I. (Ignacio), Rigobello, M. P. (Maria P.ia), Robledinos-Antón, N. (Natalia), Rodríguez-Mañas, L. (Leocadio), Rolo, A. P. (Anabela P.), Rousset, F. (Francis), Ruskovska, T. (Tatjana), Saraiva, N. (Nuno), Sasson, S. (Shlomo), Schröder, K. (Katrin), Semen, K. (Khrystyna), Seredenina, T. (Tamara), Shakirzyanova, A. (Anastasia), Smith, G. L. (Geoffrey L.), Soldati, T. (Thierry), Sousa, B. C. (Bebiana C.), Spickett, C. M. (Corinne M.), Stancic, A. (Ana), Stasia, M. J. (Marie J.osé), Steinbrenner, H. (Holger), Stepanić, V. (Višnja), Steven, S. (Sebastian), Tokatlidis, K. (Kostas), Tuncay, E. (Erkan), Turan, B. (Belma), Ursini, F. (Fulvio), Vacek, J. (Jan), Vajnerova, O. (Olga), Valentová, K. (Kateřina), Van Breusegem, F. (Frank), Varisli, L. (Lokman), Veal, E. A. (Elizabeth A.), Yalçın, A. S. (A S.uha), Yelisyeyeva, O. (Olha), Žarković, N. (Neven), Zatloukalová, M. (Martina), Zielonka, J. (Jacek), Touyz, R. M. (Rhian M.), Papapetropoulos, A. (Andreas), Grune, T. (Tilman), Lamas, S. (Santiago), Schmidt, H. H. (Harald H. H. W.), Di Lisa, F. (Fabio), Daiber, A. (Andreas), Egea, J. (Javier), Fabregat, I. (Isabel), Frapart, Y. M. (Yves M.), Ghezzi, P. (Pietro), Görlach, A. (Agnes), Kietzmann, T. (Thomas), Kubaichuk, K. (Kateryna), Knaus, U. G. (Ulla G.), Lopez, M. G. (Manuela G.), Olaso-Gonzalez, G. (Gloria), Petry, A. (Andreas), Schulz, R. (Rainer), Vina, J. (Jose), Winyard, P. (Paul), Abbas, K. (Kahina), Ademowo, O. S. (Opeyemi S.), Afonso, C. B. (Catarina B.), Andreadou, I. (Ioanna), Antelmann, H. (Haike), Antunes, F. (Fernando), Aslan, M. (Mutay), Bachschmid, M. M. (Markus M.), Barbosa, R. M. (Rui M.), Belousov, V. (Vsevolod), Berndt, C. (Carsten), Bernlohr, D. (David), Bertrán, E. (Esther), Bindoli, A. (Alberto), Bottari, S. P. (Serge P.), Brito, P. M. (Paula M.), Carrara, G. (Guia), Casas, A. I. (Ana I.), Chatzi, A. (Afroditi), Chondrogianni, N. (Niki), Conrad, M. (Marcus), Cooke, M. S. (Marcus S.), Costa, J. G. (João G.), Cuadrado, A. (Antonio), My-Chan Dang, P. (Pham), De Smet, B. (Barbara), Debelec-Butuner, B. (Bilge), Dias, I. H. (Irundika H. K.), Dunn, J. D. (Joe D.an), Edson, A. J. (Amanda J.), El Assar, M. (Mariam), El-Benna, J. (Jamel), Ferdinandy, P. (Péter), Fernandes, A. S. (Ana S.), Fladmark, K. E. (Kari E.), Förstermann, U. (Ulrich), Giniatullin, R. (Rashid), Giricz, Z. (Zoltán), Görbe, A. (Anikó), Griffiths, H. (Helen), Hampl, V. (Vaclav), Hanf, A. (Alina), Herget, J. (Jan), Hernansanz-Agustín, P. (Pablo), Hillion, M. (Melanie), Huang, J. (Jingjing), Ilikay, S. (Serap), Jansen-Dürr, P. (Pidder), Jaquet, V. (Vincent), Joles, J. A. (Jaap A.), Kalyanaraman, B. (Balaraman), Kaminskyy, D. (Danylo), Karbaschi, M. (Mahsa), Kleanthous, M. (Marina), Klotz, L.-O. (Lars-Oliver), Korac, B. (Bato), Korkmaz, K. S. (Kemal S.ami), Koziel, R. (Rafal), Kračun, D. (Damir), Krause, K.-H. (Karl-Heinz), Křen, V. (Vladimír), Krieg, T. (Thomas), Laranjinha, J. (João), Lazou, A. (Antigone), Li, H. (Huige), Martínez-Ruiz, A. (Antonio), Matsui, R. (Reiko), McBean, G. J. (Gethin J.), Meredith, S. P. (Stuart P.), Messens, J. (Joris), Miguel, V. (Verónica), Mikhed, Y. (Yuliya), Milisav, I. (Irina), Milković, L. (Lidija), Miranda-Vizuete, A. (Antonio), Mojović, M. (Miloš), Monsalve, M. (María), Mouthuy, P.-A. (Pierre-Alexis), Mulvey, J. (John), Münzel, T. (Thomas), Muzykantov, V. (Vladimir), Nguyen, I. T. (Isabel T. N.), Oelze, M. (Matthias), Oliveira, N. G. (Nuno G.), Palmeira, C. M. (Carlos M.), Papaevgeniou, N. (Nikoletta), Pavićević, A. (Aleksandra), Pedre, B. (Brandán), Peyrot, F. (Fabienne), Phylactides, M. (Marios), Pircalabioru, G. G. (Gratiela G.), Pitt, A. R. (Andrew R.), Poulsen, H. E. (Henrik E.), Prieto, I. (Ignacio), Rigobello, M. P. (Maria P.ia), Robledinos-Antón, N. (Natalia), Rodríguez-Mañas, L. (Leocadio), Rolo, A. P. (Anabela P.), Rousset, F. (Francis), Ruskovska, T. (Tatjana), Saraiva, N. (Nuno), Sasson, S. (Shlomo), Schröder, K. (Katrin), Semen, K. (Khrystyna), Seredenina, T. (Tamara), Shakirzyanova, A. (Anastasia), Smith, G. L. (Geoffrey L.), Soldati, T. (Thierry), Sousa, B. C. (Bebiana C.), Spickett, C. M. (Corinne M.), Stancic, A. (Ana), Stasia, M. J. (Marie J.osé), Steinbrenner, H. (Holger), Stepanić, V. (Višnja), Steven, S. (Sebastian), Tokatlidis, K. (Kostas), Tuncay, E. (Erkan), Turan, B. (Belma), Ursini, F. (Fulvio), Vacek, J. (Jan), Vajnerova, O. (Olga), Valentová, K. (Kateřina), Van Breusegem, F. (Frank), Varisli, L. (Lokman), Veal, E. A. (Elizabeth A.), Yalçın, A. S. (A S.uha), Yelisyeyeva, O. (Olha), Žarković, N. (Neven), Zatloukalová, M. (Martina), Zielonka, J. (Jacek), Touyz, R. M. (Rhian M.), Papapetropoulos, A. (Andreas), Grune, T. (Tilman), Lamas, S. (Santiago), Schmidt, H. H. (Harald H. H. W.), Di Lisa, F. (Fabio), and Daiber, A. (Andreas)

Abstract

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.

