Search

Your search keyword '"Knaus U"' showing total 122 results
Start Over Author "Knaus U"
122 results on '"Knaus U"'

3. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b

Author

Schnelzer, A, Prechtel, D, Knaus, U, Dehne, K, Gerhard, M, Graeff, H, Harbeck, N, Schmitt, M, and Lengyel, E

Abstract

Rac1 is a member of the Ras superfamily of small guanosine triphosphatases (GTPases) that act as molecular switches to control cytoskeletal rearrangements and cell growth. Analogous to Ras, constitutively activating point mutations of Rac1 cause tumorigenic transformation of cell lines. However, there is no information about whether Rac1 is also mutated in vivo. After RT–PCR of Rac1, several clones of seven benign and 10 malignant breast cancer tissues as well as eight breast cancer cell lines were sequenced. Only single-nucleotide polymorphisms of Rac1 could be detected, and none of these corresponded to constitutively activating point mutations that have been used in cell lines for transformation. While sequencing Rac1 in breast tissues, a new Rac1 isoform with an insertion of 19 codons within the reading frame of Rac1 close to switch region II was identified and named Rac1b. The Rac1b protein acts like a fast cycling GTPase in GTP binding and hydrolysis assays. In Northern and Western blot experiments both Rac1 RNA and Rac1 protein had a significantly higher expression in breast cancer tissues compared to normal breast tissue samples. Immunohistochemical staining of Rac1 showed weak Rac1 expression in benign breast disease but high expression level in ductal carcinoma-in-situ, primary breast cancer, and lymph node metastases. In addition, breast tumor cells from patients with recurrent disease had Rac1 expression at the plasma membrane, suggesting activation of Rac1, in patients with aggressive breast cancer.

Published
2000

6. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., McCarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., McGovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., McVean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., McCarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, James, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthias, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Miles, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics Consortium, COLORS in IBD, Oxford IBD cohort study investigators, WGS500 Consortium, INTERVAL Study, Schwerd, T., Bryant, R. V., Pandey, S., Capitani, M., Meran, L., Cazier, J. -B., Jung, J., Mondal, K., Parkes, M., Mathew, C. G., Fiedler, K., Mccarthy, D. J., Sullivan, P. B., Rodrigues, A., Travis, S. P. L., Moore, C., Sambrook, J., Ouwehand, W. H., Roberts, D. J., Danesh, J., Russell, R. K., Wilson, D. C., Kelsen, J. R., Cornall, R., Denson, L. A., Kugathasan, S., Knaus, U. G., Serra, E. G., Anderson, C. A., Duerr, R. H., Mcgovern, D. P. B., Cho, J., Powrie, Fiona, Li, V. S. W., Muise, A. M., Uhlig, H. H., Donnelly, P., Bell, J., Bentley, D., Mcvean, G., Ratcliffe, P., Taylor, J., Wilkie, A. O. M., Broxholme, J., Buck, D., Gregory, L., Gregory, J., Lunter, G., Tomlinson, I., Allan, C., Attar, M., Green, A., Humphray, S., Kingsbury, Z., Lamble, S., Lonie, L., Pagnamenta, A., Piazza, P., Polanco, G., Trebes, A., Copley, R., Fiddy, S., Grocock, R., Hatton, E., Holmes, C., Hughes, L., Humburg, P., Kanapin, A., Lise, S., Martin, H., Murray, L., Mccarthy, D., Rimmer, A., Sahgal, N., Wright, B., Yau, C., Arancibia, Carolina, Bailey, Adam, Barnes, Ellie, Bird-Lieberman, Beth, Brain, Oliver, Braden, Barbara, Collier, Jane, East, Jame, Geremia, Alessandra, Howarth, Lucy, Keshav, Satish, Klenerman, Paul, Leedham, Simon, Palmer, Rebecca, Rodrigues, Astor, Simmons, Alison, Sullivan, Peter B, Travis, Simon P L, Uhlig, Holm H, Heuschkel, Rob, Zilbauer, Matthia, Auth, Marcus K. H., Shah, Neil, Kammermeier, Jochen, Croft, Nick, Barakat, Farah, Russell, Richard K., Wilson, David C., Henderson, Paul, Braegger, Christian P., Posovszky, Carsten, Fyderek, Krzysztof, Wedrychowicz, Andrzej, Zurek, Marlen, Strisciuglio, Caterina, Elawad, Mamoun, Lo, Bernice, Parkes, Mile, Satsangi, Jack, Anderson, Carl A., Jostins, L., Kennedy, N. A., Lamb, C. A., Ahmad, T., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Satsangi, J., Simmons, A., Tremelling, M., Lee, J. C., Prescott, N. J., Lees, C. W., Barrett, J. C., UK IBD Genetics, Consortium, COLORS in, Ibd, Oxford IBD cohort study, Investigator, Wgs500, Consortium, and Interval, Study

Subjects
Male, Genotype, Colon, Immunology, Mutation, Missense, Genetic Association Studie, Polymorphism, Single Nucleotide, Article, Mice, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Genetic Association Studies, Genes, Modifier, Genome, Animal, Inflammatory Bowel Disease, High-Throughput Nucleotide Sequencing, Inflammatory Bowel Diseases, digestive system diseases, Host-Pathogen Interaction, Mice, Inbred C57BL, Child, Preschool, Host-Pathogen Interactions, NADPH Oxidase 1, Reactive Oxygen Species, Reactive Oxygen Specie, Human
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018

9. Corrigendum to 'European contribution to the study of ROS:A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)' [Redox Biol. 13 (2017) 94-162]

Author

Egea, J., Fabregat, I., Frapart, Y. M., Ghezzi, P., Görlach, A., Kietzmann, T., Kubaichuk, K., Knaus, U. G., Lopez, M. G., Olaso-Gonzalez, G., Petry, A., Schulz, R., Vina, J., Winyard, P., Abbas, K., Ademowo, O. S., Afonso, C. B., Andreadou, I., Antelmann, H., Antunes, F., Aslan, M., Bachschmid, M. M., Barbosa, R. M., Belousov, V., Berndt, C., Bernlohr, D., Bertrán, E., Bindoli, A., Bottari, S. P., Brito, P. M., Carrara, G., Casas, A. I., Chatzi, A., Chondrogianni, N., Conrad, M., Cooke, M. S., Costa, J. G., Cuadrado, A., My-Chan Dang, P., De Smet, B., Debelec-Butuner, B., Dias, I. H.K., Dunn, J. D., Edson, A. J., El Assar, M., El-Benna, J., Ferdinandy, P., Fernandes, A. S., Fladmark, K. E., Förstermann, U., Giniatullin, R., Giricz, Z., Görbe, A., Griffiths, H., Hampl, V., Hanf, A., Herget, J., Hernansanz-Agustín, P., Hillion, M., Huang, J., Ilikay, S., Jansen-Dürr, P., Jaquet, V., Joles, J. A., Kalyanaraman, B., Kaminskyy, D., Karbaschi, M., Kleanthous, M., Klotz, L. O., Korac, B., Korkmaz, K. S., Koziel, R., Kračun, D., Krause, K. H., Křen, V., Krieg, T., Laranjinha, J., Lazou, A., Li, H., Martínez-Ruiz, A., Matsui, R., McBean, G. J., Meredith, S. P., Messens, J., Miguel, V., Mikhed, Y., Milisav, I., Milković, L., Miranda-Vizuete, A., Mojović, M., Monsalve, M., Mouthuy, P. A., Mulvey, J., Münzel, T., Muzykantov, V., Nguyen, I. T.N., Oelze, M., Oliveira, N. G., Palmeira, C. M., Papaevgeniou, N., Pavićević, A., Pedre, B., Peyrot, F., Phylactides, M., Pircalabioru, G. G., Pitt, A. R., Poulsen, H. E., Prieto, I., Rigobello, M. P., Robledinos-Antón, N., Rodríguez-Mañas, L., Rolo, A. P., Rousset, F., Ruskovska, T., Saraiva, N., Sasson, S., Schröder, K., Semen, K., Seredenina, T., Shakirzyanova, A., Smith, G. L., Soldati, T., Sousa, B. C., Spickett, C. M., Stancic, A., Stasia, M. J., Steinbrenner, H., Stepanić, V., Steven, S., Tokatlidis, K., Tuncay, E., Turan, B., Ursini, F., Vacek, J., Vajnerova, O., Valentová, K., Van Breusegem, F., Varisli, L., Veal, E. A., Yalçin, A. S., Yelisyeyeva, O., Žarković, N., Zatloukalová, M., Zielonka, J., Touyz, R. M., Papapetropoulos, A., Grune, T., Lamas, S., Schmidt, H. H.H.W., Di Lisa, F., and Daiber, A.

