50 results on '"Thiersch M"'
Search Results
2. The Differential Role of Jak/Stat Signaling in Retinal Degeneration
- Author
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Lange, C., Thiersch, M., Samardzija, M., Grimm, C., Anderson, Robert E., editor, Hollyfield, Joe G., editor, and LaVail, Matthew M., editor
- Published
- 2010
- Full Text
- View/download PDF
3. Transcriptomic analysis of the mouse retina after acute and chronic normobaric and hypobaric hypoxia
- Author
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Ebner, L J A, Samardzija, M, Storti, F, Todorova, V, Karademir, D, Behr, J, Simpson, F, Thiersch, M, Grimm, C, Ebner, L J A, Samardzija, M, Storti, F, Todorova, V, Karademir, D, Behr, J, Simpson, F, Thiersch, M, and Grimm, C
- Abstract
Oxygen delivery to the retinal pigment epithelium and the outer retina is essential for metabolism, function, and survival of photoreceptors. Chronically reduced oxygen supply leads to retinal pathologies in patients and causes age-dependent retinal degeneration in mice. Hypoxia can result from decreased levels of inspired oxygen (normobaric hypoxia) or reduced barometric pressure (hypobaric hypoxia). Since the response of retinal cells to chronic normobaric or hypobaric hypoxia is mostly unknown, we examined the effect of six hypoxic conditions on the retinal transcriptome and photoreceptor morphology. Mice were exposed to short- and long-term normobaric hypoxia at 400 m or hypobaric hypoxia at 3450 m above sea level. Longitudinal studies over 11 weeks in normobaric hypoxia revealed four classes of genes that adapted differentially to the hypoxic condition. Seventeen genes were specifically regulated in hypobaric hypoxia and may affect the structural integrity of the retina, resulting in the shortening of photoreceptor segment length detected in various hypoxic groups. This study shows that retinal cells have the capacity to adapt to long-term hypoxia and that consequences of hypobaric hypoxia differ from those of normobaric hypoxia. Our datasets can be used as references to validate and compare retinal disease models associated with hypoxia.
- Published
- 2021
4. The Differential Role of Jak/Stat Signaling in Retinal Degeneration
- Author
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Lange, C., primary, Thiersch, M., additional, Samardzija, M., additional, and Grimm, C., additional
- Published
- 2009
- Full Text
- View/download PDF
5. Can iron storage disease be induced by a chronic infection such as tuberculosis in Asian elephants (Elephas maximus)?
- Author
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dPB I&I, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, Ruetten, M., Steinmetz, H., Thiersch, M., Kik, M., Gassmann, M., dPB I&I, dPB CR, Veterinair Pathologisch Diagnostisch Cnt, Ruetten, M., Steinmetz, H., Thiersch, M., Kik, M., and Gassmann, M.
- Published
- 2019
6. Can iron storage disease be induced by a chronic infection such as tuberculosis in Asian elephants (Elephas maximus)?
- Author
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Ruetten, M., primary, Steinmetz, H., additional, Thiersch, M., additional, Kik, M., additional, and Gassmann, M., additional
- Published
- 2019
- Full Text
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7. Reduced cancer mortality at high altitude: The role of glucose, lipids, iron and physical activity
- Author
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Thiersch, M., primary, Swenson, E.R., additional, Haider, T., additional, and Gassmann, M., additional
- Published
- 2017
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8. Nonessential role of beta3 and beta5 integrin subunits for efficient clearance of cellular debris after light-induced photoreceptor degeneration
- Author
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Joly, S, Samardzija, M, Wenzel, A, Thiersch, M, Grimm, C, University of Zurich, and Joly, S
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10018 Ophthalmology Clinic ,2809 Sensory Systems ,10076 Center for Integrative Human Physiology ,2804 Cellular and Molecular Neuroscience ,570 Life sciences ,biology ,610 Medicine & health ,2731 Ophthalmology - Published
- 2009
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9. Leukemia inhibitory factor extends the lifespan of injured photoreceptors in vivo
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Joly, S, Lange, C, Thiersch, M, Samardzija, M, Grimm, C, University of Zurich, and Grimm, C
- Subjects
10018 Ophthalmology Clinic ,10076 Center for Integrative Human Physiology ,570 Life sciences ,biology ,2800 General Neuroscience ,610 Medicine & health - Published
- 2008
10. The differential role of Jak/STAT signaling in retinal degeneration
- Author
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Anderson, R E, LaVail, M M, Hollyfield, J G, Anderson, R E ( R E ), LaVail, M M ( M M ), Hollyfield, J G ( J G ), Lange, C, Thiersch, M, Samardzija, M, Grimm, C; https://orcid.org/0000-0001-9318-4352, Anderson, R E, LaVail, M M, Hollyfield, J G, Anderson, R E ( R E ), LaVail, M M ( M M ), Hollyfield, J G ( J G ), Lange, C, Thiersch, M, Samardzija, M, and Grimm, C; https://orcid.org/0000-0001-9318-4352
- Abstract
Retinal degenerative diseases are a major cause of severe visual impairment or blindness in humans. To develop therapeutic strategies it is of particular importance to understand the molecular mechanisms taking place during the progression of the disease. Genes and proteins of the Janus kinase/Signal Transducer and Activator of Transcription (Jak/STAT) signaling pathway have been shown to play an important role in models of retinal degeneration (RD). Here we investigated the expression of additional genes involved in the Jak/STAT pathway in an induced (light exposure) and an inherited (rd1 mouse) model of RD. We show that STAT mRNAs as well as the Jak2/shp-1 pathway are differentially regulated in the two models. In contrast, we show that Jak3 mRNA is upregulated in both, the light damaged and the degenerative retina of the rd1 mouse. This common answer to probably different apoptotic stimuli suggests a prominent role for Jak3 in the damaged retina and could therefore be interesting for further investigations.