Published
2017

53. Protein kinases as switches for the function of upstream stimulatory factors:implications for tissue injury and cancer

Author

Horbach, T. (Tina), Götz, C. (Claudia), Kietzmann, T. (Thomas), and Dimova, E. Y. (Elitsa Y.)

Subjects
tumor, phosphorylation, cancer, therapeutic target, USF, signaling, transcription factor
Abstract

The upstream stimulatory factors (USFs) are regulators of important cellular processes. Both USF1 and USF2 are supposed to have major roles in metabolism, tissue protection and tumor development. However, the knowledge about the mechanisms that control the function of USFs, in particular in tissue protection and cancer, is limited. Phosphorylation is a versatile tool to regulate protein functions. Thereby, phosphorylation can positively or negatively affect different aspects of transcription factor function including protein stability, protein–protein interaction, cellular localization, or DNA binding. The present review aims to summarize the current knowledge about the regulation of USFs by direct phosphorylation and the consequences for USF functions in tissue protection and cancer. Correction article: Front. Pharmacol., 05 April 2016 | https://doi.org/10.3389/fphar.2016.00092

Published
2015

54. The human mitochondrial DNA depletion syndrome gene MPV17 encodes a non-selective channel that modulates membrane potential

Author

Antonenkov, V. D. (Vasily D.), Isomursu, A. (Antti), Mennerich, D. (Daniela), Vapola, M. H. (Miia H.), Weiher, H. (Hans), Kietzmann, T. (Thomas), and Hiltunen, J. K. (J. Kalervo)

Subjects
mitochondria, mitophagy, non-selective channel, Mpv17 protein, aging, mitochondrial DNA damage, membrane protein
Abstract

The human MPV17-related mitochondrial DNA depletion syndrome is an inherited autosomal recessive disease caused by mutations in the inner mitochondrial membrane protein MPV17. Although more than 30 MPV17 gene mutations were shown to be associated with mitochondrial DNA depletion syndrome, the function of MPV17 is still unknown. Mice deficient in Mpv17 show signs of premature aging. In the present study, we used electrophysiological measurements with recombinant MPV17 to reveal that this protein forms a non-selective channel with a pore diameter of 1.8 nm and located the channel’s selectivity filter. The channel was weakly cation-selective and showed several subconductance states. Voltage-dependent gating of the channel was regulated by redox conditions and pH and was affected also in mutants mimicking a phosphorylated state. Likewise, the mitochondrial membrane potential (Δψm) and the cellular production of reactive oxygen species were higher in embryonic fibroblasts from Mpv17−/− mice. However, despite the elevated Δψm, the Mpv17-deficient mitochondria showed signs of accelerated fission. Together, these observations uncover the role of MPV17 as a Δψm-modulating channel that apparently contributes to mitochondrial homeostasis under different conditions.

Published
2015

55. Redox-fibrosis:impact of TGFβ1 on ROS generators, mediators and functional consequences

Author

Richter, K. (Kati), Konzack, A. (Anja), Pihlajaniemi , T. (Taina), Heljasvaara , R. (Ritva), and Kietzmann, T. (Thomas)

Subjects
Matrix, Diet, ROS, Antioxidative enzymes, Fibrosis, Antioxidants
Abstract

Fibrosis is one of the most prevalent features of age-related diseases like obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease, or cardiomyopathy and affects millions of people in all countries. Although the understanding about the pathophysiology of fibrosis has improved a lot during the recent years, a number of mechanisms still remain unknown. Although TGF-β1 signaling, loss of metabolic homeostasis and chronic low-grade inflammation appear to play important roles in the pathogenesis of fibrosis, recent evidence indicates that oxidative stress and the antioxidant system may also be crucial for fibrosis development and persistence. These findings point to a concept of a redox-fibrosis where the cellular oxidant and antioxidant system could be potential therapeutic targets. The current review aims to summarize the existing links between TGF-β1 signaling, generation and action of reactive oxygen species, expression of antioxidative enzymes, and functional consequences including epigenetic redox-mediated responses during fibrosis.

Published
2015

56. Obesity and inflammation:reduced cytokine expression due to resveratrol in a human in vitro model of inflamed adipose tissue

Author

Zagotta, I. (Ivana), Dimova, E. Y. (Elitsa Y.), Debatin, K.-M. (Klaus-Michael), Wabitsch, M. (Martin), Kietzmann, T. (Thomas), and Fischer-Posovszky, P. (Pamela)

Subjects
obesity, endocrine system diseases, inflammation, transcriptionalactivation, adipocytes, food and beverages, resveratrol, white, cytokines
Abstract

Obesity is associated with an inflammatory status and linked with a number of pathophysiological complications among them cardiovascular disease, type 2 diabetes mellitus, or the metabolic syndrome. Resveratrol was proposed to improve obesity-related inflammatory problems, but the effect of resveratrol on cytokine expression in obesity is not completely understood. In this study, we used an in vitro model of human adipose tissue inflammation to examine the effects of resveratrol on the production of the inflammatory cytokines interleukin 6 (IL-6), IL-8, and monocyte chemoattractant protein 1 (MCP-1). We found that resveratrol reduced IL-6, IL-8, and MCP-1 levels in a concentration-dependent manner in adipocytes under inflammatory conditions. Further experiments showed that the action of resveratrol was mainly due to its NFκB inhibitory potential. Thus, our data support the concept that resveratrol can alleviate obesity-induced up-regulation of inflammatory cytokines providing a new insight toward novel treatment options in obesity.