Published
2018

11. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, R V, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, C G, Fiedler, K, McCarthy, D J, Sullivan, P B, Rodrigues, A, Travis, S P L, Moore, C, Sambrook, J, Ouwehand, W H, Roberts, D J, Danesh, J, Russell, R K, Wilson, D C, Kelsen, J R, Cornall, R, Denson, L A, Kugathasan, S, Knaus, U G, Serra, E G, Anderson, C A, Duerr, R H, McGovern, D Pb, Cho, J, Powrie, F, Li, V Sw, Muise, A M, Uhlig, H H, and Tomlinson, Ian

Subjects
Journal Article, digestive system diseases
Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.Mucosal Immunology advance online publication 1 November 2017. doi:10.1038/mi.2017.74.

Published
2017

12. Corrigendum to 'European contribution to the study of ROS : A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)' [Redox Biol. 13 (2017) 94-162]

Author

Egea, J, Fabregat, I, Frapart, Y M, Ghezzi, P, Görlach, A, Kietzmann, T, Kubaichuk, K, Knaus, U G, Lopez, M G, Olaso-Gonzalez, G, Petry, A, Schulz, R., Vina, J, Winyard, P.J., Abbas, K, Ademowo, O S, Afonso, C B, Andreadou, I, Antelmann, H, Antunes, F, Aslan, M, Bachschmid, M M, Barbosa, M.R.V., Belousov, V, Berndt, C, Bernlohr, D, Bertrán, E, Bindoli, A, Bottari, S P, Brito, P M, Carrara, G, Casas, A I, Chatzi, A, Chondrogianni, N, Conrad, M., Cooke, M S, Gil-da-Costa, Maria J, Cuadrado, A, My-Chan Dang, P, de Smet, M.B.M, Debelec-Butuner, B, Dias, I H K, Dunn, J D, Edson, A J, El Assar, M, El-Benna, J, Ferdinandy, Pter, Fernandes, A S, Fladmark, K E, Förstermann, U, Giniatullin, R, Giricz, Zoltán, Görbe, Anikó, Griffiths, Helen L, Hampl, V, Hanf, A, Herget, J, Hernansanz-Agustín, P, Hillion, M, Huang, J, Ilikay, S, Jansen-Dürr, P, Jaquet, V, Joles, J A, Kalyanaraman, B, Kaminskyy, D, Karbaschi, M, Kleanthous, M, Klotz, L O, Korac, B, Korkmaz, K. S., Koziel, R, Kračun, D, Krause, K H, Křen, V, Krieg, T., Laranjinha, J, Lazou, A, Li, H., Martínez-Ruiz, A, Matsui, R, McBean, G J, Meredith, S P, Messens, J, Miguel, V, Mikhed, Y, Milisav, I, Milković, L, Miranda-Vizuete, A, Mojović, M, Monsalve, M, Mouthuy, P A, Mulvey, J, Münzel, Thomas, Muzykantov, V, Nguyen, I T N, Oelze, M, Oliveira, Nelson Gomes, Palmeira, C M, Papaevgeniou, N, Pavićević, A, Pedre, B, Peyrot, F, Phylactides, M, Pircalabioru, G G, Pitt, A R, Poulsen, H E, Prieto, I, Rigobello, M P, Robledinos-Antón, N, Rodríguez-Mañas, L, Rolo, A P, Rousset, F, Ruskovska, T, Saraiva, N, Sasson, S, Schröder, K, Semen, K, Seredenina, T., Shakirzyanova, A, Smith, Godfrey L, Soldati, T, Sousa, B C, Spickett, C M, Stancic, A, Stasia, M.J., Steinbrenner, H, Stepanić, V, Steven, S, Tokatlidis, K, Tuncay, E, Turan, B, Ursini, F, Vacek, J, Vajnerova, O, Valentová, K, Van Breusegem, F, Varisli, L, Veal, E A, Yalçın, A S, Yelisyeyeva, O, Žarković, N, Zatloukalová, M, Zielonka, J, Touyz, R M, Papapetropoulos, A, Grune, T, Lamas, S, Schmidt, H H H W, Di Lisa, F, Daiber, A, Egea, J, Fabregat, I, Frapart, Y M, Ghezzi, P, Görlach, A, Kietzmann, T, Kubaichuk, K, Knaus, U G, Lopez, M G, Olaso-Gonzalez, G, Petry, A, Schulz, R., Vina, J, Winyard, P.J., Abbas, K, Ademowo, O S, Afonso, C B, Andreadou, I, Antelmann, H, Antunes, F, Aslan, M, Bachschmid, M M, Barbosa, M.R.V., Belousov, V, Berndt, C, Bernlohr, D, Bertrán, E, Bindoli, A, Bottari, S P, Brito, P M, Carrara, G, Casas, A I, Chatzi, A, Chondrogianni, N, Conrad, M., Cooke, M S, Gil-da-Costa, Maria J, Cuadrado, A, My-Chan Dang, P, de Smet, M.B.M, Debelec-Butuner, B, Dias, I H K, Dunn, J D, Edson, A J, El Assar, M, El-Benna, J, Ferdinandy, Pter, Fernandes, A S, Fladmark, K E, Förstermann, U, Giniatullin, R, Giricz, Zoltán, Görbe, Anikó, Griffiths, Helen L, Hampl, V, Hanf, A, Herget, J, Hernansanz-Agustín, P, Hillion, M, Huang, J, Ilikay, S, Jansen-Dürr, P, Jaquet, V, Joles, J A, Kalyanaraman, B, Kaminskyy, D, Karbaschi, M, Kleanthous, M, Klotz, L O, Korac, B, Korkmaz, K. S., Koziel, R, Kračun, D, Krause, K H, Křen, V, Krieg, T., Laranjinha, J, Lazou, A, Li, H., Martínez-Ruiz, A, Matsui, R, McBean, G J, Meredith, S P, Messens, J, Miguel, V, Mikhed, Y, Milisav, I, Milković, L, Miranda-Vizuete, A, Mojović, M, Monsalve, M, Mouthuy, P A, Mulvey, J, Münzel, Thomas, Muzykantov, V, Nguyen, I T N, Oelze, M, Oliveira, Nelson Gomes, Palmeira, C M, Papaevgeniou, N, Pavićević, A, Pedre, B, Peyrot, F, Phylactides, M, Pircalabioru, G G, Pitt, A R, Poulsen, H E, Prieto, I, Rigobello, M P, Robledinos-Antón, N, Rodríguez-Mañas, L, Rolo, A P, Rousset, F, Ruskovska, T, Saraiva, N, Sasson, S, Schröder, K, Semen, K, Seredenina, T., Shakirzyanova, A, Smith, Godfrey L, Soldati, T, Sousa, B C, Spickett, C M, Stancic, A, Stasia, M.J., Steinbrenner, H, Stepanić, V, Steven, S, Tokatlidis, K, Tuncay, E, Turan, B, Ursini, F, Vacek, J, Vajnerova, O, Valentová, K, Van Breusegem, F, Varisli, L, Veal, E A, Yalçın, A S, Yelisyeyeva, O, Žarković, N, Zatloukalová, M, Zielonka, J, Touyz, R M, Papapetropoulos, A, Grune, T, Lamas, S, Schmidt, H H H W, Di Lisa, F, and Daiber, A

Published
2018

13. Corrigendum to 'European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)' [Redox Biol. 13 (2017) 94-162]

Author

CMM Groep Burgering, MS Nefrologie, Regenerative Medicine and Stem Cells, Circulatory Health, Nefro Vasculaire Geneeskunde, Other research (not in main researchprogram), Egea, J, Fabregat, I, Frapart, Y M, Ghezzi, P, Görlach, A, Kietzmann, T, Kubaichuk, K, Knaus, U G, Lopez, M G, Olaso-Gonzalez, G, Petry, A, Schulz, R., Vina, J, Winyard, P.J., Abbas, K, Ademowo, O S, Afonso, C B, Andreadou, I, Antelmann, H, Antunes, F, Aslan, M, Bachschmid, M M, Barbosa, M.R.V., Belousov, V, Berndt, C, Bernlohr, D, Bertrán, E, Bindoli, A, Bottari, S P, Brito, P M, Carrara, G, Casas, A I, Chatzi, A, Chondrogianni, N, Conrad, M., Cooke, M S, Gil-da-Costa, Maria J, Cuadrado, A, My-Chan Dang, P, de Smet, M.B.M, Debelec-Butuner, B, Dias, I H K, Dunn, J D, Edson, A J, El Assar, M, El-Benna, J, Ferdinandy, Pter, Fernandes, A S, Fladmark, K E, Förstermann, U, Giniatullin, R, Giricz, Zoltán, Görbe, Anikó, Griffiths, Helen L, Hampl, V, Hanf, A, Herget, J, Hernansanz-Agustín, P, Hillion, M, Huang, J, Ilikay, S, Jansen-Dürr, P, Jaquet, V, Joles, J A, Kalyanaraman, B, Kaminskyy, D, Karbaschi, M, Kleanthous, M, Klotz, L O, Korac, B, Korkmaz, K. S., Koziel, R, Kračun, D, Krause, K H, Křen, V, Krieg, T., Laranjinha, J, Lazou, A, Li, H., Martínez-Ruiz, A, Matsui, R, McBean, G J, Meredith, S P, Messens, J, Miguel, V, Mikhed, Y, Milisav, I, Milković, L, Miranda-Vizuete, A, Mojović, M, Monsalve, M, Mouthuy, P A, Mulvey, J, Münzel, Thomas, Muzykantov, V, Nguyen, I T N, Oelze, M, Oliveira, Nelson Gomes, Palmeira, C M, Papaevgeniou, N, Pavićević, A, Pedre, B, Peyrot, F, Phylactides, M, Pircalabioru, G G, Pitt, A R, Poulsen, H E, Prieto, I, Rigobello, M P, Robledinos-Antón, N, Rodríguez-Mañas, L, Rolo, A P, Rousset, F, Ruskovska, T, Saraiva, N, Sasson, S, Schröder, K, Semen, K, Seredenina, T., Shakirzyanova, A, Smith, Godfrey L, Soldati, T, Sousa, B C, Spickett, C M, Stancic, A, Stasia, M.J., Steinbrenner, H, Stepanić, V, Steven, S, Tokatlidis, K, Tuncay, E, Turan, B, Ursini, F, Vacek, J, Vajnerova, O, Valentová, K, Van Breusegem, F, Varisli, L, Veal, E A, Yalçın, A S, Yelisyeyeva, O, Žarković, N, Zatloukalová, M, Zielonka, J, Touyz, R M, Papapetropoulos, A, Grune, T, Lamas, S, Schmidt, H H H W, Di Lisa, F, Daiber, A, CMM Groep Burgering, MS Nefrologie, Regenerative Medicine and Stem Cells, Circulatory Health, Nefro Vasculaire Geneeskunde, Other research (not in main researchprogram), Egea, J, Fabregat, I, Frapart, Y M, Ghezzi, P, Görlach, A, Kietzmann, T, Kubaichuk, K, Knaus, U G, Lopez, M G, Olaso-Gonzalez, G, Petry, A, Schulz, R., Vina, J, Winyard, P.J., Abbas, K, Ademowo, O S, Afonso, C B, Andreadou, I, Antelmann, H, Antunes, F, Aslan, M, Bachschmid, M M, Barbosa, M.R.V., Belousov, V, Berndt, C, Bernlohr, D, Bertrán, E, Bindoli, A, Bottari, S P, Brito, P M, Carrara, G, Casas, A I, Chatzi, A, Chondrogianni, N, Conrad, M., Cooke, M S, Gil-da-Costa, Maria J, Cuadrado, A, My-Chan Dang, P, de Smet, M.B.M, Debelec-Butuner, B, Dias, I H K, Dunn, J D, Edson, A J, El Assar, M, El-Benna, J, Ferdinandy, Pter, Fernandes, A S, Fladmark, K E, Förstermann, U, Giniatullin, R, Giricz, Zoltán, Görbe, Anikó, Griffiths, Helen L, Hampl, V, Hanf, A, Herget, J, Hernansanz-Agustín, P, Hillion, M, Huang, J, Ilikay, S, Jansen-Dürr, P, Jaquet, V, Joles, J A, Kalyanaraman, B, Kaminskyy, D, Karbaschi, M, Kleanthous, M, Klotz, L O, Korac, B, Korkmaz, K. S., Koziel, R, Kračun, D, Krause, K H, Křen, V, Krieg, T., Laranjinha, J, Lazou, A, Li, H., Martínez-Ruiz, A, Matsui, R, McBean, G J, Meredith, S P, Messens, J, Miguel, V, Mikhed, Y, Milisav, I, Milković, L, Miranda-Vizuete, A, Mojović, M, Monsalve, M, Mouthuy, P A, Mulvey, J, Münzel, Thomas, Muzykantov, V, Nguyen, I T N, Oelze, M, Oliveira, Nelson Gomes, Palmeira, C M, Papaevgeniou, N, Pavićević, A, Pedre, B, Peyrot, F, Phylactides, M, Pircalabioru, G G, Pitt, A R, Poulsen, H E, Prieto, I, Rigobello, M P, Robledinos-Antón, N, Rodríguez-Mañas, L, Rolo, A P, Rousset, F, Ruskovska, T, Saraiva, N, Sasson, S, Schröder, K, Semen, K, Seredenina, T., Shakirzyanova, A, Smith, Godfrey L, Soldati, T, Sousa, B C, Spickett, C M, Stancic, A, Stasia, M.J., Steinbrenner, H, Stepanić, V, Steven, S, Tokatlidis, K, Tuncay, E, Turan, B, Ursini, F, Vacek, J, Vajnerova, O, Valentová, K, Van Breusegem, F, Varisli, L, Veal, E A, Yalçın, A S, Yelisyeyeva, O, Žarković, N, Zatloukalová, M, Zielonka, J, Touyz, R M, Papapetropoulos, A, Grune, T, Lamas, S, Schmidt, H H H W, Di Lisa, F, and Daiber, A