Published
2015

57. Reactive oxygen species, nutrition, hypoxia and diseases:problems solved?

Author

Görlach, A. (Agnes), Dimova, E. Y. (Elitsa Y. ), Petry, A. (Andreas), Martínez-Ruiz, A. (Antonio), Hernansanz-Agustín, P. (Pablo), Rolo, A. P. (Anabela P.), Palmeira, C. M. (Carlos M.), and Kietzmann, T. (Thomas)

Subjects
Oxygen, Metabolism, Diabetes, Diseases, Free radicals, Obesity, Diets, Hypoxia, Mitochondria
Abstract

Within the last twenty years the view on reactive oxygen species (ROS) has changed; they are no longer only considered to be harmful but also necessary for cellular communication and homeostasis in different organisms ranging from bacteria to mammals. In the latter, ROS were shown to modulate diverse physiological processes including the regulation of growth factor signaling, the hypoxic response, inflammation and the immune response. During the last 60–100 years the life style, at least in the Western world, has changed enormously. This became obvious with an increase in caloric intake, decreased energy expenditure as well as the appearance of alcoholism and smoking; These changes were shown to contribute to generation of ROS which are, at least in part, associated with the occurrence of several chronic diseases like adiposity, atherosclerosis, type II diabetes, and cancer. In this review we discuss aspects and problems on the role of intracellular ROS formation and nutrition with the link to diseases and their problematic therapeutical issues.

Published
2015

58. Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is a direct regulator of epidermal growth factor receptor (EGFR) signaling in breast cancer

Author

Kozlova, N. (Nina), Wottawa, M. (Marieke), Katschinski, D. M. (Dörthe Magdalena), Kristiansen, G. (Glen), Kietzmann, T. (Thomas), Kozlova, N. (Nina), Wottawa, M. (Marieke), Katschinski, D. M. (Dörthe Magdalena), Kristiansen, G. (Glen), and Kietzmann, T. (Thomas)

Abstract

Clinical studies in breast cancer suggest important associations between intratumoral hypoxia, the upregulation of epidermal growth factor receptor (EGFR or HER1), hypoxia-inducible factor 1α (HIF-1α), and reduced patient survival. However, direct molecular links between EGFR and the hypoxia signaling system are not yet established. Since the oxygen sensor hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) is considered to be the main HIF-1α regulator, we hypothesized that PHD2 and EGFR may be interconnected at the molecular level. By analyzing samples from 313 breast cancer patients, we found that EGFR is a first clinicopathological parameter positively correlating with PHD2. Mechanistically, we identified PHD2 as a direct binding partner of EGFR and show that PHD2 regulates EGFR stability as well as its subsequent signaling in breast carcinoma cells. Overall, we introduce for the first time the direct crosstalk between the oxygen sensor PHD2 and EGFR-mediated tumorigenesis in breast cancer.

Published
2016

59. Reactive oxygen species and fibrosis:further evidence of a significant liaison

Author

Richter, K. (Kati), Kietzmann, T. (Thomas), Richter, K. (Kati), and Kietzmann, T. (Thomas)

Abstract

Age-related diseases such as obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiomyopathy are frequently associated with fibrosis. Work within the last decade has improved our understanding of the pathophysiological mechanisms contributing to fibrosis development. In particular, oxidative stress and the antioxidant system appear to be crucial modulators of processes such as transforming growth factor-β1 (TGF-β1) signalling, metabolic homeostasis and chronic low-grade inflammation, all of which play important roles in fibrosis development and persistence. In the current review, we discuss the connections between reactive oxygen species, antioxidant enzymes and TGF-β1 signalling, together with functional consequences, reflecting a concept of redox-fibrosis that can be targeted in future therapies.

Published
2016

61. PHD1 regulates p53‐mediated colorectal cancer chemoresistance

Author

Deschoemaeker, S. (Sofie), Di Conza, G. (Giusy), Lilla, S. (Sergio), Martín‐Pérez, R. (Rosa), Mennerich, D. (Daniela), Boon, L. (Lise), Hendrikx, S. (Stefanie), Maddocks, O. D. (Oliver DK), Marx, C. (Christian), Radhakrishnan, P. (Praveen), Prenen, H. (Hans), Schneider, M. (Martin), Myllyharju, J. (Johanna), Kietzmann, T. (Thomas), Vousden, K. H. (Karen H), Zanivan, S. (Sara), Mazzone, M. (Massimiliano), Deschoemaeker, S. (Sofie), Di Conza, G. (Giusy), Lilla, S. (Sergio), Martín‐Pérez, R. (Rosa), Mennerich, D. (Daniela), Boon, L. (Lise), Hendrikx, S. (Stefanie), Maddocks, O. D. (Oliver DK), Marx, C. (Christian), Radhakrishnan, P. (Praveen), Prenen, H. (Hans), Schneider, M. (Martin), Myllyharju, J. (Johanna), Kietzmann, T. (Thomas), Vousden, K. H. (Karen H), Zanivan, S. (Sara), and Mazzone, M. (Massimiliano)

Abstract

Overcoming resistance to chemotherapy is a major challenge in colorectal cancer (CRC) treatment, especially since the underlying molecular mechanisms remain unclear. We show that silencing of the prolyl hydroxylase domain protein PHD1, but not PHD2 or PHD3, prevents p53 activation upon chemotherapy in different CRC cell lines, thereby inhibiting DNA repair and favoring cell death. Mechanistically, PHD1 activity reinforces p53 binding to p38α kinase in a hydroxylation‐dependent manner. Following p53–p38α interaction and chemotherapeutic damage, p53 can be phosphorylated at serine 15 and thus activated. Active p53 allows nucleotide excision repair by interacting with the DNA helicase XPB, thereby protecting from chemotherapy‐induced apoptosis. In accord with this observation, PHD1 knockdown greatly sensitizes CRC to 5‐FU in mice. We propose that PHD1 is part of the resistance machinery in CRC, supporting rational drug design of PHD1‐specific inhibitors and their use in combination with chemotherapy.

Published
2015

62. Mitochondrial dysfunction due to lack of manganese superoxide dismutase promotes hepatocarcinogenesis

Author

Konzack, A. (Anja), Jakupovic, M. (Mirza), Kubaichuk, K. (Kateryna), Görlach, A. (Agnes), Dombrowski, F. (Frank), Miinalainen, I. (Ilkka), Sormunen, R. (Raija), Kietzmann, T. (Thomas), Konzack, A. (Anja), Jakupovic, M. (Mirza), Kubaichuk, K. (Kateryna), Görlach, A. (Agnes), Dombrowski, F. (Frank), Miinalainen, I. (Ilkka), Sormunen, R. (Raija), and Kietzmann, T. (Thomas)

Abstract

Aims: One of the cancer hallmarks is mitochondrial dysfunction associated with oxidative stress. Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (MnSOD). Accordingly, carcinogenesis would be associated with a dysregulation in MnSOD expression. However, the association studies available so far are conflicting, and no direct proof concerning the role of MnSOD as a tumor promoter or suppressor has been provided. Therefore, we investigated the role of MnSOD in carcinogenesis by studying the effect of MnSOD deficiency in cells and in the livers of mice. Results: We found that loss of MnSOD in hepatoma cells contributed to their conversion toward a more malignant phenotype, affecting all cellular properties generally associated with metabolic transformation and tumorigenesis. In vivo, hepatocyte-specific MnSOD-deficient mice showed changed organ architecture, increased expression of tumor markers, and a faster response to carcinogenesis. Moreover, deficiency of MnSOD in both the in vitro and in vivo model reduced β-catenin and hypoxia-inducible factor-1⍺ levels. Innovation: The present study shows for the first time the important correlation between MnSOD presence and the regulation of two major pathways involved in carcinogenesis, the Wnt/β-catenin and hypoxia signaling pathway. Conclusion: Our study points toward a tumor suppressive role of MnSOD in liver, where the Wnt/β-catenin and hypoxia pathway may be crucial elements.