Published
2018

15. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis

Author

Cooke, G, primary, Kamal, I, additional, Strengert, M, additional, Hams, E, additional, Mawhinney, L, additional, Tynan, A, additional, O’Reilly, C, additional, O’Dwyer, D N, additional, Kunkel, S L, additional, Knaus, U G, additional, Shields, D C, additional, Moller, D R, additional, Bowie, A G, additional, Fallon, P G, additional, Hogaboam, C M, additional, Armstrong, M E, additional, and Donnelly, S C, additional

Published
2017
Full Text
View/download PDF

16. 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

19. Second Interim Report of the Working Group on Aquaculture (WGAQUA)

Author

Bannister, R. (Raymond), Bengtson, D. (David), Boyd, A. (Adele), Boxaspen, K. (Karin), Busby, C. (Corina), Callier, M. (Myriam), Cranford, P. (Peter), Cross, S. (Stephen), Djupevåg, E.M. (Else Marie), Flimlin, G. (Gef), Focken, U. (Ulfert), Gestal, C. (Camino), García-Tasende, M. (Manuel), González-Castro, C. (Carmen), Hareide, H. (Henrik), Iglesias-Estévez, J. (José), Jackson, D. (Dave), Kamermans, P. (Pauline), Knaus, U. (Ulrich), Landry, T. (Thomas), McKindsey, C. (Chris), Moberg, O. (Olav), Moore, H. (Heather), O’Beirn, F. (Francis), Simonsen, K. (Knud), Svåsand, T. (Terje), Strand, O. (Oivind), and ICES

Published
2014

21. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis.

Author

Kunkel, S. L., Cooke, G., Strengert, M., O'Dwyer, D. N., Knaus, U. G., Kamal, I., Hams, E., Mawhinney, L., Tynan, A., O'Reilly, C., Armstrong, M. E., Donnelly, S. C., Fallon, P. G., Shields, D. C., Moller, D. R., Bowie, A. G., and Hogaboam, C. M.

Subjects
SARCOIDOSIS, TOLL-like receptors, GENETIC polymorphisms, PHENOTYPES, ETIOLOGY of diseases, GRANULOMA, GENETICS
Abstract

Background/Introduction: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. Aim: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. Design: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. Methods: Cohorts of Irish sarcoidosis patients (n=228), healthy Irish controls (n=263) and a secondary cohort of American sarcoidosis patients (n=123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. Results: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 Fhomozygous pulmonary sarcoidosis patients resulted in reduced IFN-β and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. Discussion/Conclusion: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker. [ABSTRACT FROM AUTHOR]

Published
2018
Full Text
View/download PDF

22. ROS in gastrointestinal inflammation: Rescue Or Sabotage?

Author

Aviello, G, Knaus, UG, and Knaus, U G

Subjects
OXYGEN in the body, GASTROENTERITIS, NADPH oxidase, IMMUNOLOGICAL tolerance, CELLULAR signal transduction, HOMEOSTASIS, REACTIVE oxygen species, ANIMALS, GASTROINTESTINAL system, INFLAMMATION, OXIDATION-reduction reaction
Abstract

The intestine is composed of many distinct cell types that respond to commensal microbiota or pathogens with immune tolerance and proinflammatory signals respectively. ROS produced by mucosa-resident cells or by newly recruited innate immune cells are essential for antimicrobial responses and regulation of signalling pathways including processes involved in wound healing. Impaired ROS production due to inactivating patient variants in genes encoding NADPH oxidases as ROS source has been associated with Crohn's disease and pancolitis, whereas overproduction of ROS due to up-regulation of oxidases or altered mitochondrial function was linked to ileitis and ulcerative colitis. Here, we discuss recent advances in our understanding of how maintaining a redox balance is crucial to preserve gut homeostasis.Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]

Published
2017
Full Text
View/download PDF

23. NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease

Author

Schwerd, T, Bryant, R V, Pandey, S, Capitani, M, Meran, L, Cazier, J-B, Jung, J, Mondal, K, Parkes, M, Mathew, C G, Fiedler, K, McCarthy, D J, Sullivan, P B, Rodrigues, A, Travis, S P L, Moore, C, Sambrook, J, Ouwehand, W H, Roberts, D J, Danesh, J, Russell, R K, Wilson, D C, Kelsen, J R, Cornall, R, Denson, L A, Kugathasan, S, Knaus, U G, Serra, E G, Anderson, C A, Duerr, R H, McGovern, D PB, Cho, J, Powrie, F, Li, V SW, Muise, A M, and Uhlig, H H

Abstract

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

Published
2018
Full Text
View/download PDF

24. Boswellia and the complement system: A multiherbal drug for multitarget therapy

Author

Wagner, H. and Knaus, U.

Subjects
Inflammation -- Care and treatment -- Research, Organic acids -- Usage -- Health aspects -- Research -- Chemical properties, Boswellia -- Usage -- Health aspects -- Chemical properties -- Research, Biological sciences, Health, Science and technology
Abstract

Because a pathologically prolonged and sustained activation of the complement system is implicated in a variety of inflammatory disorders, from rheumatoid arthritis and glomerulonephritis to systemic lupus erythematodes, we have [...]

Published
2008

31. Activation of the leukocyte NADPH oxidase by protein kinase C in a partially recombinant cell-free system.

Author

Lopes, L R, Hoyal, C R, Knaus, U G, and Babior, B M

Abstract

The leukocyte NADPH oxidase is an enzyme present in phagocytes and B lymphocytes that when activated catalyzes the production of O-2 from oxygen at the expense of NADPH. A correlation between the activation of the oxidase and the phosphorylation of p47(PHOX), a cytosolic oxidase component, is well recognized in whole cells, and direct evidence for a relationship between the phosphorylation of this oxidase component and the activation of the oxidase has been obtained in a number of cell-free systems containing neutrophil membrane and cytosol. Using superoxide dismutase-inhibitable cytochrome c reduction to quantify O-2 production, we now show that p47(PHOX) phosphorylated by protein kinase C activates the NADPH oxidase not only in a cell-free system containing neutrophil membrane and cytosol, but also in a system in which the cytosol is replaced by the recombinant proteins p67(PHOX), Rac2, and phosphorylated p47(PHOX), suggesting that neutrophil plasma membrane plus those three cytosolic proteins are both necessary and sufficient for oxidase activation. In both the cytosol-containing and recombinant cell-free systems, however, activation by SDS yielded greater rates of O-2 production than activation by protein kinase C-phosphorylated p47(PHOX), indicating that a system that employs protein kinase C-phosphorylated p47(PHOX) as the sole activating agent, although more physiological than the SDS-activated system, is nevertheless incomplete.

Published
1999

32. Effects of boswellic acid of Boswellia serrataand other triterpenic acids on the complement system

Author

Knaus, U. and Wagner, H.

Abstract

β-boswellic acid (BA), one major constituent of the resin of Boswellia serrataand other triterpenic acids of plant origin (crataegolic-, ursolic-, oleanolic- and glycyrrhetic acid) were found to possess anti-complementary activity in the classical and in the alternative complement pathway. Significant reduction of immunohemolysis in vitrowas observed at BA concentrations between 0.005–0.1 mM with an IC50value of about 10 μmol/l.

Published
1996
Full Text
View/download PDF

34. Two signaling mechanisms for activation of alphaM beta2 avidity in polymorphonuclear neutrophils.

Author

Jones, S L, Knaus, U G, Bokoch, G M, and Brown, E J

Abstract

Circulating polymorphonuclear neutrophils (PMN) are quiescent, nonadherent cells that rapidly activate at sites of inflammation, where they develop the capacity to perform a repertoire of functions that are essential for host defense. Induction of integrin-mediated adhesion, which requires an increase in integrin avidity, is critical for the development of these effector functions. Although a variety of stimuli can activate integrins in PMN, the signaling cascades involved are unclear. Phosphatidylinositol (PI) 3-kinase has been implicated in integrin activation in a variety of cells, including PMN. In this work, we have examined activation of the PMN integrin alphaM beta2, assessing both adhesion and generation of the epitope recognized by the activation-specific antibody CBRM1/5. We have found that PI 3-kinase has a role in activation of alphaM beta2 by immune complexes, but we have found no role for it in alphaM beta2 activation by ligands for trimeric G protein-coupled receptors, including formylmethionylleucylphenylalanine (fMLP), interleukin-8, and C5a. Cytochalasin D inhibition suggests a role for the actin cytoskeleton in immune complex activation of alphaM beta2, but cytochalasin has no effect on fMLP-induced activation. Similarly, immune complex activation of the Rac/Cdc42-dependent serine/threonine kinase Pak1 is blocked by PI 3-kinase inhibitors, but fMLP-induced activation is not. These results demonstrate that two signaling pathways exist in PMN for activation of alphaM beta2. One, induced by FcgammaR ligation, is PI 3-kinase-dependent and requires the actin cytoskeleton. The second, initiated by G protein-linked receptors, is PI 3-kinase-independent and cytochalasin-insensitive. Pak1 may be in a final common pathway leading to activation of alphaM beta2.

Published
1998

35. Interaction of the Nck adapter protein with p21-activated kinase (PAK1).

Author

Bokoch, G M, Wang, Y, Bohl, B P, Sells, M A, Quilliam, L A, and Knaus, U G

Abstract

The p21-activated kinases (PAKs) link G protein-coupled receptors and growth factor receptors (S. Dharmawardhane, R. H. Daniels, and G. M. Bokoch, submitted for publication) to activation of MAP kinase cascades and to cytoskeletal reorganization (M. A. Sells, U. G. Knaus, D. Ambrose, S. Bagrodia, G. M. Bokoch, and J. Chernoff, submitted for publication). The proteins that interact with PAK to mediate its cellular effects and to couple it to upstream receptors are unknown. We describe here a specific interaction of the Nck adapter molecule with PAK1 both in vitro and in vivo. PAK1 and Nck associate in COS-7 and Swiss 3T3 cells constitutively, but this interaction is strengthened upon platelet-derived growth factor receptor stimulation. We show that Nck binds to PAK1 through its second Src homology 3 (SH3) domain, while PAK1 interacts with Nck via the first proline-rich SH3 binding motif at its amino terminus. The interaction of active PAK1 with Nck leads to the phosphorylation of Nck at multiple sites. Association of Nck with PAK1 may serve to link this important regulatory kinase to cell activation by growth factor receptors.

Published
1996

36. A GTPase-independent mechanism of p21-activated kinase activation. Regulation by sphingosine and other biologically active lipids.

Author

Bokoch, G M, Reilly, A M, Daniels, R H, King, C C, Olivera, A, Spiegel, S, and Knaus, U G

Abstract

p21-activated kinases (PAKs) are serine/threonine kinases that have been identified as targets for the small GTPases Rac and Cdc42. PAKs have been implicated in cytoskeletal regulation, stimulation of mitogen-activated protein kinase cascades, and in control of the phagocyte NADPH oxidase. Membrane targeting of PAK1 induced increased kinase activity in a GTPase-independent manner, suggesting that other mechanisms for PAK regulation exist. We observed concentration- and time-dependent activation of PAK1 by sphingosine and several related long chain sphingoid bases but not by ceramides or a variety of other lipids. Although phospholipids were generally ineffective, phosphatidic acid and phosphatidylinositol also had stimulatory effects on PAK1. Lipid stimulation induced a similar level of PAK1 activity as did stimulation by GTPases, and the patterns of PAK1 autophosphorylation determined after partial tryptic digestion and two-dimensional peptide analysis were similar with each class of activator. Lipid stimulation of PAK1 activity was dependent upon intact PAK kinase activity, as indicated by studies with a kinase-dead PAK1 mutant. Treatment of COS-7 cells expressing wild type PAK1 with sphingosine, fumonisin B, or sphingomyelinase, all of which are able to elevate the levels of free sphingosine, induced increased activity of PAK1 as determined using a p47(phox) peptide substrate. Studies using PAK1 mutants suggest that lipids act at a site overlapping or identical to the GTPase-binding domain on PAK. The inactive sphingosine derivative N,N-dimethylsphingosine was an effective inhibitor of PAK1 activation in response to either sphingosine or Cdc42. Our results demonstrate a novel GTPase-independent mechanism of PAK activation and, additionally, suggest that PAK(s) may be important mediators of the biological effects of sphingolipids.

Published
1998

37. The renaturable 69- and 63-kDa protein kinases that undergo rapid activation in chemoattractant-stimulated guinea pig neutrophils are p21-activated kinases.

Author

Ding, J, Knaus, U G, Lian, J P, Bokoch, G M, and Badwey, J A

Abstract

Neutrophils stimulated with the chemoattractant fMet-Leu-Phe (fMLP) are known to exhibit rapid activation of four protein kinases with molecular masses of approximately 69, approximately 63, approximately 49, and approximately 40-kDa. Activation of these kinases is blocked by antagonists of phosphatidylinositol 3-kinase and type 1 and/or type 2A protein phosphatases. These enzymes can be detected by their ability to undergo renaturation and catalyze the phosphorylation of a peptide substrate that corresponds to amino acid residues 297-331 of the 47-kDa subunit of the NADPH-oxidase complex fixed within a gel. In this report, we demonstrate that an antibody generated to a fusion protein containing amino acid residues 175-306 of p21-activated protein kinase 1 (Pak1) reacts with three proteins in guinea pig neutrophils with molecular masses in the 60-70-kDa range during Western blotting. This antibody immunoprecipitates both the 69- and 63-kDa renaturable kinases from lysates of stimulated cells along with a minor 60-kDa kinase. No activities were observed for any of these enzymes in immunoprecipitates from unstimulated neutrophils. However, addition of ATP and activated Rac 1 or Cdc42 to immunoprecipitates from unstimulated cells resulted in the stimulation of two renaturable kinases with molecular masses in the 69- and 63-kDa range. These immunoprecipitates also contained two novel protein kinases with masses of approximately49 and 40 kDa that were selectively activated by Cdc42. In contrast, the 69- and 63-kDa kinases were not immunoprecipitated from lysates of stimulated neutrophils with an antibody to Pak2 or with nonimmune serum. These data indicate that the renaturable 69- and 63-kDa kinases are Paks and reveal some of the upstream events that are necessary for the rapid activation of this family of protein kinases in neutrophils.