Published
2015

63. Antioxidant responses and cellular adjustments to oxidative stress

Author

Espinosa-Diez, C. (Cristina), Miguel, V. (Verónica), Mennerich, D. (Daniela), Kietzmann, T. (Thomas), Sánchez-Pérez, P. (Patricia), Cadenas, S. (Susana), Lamas, S. (Santiago), Espinosa-Diez, C. (Cristina), Miguel, V. (Verónica), Mennerich, D. (Daniela), Kietzmann, T. (Thomas), Sánchez-Pérez, P. (Patricia), Cadenas, S. (Susana), and Lamas, S. (Santiago)

Abstract

Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases.

Published
2015

65. FoxO1 and HNF-4 are involved in regulation of hepatic glucokinase gene expression by resveratrol

Author

Kumar Ganjam, G. (Goutham), Dimova, E. Y. (Elitsa Y.), Unterman, T. G. (Terry G.), and Kietzmann, T. (Thomas)

Subjects
endocrine system, food and beverages, lipids (amino acids, peptides, and proteins), digestive system, hormones, hormone substitutes, and hormone antagonists
Abstract

Resveratrol, a polyphenol derived from grapes, exerts important effects on glucose and lipid metabolism, yet detailed mechanisms mediating these effects remain unknown. The liver plays a central role in energy homeostasis, and glucokinase (GK) is a key enzyme involved in glucose utilization. Resveratrol activates SIRT1 (sirtuin 1), which promotes deacetylation of the forkhead transcription factor FoxO1. Previously, we reported that FoxO1 can suppress and that HNF-4 can stimulate GK expression in the liver. Here, we examined the role of FoxO1 and HNF-4 in mediating resveratrol effects on liver GK expression. Resveratrol suppressed hepatic GK expression in vivo and in isolated hepatocytes, and knocking down FoxO1 with shRNAs disrupted this effect. Reporter gene, gel shift, supershift assay, and chromatin immunoprecipitation studies show that FoxO1 binds to the GK promoter and that the interplay between FoxO1 and HNF-4 within the GK promoter is essential for mediating the effects of resveratrol. Resveratrol promotes deacetylation of FoxO1 and enhances its recruitment to the FoxO-binding element. Conversely, resveratrol suppresses recruitment of HNF-4 to its binding site, and knockdown of FoxO1 blocks this effect of resveratrol. Coprecipitation and chromatin immunoprecipitation studies show that resveratrol enhances interaction between FoxO1 and HNF-4, reduces binding of HNF-4 to its own site, and promotes its recruitment to the FoxO site in a FoxO1-dependent manner. These results provide the first evidence that resveratrol represses GK expression via FoxO1 and that the interaction between FoxO1 and HNF-4 contributes to these effects of resveratrol.

Published
2009

67. GSK3β-dependent phosphorylation alters DNA binding, transactivity and half-life of the transcription factor USF2

Author

Horbach, T. (Tina), Franklin Chi, T. (Tabughang), Götz, C. (Claudia), Sharma, S. (Satyan), Juffer, A. H. (André H.), Dimova, E. Y. (Elitsa Y.), Kietzmann, T. (Thomas), Horbach, T. (Tina), Franklin Chi, T. (Tabughang), Götz, C. (Claudia), Sharma, S. (Satyan), Juffer, A. H. (André H.), Dimova, E. Y. (Elitsa Y.), and Kietzmann, T. (Thomas)

Abstract

The upstream stimulatory factor 2 (USF2) is a regulator of important cellular processes and is supposed to have also a role during tumor development. However, the knowledge about the mechanisms that control the function of USF2 is limited. The data of the current study show that USF2 function is regulated by phosphorylation and identified GSK3β as an USF2-phosphorylating kinase. The phosphorylation sites within USF2 could be mapped to serine 155 and threonine 230. In silico analyses of the 3-dimensional structure revealed that phosphorylation of USF2 by GSK3β converts it to a more open conformation which may influence transactivity, DNA binding and target gene expression. Indeed, experiments with GSK-3β-deficient cells revealed that USF2 transactivity, DNA binding and target gene expression were reduced upon lack of GSK3β. Further, experiments with USF2 variants mimicking GSK3β phosphorylated USF2 in GSK3β-deficient cells showed that phosphorylation of USF2 by GSK3β did not affect cell proliferation but increased cell migration. Together, this study reports a new mechanism by which USF2 may contribute to cancerogenesis.

Published
2014

71. Reactive oxygen species modulate HIF-1 mediated PAI-1 expression: involvement of the GTPase Rac1

Author

Görlach A, Berchner-Pfannschmidt U, Wotzlaw C, Rh, Cool, Joachim Fandrey, Acker H, Jungermann K, and Kietzmann T

Subjects
Cell Nucleus, Male, rac1 GTP-Binding Protein, Mutation, Missense, NF-kappa B, Nuclear Proteins, Hematology, Hypoxia-Inducible Factor 1, alpha Subunit, Transfection, Rats, DNA-Binding Proteins, Gene Expression Regulation, Plasminogen Activator Inhibitor 1, Hepatocytes, Animals, Hypoxia-Inducible Factor 1, RNA, Messenger, Rats, Wistar, Hypoxia, Reactive Oxygen Species, Transcription Factors
Abstract

SummaryThe hypoxia-inducible transcription factor HIF-1 mediates upregulation of plasminogen activator inhibitor-1 (PAI-1) expression under hypoxia. Reactive oxygen species (ROS) have also been implicated in PAI-1 gene expression. However, the role of ROS in HIF-1-mediated regulation of PAI-1 is not clear. We therefore investigated the role of the GTPase Rac1 which modulates ROS production in the pathway leading to HIF-1 and PAI-1 induction.Overexpression of constitutively activated (RacG12V) or dominant-negative (RacT17N) Rac1 increased or decreased, respectively, ROS production. In RacG12V-expressing cells, PAI-1 mRNA levels as well as HIF-1α nuclear presence were reduced under normoxia and hypoxia whereas expression of RacT17N resulted in opposite effects. Treatment with the antioxidant pyrrolidinedithiocarbamate or coexpression of the redox factor-1 restored HIF-1 and PAI-1 promoter activity in RacG12V-cells. In contrast, NFκB activation was enhanced in RacG12V-cells, but abolished by RacT17N. Thus, these findings suggest a mechanism explaining modified fibrinolysis and tissue remodeling in an oxidized environment.