Published
1996

38. Structural requirements for PAK activation by Rac GTPases.

Author

Knaus, U G, Wang, Y, Reilly, A M, Warnock, D, and Jackson, J H

Abstract

The Rho family GTPases, Rac1 and Rac2, regulate a variety of cellular functions including cytoskeletal reorganization, the generation of reactive oxygen species, G1 cell cycle progression and, in concert with Ras, oncogenic transformation. Among the many putative protein targets identified for Rac (and/or Cdc42), the Ser/Thr kinase p21-activated kinase (PAK) is a prime candidate for mediating some of Rac's cellular effects. This report shows that Rac1 binds to and stimulates the kinase activity of PAK1 approximately 2- and 4-5-fold, respectively, better than Rac2. Mutational analysis was employed to determine the structural elements on Rac and PAK that are important for optimal binding and activation. The most notable difference between the highly homologous Rac isomers is the composition of their C-terminal polybasic domains. Mutation of these six basic residues in Rac1 to neutral amino acids dramatically decreased the ability of Rac1 to bind PAK1 and almost completely abolished its ability to stimulate PAK activity. Moreover, replacing the highly charged polybasic domain of Rac1 with the less charged domain of Rac2 (and vice versa) completely reversed the PAK binding/activation properties of the two Rac isomers. Thus, polybasic domain differences account for the disparate abilities of Rac1 and Rac2 to activate PAK. PAK proteins also contain a basic region, consisting of three contiguous lysine residues (Lys66-Lys67-Lys68), which lies outside of the previously identified Cdc42/Rac-binding domain. Mutation of these Lys residues to neutral residues decreased PAK binding to activated Rac1 and Rac2 (but not Cdc42) and greatly reduced PAK1 activation by Rac1, Rac2, and Cdc42 proteins in vivo. In contrast, mutation of lysines 66-68 to basic Arg residues did not decrease (and in some cases enhanced) the ability of Rac1, Rac2, and Cdc42 to bind and activate PAK1. Our studies suggest that the polybasic domain of Rac is a novel effector domain that may allow the two Rac isomers to activate different effector proteins. In addition, our results indicate that a basic region in PAK is required for PAK activation and that binding of Rac/Cdc42 to PAK is not sufficient for kinase activation.

Published
1998

42. Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1.

Author

Zhang, S, Han, J, Sells, M A, Chernoff, J, Knaus, U G, Ulevitch, R J, and Bokoch, G M

Abstract

The stress-activated p38 mitogen-activated protein (MAP) kinase defines a subgroup of the mammalian MAP kinases that appear to play a key role in regulating inflammatory responses. Co-expression of constitutively active forms of Rac and Cdc42 leads to activation of p38 while dominant negative Rac and Cdc42 inhibit the ability of interleukin-1 to increase p38 activity. p21-activated kinase 1 (Pak1) is a potential mediator of Rac/Cdc42 signaling, and we observe that Pak1 stimulates p38 activity. A dominant negative Pak1 suppresses both interleukin-1- and Rac/Cdc42-induced p38 activity. Rac and Cdc42 appear to regulate a protein kinase cascade initiated at the level of Pak and leading to activation of p38 and JNK.

Published
1995

43. Cellular ROS imaging with hydro-Cy3 dye is strongly influenced by mitochondrial membrane potential

Author

Gabriella Aviello, Ulla G. Knaus, Dmitri B. Papkovsky, Alexander V. Zhdanov, Zhdanov, A. V., Aviello, G., Knaus, U. G., and Papkovsky, D. B.

Subjects
0301 basic medicine, Oligomycin, Biophysics, Carbocyanine, Mitochondrion, Biology, Biochemistry, Fluorescence, Mice, 03 medical and health sciences, chemistry.chemical_compound, Superoxides, Live cell imaging, Cell Line, Tumor, Fluorescence microscope, Animals, Humans, Molecular Biology, Membrane Potential, Mitochondrial, chemistry.chemical_classification, Membrane potential, Reactive oxygen species, Animal, Superoxide, ROS probe, Carbocyanines, Hydrocyanines, HCT116 Cells, Hydrocyanine, Photobleaching, Mitochondria, Mice, Inbred C57BL, 030104 developmental biology, chemistry, ROS probes, HCT116 Cell, Oligomycins, Mitochondrial membrane potential, Reactive Oxygen Species, Reactive Oxygen Specie, Hydro-Cy3, Oxidation-Reduction, Human
Abstract

Background Hydrocyanines are widely used as fluorogenic probes to monitor reactive oxygen species (ROS) generation in cells. Their brightness, stability to autoxidation and photobleaching, large signal change upon oxidation, pH independence and red/near infrared emission are particularly attractive for imaging ROS in live tissue. Methods Using confocal fluorescence microscopy we have examined an interference of mitochondrial membrane potential (ΔΨm) with fluorescence intensity and localisation of a commercial hydro-Cy3 probe in respiring and non-respiring colon carcinoma HCT116 cells. Results We found that the oxidised (fluorescent) form of hydro-Cy3 is highly homologous to the common ΔΨm-sensitive probe JC-1, which accumulates and aggregates only in ‘energised’ negatively charged mitochondrial matrix. Therefore, hydro-Cy3 oxidised by hydroxyl and superoxide radicals tends to accumulate in mitochondrial matrix, but dissipates and loses brightness as soon as ΔΨm is compromised. Experiments with mitochondrial inhibitor oligomycin and uncoupler FCCP, as well as a common ROS producer paraquat demonstrated that signals of the oxidised hydro-Cy3 probe rapidly and strongly decrease upon mitochondrial depolarisation, regardless of the rate of cellular ROS production. Conclusions While analysing ROS-derived fluorescence of commercial hydrocyanine probes, an accurate control of ΔΨm is required. General significance If not accounted for, non-specific effect of mitochondrial polarisation state on the behaviour of oxidised hydrocyanines can cause artefacts and data misinterpretation in ROS studies.

Published
2017

44. Defects in Nicotinamide-adenine Dinucleotide Phosphate Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease

Author

Sandeep S. Dhillon, Billy Bourke, Anne M. Griffiths, Conghui H. Guo, Dermot P.B. McGovern, James H. Doroshow, Inga Peter, Luis Alvarez, Lidija Kovačič, Abdul Elkadri, Scott B. Snapper, Aleixo M. Muise, Ken Y. Hui, Judy H. Cho, Gabriella Aviello, Steven R. Brant, Cornelia Thoeni, Kim O’Neill, Holm H. Uhlig, John H. Brumell, PK Hayes, Ulla G. Knaus, Mark S. Silverberg, Hayes, P., Dhillon, S., O'Neill, K., Thoeni, C., Hui, K. Y., Elkadri, A., Guo, C. H., Kovacic, L., Aviello, G., Alvarez, L. A., Griffiths, A. M., Snapper, S. B., Brant, S. R., Doroshow, J. H., Silverberg, M. S., Peter, I., Mcgovern, D. P. B., Cho, J., Brumell, J. H., Uhlig, H. H., Bourke, B., Muise, A. M., and Knaus, U. G.

Subjects
WT, wild type, NADPH Oxidase, Inflammatory bowel disease, 0302 clinical medicine, Chronic granulomatous disease, Cellular localization, Original Research, NOX1, NADPH oxidase 1, VEOIBD, very early onset inflammatory bowel disease, 0303 health sciences, NADPH oxidase, IBD, inflammatory bowel disease, HA, human influenza hemagglutinin, Gastroenterology, NADPH Oxidase 1, NADPH, nicotinamide-adenine dinucleotide phosphate, 3. Good health, medicine.anatomical_structure, NOX1, cardiovascular system, 030211 gastroenterology & hepatology, SNP, single-nucleotide polymorphism, Reactive Oxygen Specie, AJ, Ashkenazi Jewish, PMA, phorbol 12-myristate 13-acetate, PBS, phosphate-buffered saline, Biology, MAF, minor allele frequency, Microbiology, 03 medical and health sciences, PAS, periodic acid–Schiff, ROS, reactive oxygen species, medicine, lcsh:RC799-869, DUOX2, VEOIBD, 030304 developmental biology, DUOX2, dual oxidase 2, FAD, flavin adenine nucleotide, Hepatology, Inflammatory Bowel Disease, CGD, chronic granulomatous disease, Dual oxidase 2, medicine.disease, UC, ulcerative colitis, Immunology, Paneth cell, biology.protein, lcsh:Diseases of the digestive system. Gastroenterology, Reactive Oxygen Species
Abstract

Background & Aims: Defects in intestinal innate defense systems predispose patients to inflammatory bowel disease (IBD). Reactive oxygen species (ROS) generated by nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases in the mucosal barrier maintain gut homeostasis and defend against pathogenic attack. We hypothesized that molecular genetic defects in intestinal NADPH oxidases might be present in children with IBD. Methods: After targeted exome sequencing of epithelial NADPH oxidases NOX1 and DUOX2 on 59 children with very early onset inflammatory bowel disease (VEOIBD), the identified mutations were validated using Sanger Sequencing. A structural analysis of NOX1 and DUOX2 variants was performed by homology in silico modeling. The functional characterization included ROS generation in model cell lines and in in vivo transduced murine crypts, protein expression, intracellular localization, and cell-based infection studies with the enteric pathogens Campylobacter jejuni and enteropathogenic Escherichia coli. Results: We identified missense mutations in NOX1 (c.988G>A, p.Pro330Ser; c.967G>A, p.Asp360Asn) and DUOX2 (c.4474G>A, p.Arg1211Cys; c.3631C>T, p.Arg1492Cys) in 5 of 209 VEOIBD patients. The NOX1 p.Asp360Asn variant was replicated in a male Ashkenazi Jewish ulcerative colitis cohort. Patients with both NOX1 and DUOX2 variants showed abnormal Paneth cell metaplasia. All NOX1 and DUOX2 variants showed reduced ROS production compared with wild-type enzymes. Despite appropriate cellular localization and comparable pathogen-stimulated translocation of altered oxidases, cells harboring NOX1 or DUOX2 variants had defective host resistance to infection with C. jejuni. Conclusions: This study identifies the first inactivating missense variants in NOX1 and DUOX2 associated with VEOIBD. Defective ROS production from intestinal epithelial cells constitutes a risk factor for developing VEOIBD. Keywords: Inflammatory Bowel Disease, NADPH Oxidase, NOX1, DUOX2, Reactive Oxygen Species, VEOIBD

Published
2015
Full Text
View/download PDF

45. Defensive Mutualism Rescues NADPH Oxidase Inactivation in Gut Infection

Author

Malgorzata Kubica, Dmitri B. Papkovsky, Rosanne Y. Hertzberger, Lorraine Brennan, Gabriella Aviello, Billy Bourke, Marie-Hélène Paclet, Alexander V. Zhdanov, Gratiela Gradisteanu Pircalabioru, Ulla G. Knaus, Pircalabioru, G., Aviello, G., Kubica, M., Zhdanov, A., Paclet, M. -H., Brennan, L., Hertzberger, R., Papkovsky, D., Bourke, B., and Knaus, U. G.

Subjects
0301 basic medicine, Virulence, NADPH Oxidase, Biology, Granulomatous Disease, Chronic, Microbiology, 03 medical and health sciences, Mice, 0302 clinical medicine, Intestinal mucosa, Virology, medicine, Animals, Intestinal Mucosa, Symbiosis, Lactobacillu, chemistry.chemical_classification, Reactive oxygen species, NADPH oxidase, Animal, Enterobacteriaceae Infections, NOX4, NADPH Oxidases, medicine.disease, Enterobacteriaceae Infection, Intestinal epithelium, Dysbiosi, Gastrointestinal Microbiome, Mice, Inbred C57BL, Lactobacillus, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, NOX1, Immunology, cardiovascular system, biology.protein, Citrobacter rodentium, Dysbiosis, Parasitology, Reactive Oxygen Specie, Reactive Oxygen Species
Abstract

NOX/DUOX family of NADPH oxidases are expressed in diverse tissues and are the primary enzymes for the generation of reactive oxygen species (ROS). The intestinal epithelium expresses NOX1, NOX4, and DUOX2, whose functions are not well understood. To address this, we generated mice with complete or epithelium-restricted deficiency in the obligatory NOX dimerization partner Cyba (p22(phox)). We discovered that NOX1 regulates DUOX2 expression in the intestinal epithelium, which magnified the epithelial ROS-deficiency. Unexpectedly, epithelial deficiency of Cyba resulted in protection from C. rodentium and L. monocytogenes infection. Microbiota analysis linked epithelial Cyba deficiency to an enrichment of H2O2-producing bacterial strains in the gut. In particular, elevated levels of lactobacilli physically displaced and attenuated C. rodentium virulence by H2O2-mediated suppression of the virulence-associated LEE pathogenicity island. This transmissible compensatory adaptation relied on environmental factors, an important consideration for prevention and therapy of enteric disease.

Published
2015

46. Immunologically active metallic ion-containing polysaccharides of Achyrocline satureioides

Author

L. Tubaro, Hildebert Wagner, Ulla G. Knaus, J. Puhlmann, W. Schaefer, Puhlmann, J., Knaus, U., Tubaro, Aurelia, Schaefer, W., and Wagner, H.

Subjects
chemistry.chemical_classification, Complement Inactivator Proteins, Chromatography, Plants, Medicinal, Chemistry, Size-exclusion chromatography, Molecular Sequence Data, Plant Science, General Medicine, Horticulture, Carbohydrate, Polysaccharide, Biochemistry, In vitro, Metal, Column chromatography, Carbohydrate Sequence, In vivo, Metals, visual_art, visual_art.visual_art_medium, Pectins, Achyrocline satureioides, Molecular Biology
Abstract

Two homogeneous, metallic ion-containing pectic polysaccharides with mean M r s of 7600 and 15 000 were isolated from dried aerial parts of Achyrocline satureioides by anion exchange column chromatography on DEAE-Sepharose CL-6B and gel filtration column chromatography on Fractogel TSK HW-50 (S). The structures, as determined by methylation analysis, carboxyl reduction, and partial acid hydrolysis, were shown to be rhamnogalacturonans. Both pectins show a pronounced anticomplementary effect in vitro . The larger carbohydrate AS 4 of higher M r exerts anti-inflammatory activity and a strong enhancement of phagocytosis in vivo .

Published
1992

47. Aquaponic growth of basil (Ocimum basilicum) with African catfish (Clarias gariepinus) in standard substrate combined with a Humicacid Fiber-Substrate (HFS).