Published
2003

72. Resveratrol suppresses PAI-1 gene expression in a human in vitro model of inflamed adipose tissue

Author

Zagotta, I. (Ivana), Dimova, E. Y. (Elitsa Y.), Funcke, J.-B. (Jan-Bernd), Wabitsch, M. (Martin), Kietzmann, T. (Thomas), Fischer-Posovszky, P. (Pamela), Zagotta, I. (Ivana), Dimova, E. Y. (Elitsa Y.), Funcke, J.-B. (Jan-Bernd), Wabitsch, M. (Martin), Kietzmann, T. (Thomas), and Fischer-Posovszky, P. (Pamela)

Abstract

Increased plasminogen activator inhibitor-1 (PAI-1) levels are associated with a number of pathophysiological complications; among them is obesity. Resveratrol was proposed to improve obesity-related health problems, but the effect of resveratrol on PAI-1 gene expression in obesity is not completely understood. In this study, we used SGBS adipocytes and a model of human adipose tissue inflammation to examine the effects of resveratrol on the production of PAI-1. Treatment of SGBS adipocytes with resveratrol reduced PAI-1 mRNA and protein in a time- and concentration-dependent manner. Further experiments showed that obesity-associated inflammatory conditions lead to the upregulation of PAI-1 gene expression which was antagonized by resveratrol. Although signaling via PI3K, Sirt1, AMPK, ROS, and Nrf2 appeared to play a significant role in the modulation of PAI-1 gene expression under noninflammatory conditions, those signaling components were not involved in mediating the resveratrol effects on PAI-1 production under inflammatory conditions. Instead, we demonstrate that the resveratrol effects on PAI-1 induction under inflammatory conditions were mediated via inhibition of the NFκB pathway. Together, resveratrol can act as NFκB inhibitor in adipocytes and thus the subsequently reduced PAI-1 expression in inflamed adipose tissue might provide a new insight towards novel treatment options of obesity.

Published
2013

78. Hypoxie-induzierter Zelltod und Veränderungen der HIF-1-Aktivität in PC12-Zellen

Author

Gross, J., Kietzmann, T., Jelkmann, W., Charlier, Nico Nawid, Gross, J., Kietzmann, T., Jelkmann, W., and Charlier, Nico Nawid

Abstract

Der Transkriptionsfaktor hypoxia inducible factor-1 (HIF-1) trägt zur Expression von adaptiven Genen unter hypoxischen Bedingungen bei. Zusätzlich wurde vermutet, dass HIF-1 eine Rolle in der Regulation des späten neuronalen Zelltodes spielt. Suspensionszellen und adhärenten PC12-Zellen mit Nervenwachstumsfaktor (NGF) behandelt, wurden als ein experimentelles Modell für die Untersuchung der Beziehung zwischen Hypoxie induziertem Zelltod und Aktivität von HIF-1 herangezogen. Zelltod wurde durchflusszytometrisch mit einer Doppelfärbung (Annexin V und Propidium-Jodid) der Zellen und durch eine Analyse der allgemeinen Zelltodparameter wie LDH und die mitochondriale Dehydrogenase bestimmt. Parallel wurden Zellen mit einem Kontrollvektor und einem hypoxiesensitiven Vektor mit drei Hypoxie-bindenden-Elementen (HBE) transfiziert und die durch HIF-1 aktivierte Luciferase gemessen. Hypoxieexposition der NGF-behandelten PC12-Zellen resultierte in einer höheren Zelltodrate verglichen mit den unbehandelten Kontrollzellen. PC12 Zellen, zwei Tage mit NGF behandelt, zeigten eine bis zu 10-fach verminderte HIF-1-Aktivität. Diese Verminderung könnte zu dem erhöhten hypoxie-induzierten Zelltod durch verminderte Expression von HIF-1alpha-regulierten Genen, welche für die Anpassung an Hypoxie verantwortlich sind, beitragen. Die Verminderung der HIF-1 Aktivität und der Anstieg der Hypoxiesensitivität könnte darauf hinweisen, dass NGF als eine Art hierarchisch organisiertes Signalmolekül fungiert., The transcription factor hypoxia-inducible factor-1 (HIF-1) strongly contributes to the expression of adaptive genes under hypoxic conditions. In addition, HIF-1 has been implicated in the regulation of delayed neuronal cell death. Suspension-grown and adherent PC12 cells treated with NGF were used as an experimental model for studying the relationship between hypoxia-induced cell death and activation of HIF-1. Cell damage was assessed by flow cytometry of double-stained (annexin V and propidiumiodide) cells, and by analysis of the overall death parameters LDH and mitochondrial dehydrogenase. In parallel, cells were transfected with a control and a three-hypoxia-responsive-elements (HRE)-containing vector and HIF-1-driven luciferase activity was determined. Exposure of NGF-treated PC12 cells to hypoxia resulted in a higher cell death rate when compared to untreated controls. PC12 cells exposed for 2 days to NGF exhibited a decrease of HIF-1 activity up to a factor of ten. This decrease may contribute to the enhanced hypoxia-induced cell death via reduced expression of HIF-1alpha-regulated genes resposible for adaptation to hypoxia, like those for glucose transport proteins and enzymes of the glycolytic chain. The decrease in HIF-1 activity and the increase in hypoxia sensitivity may suggest that NGF act as an hierachically organized signaling molecule.

Published
2004

80. Sunday, 18 July 2010

Author

Schuchardt, M., primary, Toelle, M., additional, Huang, T., additional, Wiedon, A., additional, Van Der Giet, M., additional, Mill, C., additional, George, S., additional, Jeremy, J., additional, Santulli, G., additional, Illario, M., additional, Cipolletta, E., additional, Sorriento, D., additional, Del Giudice, C., additional, Anastasio, A., additional, Trimarco, B., additional, Iaccarino, G., additional, Jobs, A., additional, Wagner, C., additional, Kurtz, A., additional, De Wit, C., additional, Koller, A., additional, Suvorava, T., additional, Weber, M., additional, Dao, V., additional, Kojda, G., additional, Tsaousi, A., additional, Lyon, C., additional, Williams, H., additional, Barth, N., additional, Loot, A., additional, Fleming, I., additional, Keul, P., additional, Lucke, S., additional, Graeler, M., additional, Heusch, G., additional, Levkau, B., additional, Biessen, E., additional, De Jager, S., additional, Bermudez-Pulgarin, B., additional, Bot, I., additional, Abia, R., additional, Van Berkel, T., additional, Renger, A., additional, Noack, C., additional, Zafiriou, M., additional, Dietz, R., additional, Bergmann, M., additional, Zelarayan, L., additional, Hammond, J., additional, Hamelet, J., additional, Van Assche, T., additional, Belge, C., additional, Vanderper, A., additional, Langin, D., additional, Herijgers, P., additional, Balligand, J., additional, Perrot, A., additional, Neubert, M., additional, Posch, M., additional, Oezcelik, C., additional, Waldmuller, S., additional, Berger, F., additional, Scheffold, T., additional, Bouvagnet, P., additional, Ozcelik, C., additional, Lebreiro, A., additional, Martins, E., additional, Lourenco, P., additional, Cruz, C., additional, Martins, M., additional, Bettencourt, P., additional, Maciel, M., additional, Abreu-Lima, C., additional, Pilichou, K., additional, Bauce, B., additional, Rampazzo, A., additional, Carturan, E., additional, Corrado, D., additional, Thiene, G., additional, Basso, C., additional, Piccini, I., additional, Fortmueller, L., additional, Kuhlmann, M., additional, Schaefers, M., additional, Carmeliet, P., additional, Kirchhof, P., additional, Fabritz, L., additional, Sanchez, J., additional, Rodriguez-Sinovas, A., additional, Agullo, E., additional, Garcia-Dorado, D., additional, Lymperopoulos, A., additional, Rengo, G., additional, Gao, E., additional, Zincarelli, C., additional, Koch, W., additional, Morgan, P., additional, Diez, A., additional, Perez, N., additional, Cingolani, H., additional, Zahradnikova, A., additional, Polakova, E., additional, Zahradnik, I., additional, Fluschnik, N., additional, Sossalla, S., additional, Ort, K., additional, Neef, S., additional, Hasenfuss, G., additional, Maier, L., additional, Weinert, S., additional, Poitz, D., additional, Herold, J., additional, Schmeisser, A., additional, Strasser, J., additional, Braun-Dullaeus, R., additional, Nazari-Jahantigh, M., additional, Weber, C., additional, Schober, A., additional, Leuner, A., additional, Eichhorn, B., additional, Ravens, U., additional, Morawietz, H., additional, Babes, E., additional, Babes, V., additional, Popescu, M., additional, Ardelean, A., additional, Rus, M., additional, Bustea, C., additional, Gwozdz, P., additional, Csanyi, G., additional, Luzak, B., additional, Gajda, M., additional, Mateuszuk, L., additional, Chmura-Skirlinska, A., additional, Watala, C., additional, Chlopicki, S., additional, Kierzkowska, I., additional, Sulicka, J., additional, Kwater, A., additional, Strach, M., additional, Surdacki, A., additional, Siedlar, M., additional, Grodzicki, T., additional, Olieslagers, S., additional, Pardali, L., additional, Tchaikovski, V., additional, Ten Dijke, P., additional, Waltenberger, J., additional, Renner, M., additional, Redwan, B., additional, Winter, M., additional, Panzenboeck, A., additional, Jakowitsch, J., additional, Sadushi-Kolici, R., additional, Bonderman, D., additional, Lang, I., additional, Toso, A., additional, Tanini, L., additional, Pizzetti, T., additional, Leoncini, M., additional, Maioli, M., additional, Tedeschi, D., additional, Oliviero, C., additional, Bellandi, F., additional, Casprini, P., additional, Amato, M., additional, Molins, B., additional, Pena, E., additional, Badimon, L., additional, Ferreiro Gutierrez, J., additional, Ueno, M., additional, Alissa, R., additional, Dharmashankar, K., additional, Capodanno, D., additional, Desai, B., additional, Bass, T., additional, Angiolillo, D., additional, Chabielska, E., additional, Gromotowicz, A., additional, Szemraj, J., additional, Stankiewicz, A., additional, Zakrzeska, A., additional, Mohammed, S., additional, Molla, F., additional, Soldo, A., additional, Russo, I., additional, Germano, G., additional, Balconi, G., additional, Staszewsky, L., additional, Latini, R., additional, Lynch, F., additional, Austin, C., additional, Prendergast, B., additional, Keenan, D., additional, Malik, R., additional, Izzard, A., additional, Heagerty, A., additional, Czikora, A., additional, Lizanecz, E., additional, Rutkai, I., additional, Boczan, J., additional, Porszasz, R., additional, Papp, Z., additional, Edes, I., additional, Toth, A., additional, Colantuoni, A., additional, Vagnani, S., additional, Lapi, D., additional, Maroz-Vadalazhskaya, N., additional, Koslov, I., additional, Shumavetz, V., additional, Glibovskaya, T., additional, Ostrovskiy, Y., additional, Koutsiaris, A., additional, Tachmitzi, S., additional, Kotoula, M., additional, Giannoukas, A., additional, Tsironi, E., additional, Darago, A., additional, Orosz, P., additional, Megyesi, Z., additional, Schudeja, S., additional, Matschke, K., additional, Deussen, A., additional, Castro, M., additional, Cena, J., additional, Walsh, M., additional, Schulz, R., additional, Poddar, K., additional, Rha, S., additional, Ramasamy, S., additional, Park, J., additional, Choi, C., additional, Seo, H., additional, Park, C., additional, Oh, D., additional, Almeida, J., additional, Pimenta, S., additional, Bernardes, J., additional, Machado, J., additional, Sabatasso, S., additional, Laissue, J., additional, Hlushchuk, R., additional, Brauer-Krisch, E., additional, Bravin, A., additional, Blattmann, H., additional, Michaud, K., additional, Djonov, V., additional, Hirschberg, K., additional, Tarcea, V., additional, Pali, S., additional, Korkmaz, S., additional, Loganathan, S., additional, Merkely, B., additional, Karck, M., additional, Szabo, G., additional, Pagliani, L., additional, Faggin, E., additional, Rattazzi, M., additional, Puato, M., additional, Presta, M., additional, Grego, F., additional, Deriu, G., additional, Pauletto, P., additional, Kaiser, R., additional, Albrecht, K., additional, Schgoer, W., additional, Theurl, M., additional, Beer, A., additional, Wiedemann, D., additional, Steger, C., additional, Bonaros, N., additional, Kirchmair, R., additional, Kharlamov, A., additional, Cabaravdic, M., additional, Breuss, J., additional, Uhrin, P., additional, Binder, B., additional, Fiordaliso, F., additional, Maggioni, M., additional, Biondi, A., additional, Masson, S., additional, Cervo, L., additional, Francke, A., additional, Soenke, W., additional, Strasser, R., additional, Hecht, N., additional, Vajkoczy, P., additional, Woitzik, J., additional, Hackbusch, D., additional, Gatzke, N., additional, Duelsner, A., additional, Tsuprykov, O., additional, Slavic, S., additional, Buschmann, I., additional, Kappert, K., additional, Massaro, M., additional, Scoditti, E., additional, Carluccio, M., additional, Storelli, C., additional, Distante, A., additional, De Caterina, R., additional, Barandi, L., additional, Harmati, G., additional, Simko, J., additional, Horvath, B., additional, Szentandrassy, N., additional, Banyasz, T., additional, Magyar, J., additional, Nanasi, P., additional, Kaya, A., additional, Uzunhasan, I., additional, Yildiz, A., additional, Yigit, Z., additional, Turkoglu, C., additional, Doisne, N., additional, Zannad, N., additional, Hivert, B., additional, Cosnay, P., additional, Maupoil, V., additional, Findlay, I., additional, Virag, L., additional, Kristof, A., additional, Koncz, I., additional, Szel, T., additional, Jost, N., additional, Biliczki, P., additional, Papp, J., additional, Varro, A., additional, Bukowska, A., additional, Skopp, K., additional, Hammwoehner, M., additional, Huth, C., additional, Bode-Boeger, S., additional, Goette, A., additional, Workman, A., additional, Dempster, J., additional, Marshall, G., additional, Rankin, A., additional, Revnic, C., additional, Ginghina, C., additional, Revnic, F., additional, Yakushev, S., additional, Petrushanko, I., additional, Makhro, A., additional, Segato Komniski, M., additional, Mitkevich, V., additional, Makarov, A., additional, Gassmann, M., additional, Bogdanova, A., additional, Rutkovskiy, A., additional, Mariero, L., additional, Stenslokken, K., additional, Valen, G., additional, Vaage, J., additional, Dizayee, S., additional, Kaestner, S., additional, Kuck, F., additional, Piekorz, R., additional, Hein, P., additional, Matthes, J., additional, Nurnberg, B., additional, Herzig, S., additional, Hertel, F., additional, Switalski, A., additional, Bender, K., additional, Kienitz, M.-C., additional, Pott, L., additional, Fornai, L., additional, Angelini, A., additional, Erika Amstalden Van Hove, E., additional, Fedrigo, M., additional, Heeren, R., additional, Kruse, M., additional, Pongs, O., additional, Lehmann, H., additional, Martens-Lobenhoffer, J., additional, Roehl, F., additional, Radicke, S., additional, Cotella, C., additional, Sblattero, D., additional, Schaefer, M., additional, Wettwer, E., additional, Santoro, C., additional, Seyler, C., additional, Kulzer, M., additional, Zitron, E., additional, Scholz, E., additional, Welke, F., additional, Thomas, D., additional, Karle, C., additional, Schmidt, K., additional, Dobrev, D., additional, Houshmand, N., additional, Menesi, D., additional, Cotella, D., additional, Szuts, V., additional, Puskas, L., additional, Kiss, I., additional, Deak, F., additional, Tereshchenko, S., additional, Gladyshev, M., additional, Kalachova, G., additional, Syshchik, N., additional, Gogolashvili, N., additional, Dedok, E., additional, Evert, L., additional, Wenzel, J., additional, Brandenburger, M., additional, Bogdan, R., additional, Richardt, D., additional, Reppel, M., additional, Hescheler, J., additional, Dendorfer, A., additional, Terlau, H., additional, Wiegerinck, R., additional, Galvez-Monton, C., additional, Jorge, E., additional, Martinez, R., additional, Ricart, E., additional, Cinca, J., additional, Bagavananthem Andavan, G., additional, Lemmens Gruber, R., additional, Brack, K., additional, Coote, J., additional, Ng, G., additional, Daimi, H., additional, Haj Khelil, A., additional, Neji, A., additional, Ben Hamda, K., additional, Maaoui, S., additional, Aranega, A., additional, Chibani, J., additional, Franco Jaime, D., additional, Tanko, A.-S., additional, Daniel, J.-M., additional, Bielenberg, W., additional, Stieger, P., additional, Tillmanns, H., additional, Sedding, D., additional, Fortini, C., additional, Toffoletto, B., additional, Fucili, A., additional, Beltrami, A., additional, Fiorelli, V., additional, Francolini, G., additional, Ferrari, R., additional, Beltrami, C., additional, Castellani, C., additional, Ravara, B., additional, Tavano, R., additional, Vettor, R., additional, De Coppi, P., additional, Papini, E., additional, Gunetti, M., additional, Fagioli, F., additional, Suffredini, S., additional, Sartiani, L., additional, Stillitano, F., additional, Mugelli, A., additional, Cerbai, E., additional, Krausgrill, B., additional, Halbach, M., additional, Soemantri, S., additional, Schenk, K., additional, Lange, N., additional, Saric, T., additional, Muller-Ehmsen, J., additional, Kavanagh, D., additional, Zhao, Y., additional, Yemm, A., additional, Kalia, N., additional, Wright, E., additional, Farrell, K., additional, Wallrapp, C., additional, Geigle, P., additional, Lewis, A., additional, Stratford, P., additional, Malik, N., additional, Holt, C., additional, Raths, M., additional, Zagallo, M., additional, Luni, C., additional, Serena, E., additional, Cimetta, E., additional, Zatti, S., additional, Giobbe, G., additional, Elvassore, N., additional, Zaglia, T., additional, Zambon, A., additional, Gordon, K., additional, Mioulane, M., additional, Foldes, G., additional, Ali, N., additional, Harding, S., additional, Gorbe, A., additional, Szunyog, A., additional, Varga, Z., additional, Pirity, M., additional, Rungaruniert, S., additional, Dinnyes, A., additional, Csont, T., additional, Ferdinandy, P., additional, Iqbal, A., additional, Schneider, M. D., additional, Khodjaeva, E., additional, Ibadov, R., additional, Khalikulov, K., additional, Mansurov, A., additional, Astvatsatryan, A., additional, Senan, M., additional, Nemeth