Author

Knaus U, Hübner DH, Küchenmeister C, Appelbaum S, Iten W, and Palm HW

Subjects
Animals, Fertilizers, Soil chemistry, Plant Leaves growth & development, Plant Leaves metabolism, Chlorophyll metabolism, Ocimum basilicum growth & development, Ocimum basilicum metabolism, Catfishes growth & development, Aquaculture methods
Abstract

A major challenge in agriculture, horticulture and aquaponics practices is the reduction of mineral fertilisers and peat to reduce CO 2 emissions and increase sustainability. This study used a three-phase-natural fertiliser, the Humicacid Fiber-Substrate (HFS), made from natural regenerative organic and mineral-fractions (Humus-Mineral-Complex), to reduce the peat content in plant pots for aquaponics farming. Basil (Ocimum basilicum) growth was compared with i) 100% standard media substrate ("Einheitserde", white peat 80%, clay 20%), and ii) 85% "Einheitserde" and 15% of HFS under irrigation with aquaculture process waters from an extensive and intensive production of African catfish (Clarias gariepinus) under coupled aquaponic conditions. The substitution with 15% HFS and use of intensive fish water resulted in comparable plant growth to a fertiliser solution as control, and in higher leaf width and leaf green weight and lower root dry weight compared with the standard media substrate "Einheitserde". Basil leaf chlorophyll content from the aquaponics was higher compared with local market plants. This suggests the possible substitution of the peat substrate "Einheitserde" with at least 15% HFS to reduce the natural peat fraction. Further studies on crop-specific substrates are needed to reduce peat in aquaponics farming plant cultivation., (© 2024. The Author(s).)

Published
2024
Full Text
View/download PDF

48. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis.

Author

Cooke G, Kamal I, Strengert M, Hams E, Mawhinney L, Tynan A, O'Reilly C, O'Dwyer DN, Kunkel SL, Knaus UG, Shields DC, Moller DR, Bowie AG, Fallon PG, Hogaboam CM, Armstrong ME, and Donnelly SC

Subjects
Adolescent, Adult, Aged, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Ireland, Logistic Models, Male, Middle Aged, Phenotype, Young Adult, Polymorphism, Single Nucleotide, Sarcoidosis, Pulmonary genetics, Toll-Like Receptor 3 genetics
Abstract

Background/introduction: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available., Aim: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients., Design: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis., Methods: Cohorts of Irish sarcoidosis patients (n = 228), healthy Irish controls (n = 263) and a secondary cohort of American sarcoidosis patients (n = 123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses., Results: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-β and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients., Discussion/conclusion: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker.

Published
2018
Full Text
View/download PDF

49. Corrigendum to "European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)" [Redox Biol. 13 (2017) 94-162].

Author

Egea J, Fabregat I, Frapart YM, Ghezzi P, Görlach A, Kietzmann T, Kubaichuk K, Knaus UG, Lopez MG, Olaso-Gonzalez G, Petry A, Schulz R, Vina J, Winyard P, Abbas K, Ademowo OS, Afonso CB, Andreadou I, Antelmann H, Antunes F, Aslan M, Bachschmid MM, Barbosa RM, Belousov V, Berndt C, Bernlohr D, Bertrán E, Bindoli A, Bottari SP, Brito PM, Carrara G, Casas AI, Chatzi A, Chondrogianni N, Conrad M, Cooke MS, Costa JG, Cuadrado A, My-Chan Dang P, De Smet B, Debelec-Butuner B, Dias IHK, Dunn JD, Edson AJ, El Assar M, El-Benna J, Ferdinandy P, Fernandes AS, Fladmark KE, Förstermann U, Giniatullin R, Giricz Z, Görbe A, Griffiths H, Hampl V, Hanf A, Herget J, Hernansanz-Agustín P, Hillion M, Huang J, Ilikay S, Jansen-Dürr P, Jaquet V, Joles JA, Kalyanaraman B, Kaminskyy D, Karbaschi M, Kleanthous M, Klotz LO, Korac B, Korkmaz KS, Koziel R, Kračun D, Krause KH, Křen V, Krieg T, Laranjinha J, Lazou A, Li H, Martínez-Ruiz A, Matsui R, McBean GJ, Meredith SP, Messens J, Miguel V, Mikhed Y, Milisav I, Milković L, Miranda-Vizuete A, Mojović M, Monsalve M, Mouthuy PA, Mulvey J, Münzel T, Muzykantov V, Nguyen ITN, Oelze M, Oliveira NG, Palmeira CM, Papaevgeniou N, Pavićević A, Pedre B, Peyrot F, Phylactides M, Pircalabioru GG, Pitt AR, Poulsen HE, Prieto I, Rigobello MP, Robledinos-Antón N, Rodríguez-Mañas L, Rolo AP, Rousset F, Ruskovska T, Saraiva N, Sasson S, Schröder K, Semen K, Seredenina T, Shakirzyanova A, Smith GL, Soldati T, Sousa BC, Spickett CM, Stancic A, Stasia MJ, Steinbrenner H, Stepanić V, Steven S, Tokatlidis K, Tuncay E, Turan B, Ursini F, Vacek J, Vajnerova O, Valentová K, Van Breusegem F, Varisli L, Veal EA, Yalçın AS, Yelisyeyeva O, Žarković N, Zatloukalová M, Zielonka J, Touyz RM, Papapetropoulos A, Grune T, Lamas S, Schmidt HHHW, Di Lisa F, and Daiber A

Published
2018
Full Text
View/download PDF

50. Reduction of falls and fractures after permanent pacemaker implantation in elderly patients with sinus node dysfunction.

Author

Brenner R, Ammann P, Yoon SI, Christen S, Hellermann J, Girod G, Knaus U, Duru F, Krasniqi N, Ramsay D, Sticherling C, Lippuner K, and Kühne M

Subjects
Age Factors, Aged, Aged, 80 and over, Aging, Female, Humans, Male, Prospective Studies, Retrospective Studies, Risk Factors, Sick Sinus Syndrome complications, Sick Sinus Syndrome diagnosis, Sick Sinus Syndrome physiopathology, Switzerland, Time Factors, Treatment Outcome, Accidental Falls prevention & control, Cardiac Pacing, Artificial, Pacemaker, Artificial, Sick Sinus Syndrome therapy
Abstract

Aims: Elderly patients with sinus node dysfunction (SND) are at increased risk of falls with possible injuries. However, the incidence of these adverse events and its reduction after permanent pacemaker (PPM) implantation are not known., Methods and Results: Eighty-seven patients (mean [SD] age 75.4 [8.3] years, 51% women) with SND and an indication for cardiac pacing were included and were examined by a standardized interview targeting fall history. The incidence and total number of falls, falls with injury, falls requiring treatment, and falls resulting in a fracture were assessed for the time period of 12 months before (retrospectively) and after PPM implantation (prospectively). Furthermore, symptoms such as syncope, dizziness, and dyspnea were evaluated before and after PPM implantation. The implantation of a PPM was associated with a reduced proportion of patients experiencing at least one fall by 71% (from 53 to 15%, P < 0.001) and a reduction of the absolute number of falls by 90% (from 127 to 13, P < 0.001) during the 12 months before vs. after PPM implant. Falls with injury (28 vs. 10%, P = 0.005), falls requiring medical attention (31 vs. 8%, P < 0.001), and falls leading to fracture (8 vs. 0%, P = 0.013) were similarly reduced. Notably, fewer patients had syncope (4 vs. 45%, P < 0.001) and dizziness after PPM implantation (12 vs. 45%, P < 0.001)., Conclusion: Falls, fall-related injuries, and fall-related fractures are frequent in SND patients. Permanent pacemaker implantation is associated with a significantly reduced risk of these adverse events, although no causal relationship could be established due to the study design., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Published
2017
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results