, A., additional, Lenkey, Z., additional, Ajtay, Z., additional, Cziraki, A., additional, Sulyok, E., additional, Horvath, I., additional, Lobenhoffer, J., additional, Bode-Boger, S., additional, Li, J., additional, He, Y., additional, Yang, X., additional, Wang, F., additional, Xu, H., additional, Li, X., additional, Zhao, X., additional, Lin, Y., additional, Juszynski, M., additional, Ciszek, B., additional, Jablonska, A., additional, Stachurska, E., additional, Ratajska, A., additional, Atkinson, A., additional, Inada, S., additional, Sleiman, R., additional, Zhang, H., additional, Boyett, M., additional, Dobrzynski, H., additional, Fedorenko, O., additional, Hao, G., additional, Yanni, J., additional, Buckley, D., additional, Anderson, R., additional, Ma, Y., additional, Ma, X., additional, Hu, Y., additional, Yang, Y., additional, Huang, D., additional, Liu, F., additional, Huang, Y., additional, Liu, C., additional, Jedrzejczyk, T., additional, Balwicki, L., additional, Wierucki, L., additional, Zdrojewski, T., additional, Agarkova, I., additional, Vogel, J., additional, Korybalska, K., additional, Pyda, M., additional, Witowski, J., additional, Ibatov, A., additional, Sozmen, N., additional, Seymen, A., additional, Tuncay, E., additional, Turan, B., additional, Chen, B., additional, Houston-Feenstra, L., additional, Chiong, J. R., additional, Jutzy, K., additional, Furundzija, V., additional, Kaufmann, J., additional, Meyborg, H., additional, Fleck, E., additional, Stawowy, P., additional, Ksiezycka-Majczynska, E., additional, Lubiszewska, B., additional, Kruk, M., additional, Kurjata, P., additional, Ruzyllo, W., additional, Driesen, R., additional, Coenen, T., additional, Fagard, R., additional, Sipido, K., additional, Petrov, V., additional, Aksentijevic, D., additional, Lygate, C., additional, Makinen, K., additional, Sebag-Montefiore, L., additional, Medway, D., additional, Schneider, J., additional, Neubauer, S., additional, Gasser, R., additional, Holzwart, E., additional, Rainer, P., additional, Von Lewinski, D., additional, Maechler, H., additional, Gasser, S., additional, Roessl, U., additional, Pieske, B., additional, Krueger, J., additional, Kintscher, U., additional, Podramagi, T., additional, Paju, K., additional, Piirsoo, A., additional, Roosimaa, M., additional, Kadaja, L., additional, Orlova, E., additional, Ruusalepp, A., additional, Seppet, E., additional, Auquier, J., additional, Ginion, A., additional, Hue, L., additional, Horman, S., additional, Beauloye, C., additional, Vanoverschelde, J., additional, Bertrand, L., additional, Fekete, V., additional, Zvara, A., additional, Pipis, J., additional, Konya, C., additional, Csonka, C., additional, Kraigher-Krainer, E., additional, Von Lewinksi, D., additional, Gonzalez-Loyola, A., additional, Barba, I., additional, Fernandez-Sanz, C., additional, Ruiz-Meana, M., additional, Forteza, M., additional, Bodi Peris, V., additional, Monleon, D., additional, Mainar, L., additional, Morales, J., additional, Moratal, D., additional, Trapero, I., additional, Chorro, F., additional, Leszek, P., additional, Sochanowicz, B., additional, Szperl, M., additional, Kolsut, P., additional, Piotrowski, W., additional, Rywik, T., additional, Danko, B., additional, Kruszewski, M., additional, Stanley, W., additional, Khairallah, R., additional, Khanna, N., additional, O'shea, K., additional, Kristian, T., additional, Hecker, P., additional, Des Rosiers, R., additional, Fiskum, G., additional, Fernandez-Alfonso, M., additional, Guzman-Ruiz, R., additional, Somoza, B., additional, Gil-Ortega, M., additional, Attane, C., additional, Castan-Laurell, I., additional, Valet, P., additional, Ruiz-Gayo, M., additional, Denissevich, T., additional, Schrepper, A., additional, Schwarzer, M., additional, Amorim, P., additional, Schoepe, M., additional, Mohr, F., additional, Doenst, T., additional, Chiellini, G., additional, Ghelardoni, S., additional, Saba, A., additional, Marchini, M., additional, Frascarelli, S., additional, Raffaelli, A., additional, Scanlan, T., additional, Zucchi, R., additional, Van Den Akker, N., additional, Molin, D., additional, Kolk, F., additional, Jeukens, F., additional, Olde Engberink, R., additional, Post, M., additional, Verbruggen, S., additional, Schulten, H., additional, Rochais, F., 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additional, Hintenberger, R., additional, Kaun, C., additional, Pfaffenberger, S., additional, Maurer, G., additional, Huber, K., additional, Wojta, J., additional, Demyanets, S., additional, Titov, V., additional, Chin-Dusting, J., additional, Vaisman, B., additional, Khong, S., additional, Remaley, A., additional, Andrews, K., additional, Hoeper, A., additional, Khalid, A., additional, Fuglested, B., additional, Aasum, E., additional, Larsen, T., additional, Diebold, I., additional, Petry, A., additional, Djordjevic, T., additional, Belaiba, R., additional, Fratz, S., additional, Hess, J., additional, Kietzmann, T., additional, Goerlach, A., additional, Chess, D., additional, Walsh, K., additional, Van Der Velden, J., additional, Moreira-Goncalves, D., additional, Paulus, W., additional, Niessen, H., additional, Perlini, S., additional, Azibani, F., additional, Tournoux, F., additional, Fazal, L., additional, Polidano, E., additional, Merval, R., additional, Chatziantoniou, C., additional, Samuel, J., additional, Delcayre, C., additional, Mgandela, P., additional, Brooksbank, R., additional, Maswanganyi, T., additional, Woodiwiss, A., additional, Norton, G., additional, Makaula, S., additional, Bucciantini, M., additional, Spinelli, V., additional, Coppini, R., additional, Russo, E., additional, Stefani, M., additional, Sukumaran, V., additional, Watanabe, K., additional, Ma, M., additional, Thandavarayan, R., additional, Azrozal, W., additional, Sari, F., additional, Shimazaki, H., additional, Kobayashi, Y., additional, Roleder, T., additional, Golba, K., additional, Deja, M., additional, Malinowski, M., additional, Wos, S., additional, Grebe, M., additional, Preissner, K., additional, Ercan, E., additional, Guven, A., additional, Asgun, F., additional, Ickin, M., additional, Ercan, F., additional, Kaplan, A., additional, Yavuz, O., additional, Bagla, S., additional, Kuka, J., additional, Vilskersts, R., additional, Vavers, E., additional, Liepins, E., 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2010
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