- Published
- 2010
11. The hypoxic transcriptome of the retina: identification of factors with potential neuroprotective activity
- Author
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Anderson, R E, Anderson, R E ( R E ), Thiersch, M, Raffelsberger, W, Frigg, E, Samardzija, M, Blank, P, Poch, O, Grimm, C; https://orcid.org/0000-0001-9318-4352, Anderson, R E, Anderson, R E ( R E ), Thiersch, M, Raffelsberger, W, Frigg, E, Samardzija, M, Blank, P, Poch, O, and Grimm, C; https://orcid.org/0000-0001-9318-4352
- Published
- 2008
12. In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death
- Author
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Samardzija, M., primary, Tanimoto, N., additional, Kostic, C., additional, Beck, S., additional, Oberhauser, V., additional, Joly, S., additional, Thiersch, M., additional, Fahl, E., additional, Drumea-Mirancea, M., additional, Arsenijevic, Y., additional, von Lintig, J., additional, Wenzel, A., additional, Seeliger, M. W., additional, and Grimm, C., additional
- Published
- 2012
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13. In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death
- Author
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Samardzija, M., primary, Tanimoto, N., additional, Kostic, C., additional, Beck, S., additional, Oberhauser, V., additional, Joly, S., additional, Thiersch, M., additional, Fahl, E., additional, Arsenijevic, Y., additional, von Lintig, J., additional, Wenzel, A., additional, Seeliger, M. W., additional, and Grimm, C., additional
- Published
- 2010
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- View/download PDF
14. In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death
- Author
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Samardzija, M., primary, Tanimoto, N., additional, Kostic, C., additional, Beck, S., additional, Oberhauser, V., additional, Joly, S., additional, Thiersch, M., additional, Fahl, E., additional, Arsenijevic, Y., additional, von Lintig, J., additional, Wenzel, A., additional, Seeliger, M. W., additional, and Grimm, C., additional
- Published
- 2009
- Full Text
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15. Leukemia Inhibitory Factor Extends the Lifespan of Injured Photoreceptors In Vivo
- Author
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Joly, S., primary, Lange, C., additional, Thiersch, M., additional, Samardzija, M., additional, and Grimm, C., additional
- Published
- 2008
- Full Text
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16. R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal
- Author
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Samardzija, M., primary, von Lintig, J., additional, Tanimoto, N., additional, Oberhauser, V., additional, Thiersch, M., additional, Reme, C. E., additional, Seeliger, M., additional, Grimm, C., additional, and Wenzel, A., additional
- Published
- 2007
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17. Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection
- Author
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Wenzel Andreas, Poch Olivier, Samardzija Marijana, Frigg Rico, Raffelsberger Wolfgang, Thiersch Markus, and Grimm Christian
- Subjects
Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Retinal degeneration is a main cause of blindness in humans. Neuroprotective therapies may be used to rescue retinal cells and preserve vision. Hypoxic preconditioning stabilizes the transcription factor HIF-1α in the retina and strongly protects photoreceptors in an animal model of light-induced retinal degeneration. To address the molecular mechanisms of the protection, we analyzed the transcriptome of the hypoxic retina using microarrays and real-time PCR. Results Hypoxic exposure induced a marked alteration in the retinal transcriptome with significantly different expression levels of 431 genes immediately after hypoxic exposure. The normal expression profile was restored within 16 hours of reoxygenation. Among the differentially regulated genes, several candidates for neuroprotection were identified like metallothionein-1 and -2, the HIF-1 target gene adrenomedullin and the gene encoding the antioxidative and cytoprotective enzyme paraoxonase 1 which was previously not known to be a hypoxia responsive gene in the retina. The strongly upregulated cyclin dependent kinase inhibitor p21 was excluded from being essential for neuroprotection. Conclusion Our data suggest that neuroprotection after hypoxic preconditioning is the result of the differential expression of a multitude of genes which may act in concert to protect visual cells against a toxic insult.
- Published
- 2008
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18. In conditions of limited chromophore supply rods entrap 11-cis-retinal leading to loss of cone function and cell death.
- Author
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Samardzija, M., Tanimoto, N., Kostic, C., Beck, S., Oberhauser, V., Joly, S., Thiersch, M., Fahl, E., Arsenijevic, Y., von Lintig, J., Wenzel, A., Seeliger, M.W., and Grimm, C.
- Published
- 2011
- Full Text
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19. Reduced cancer mortality at high altitude: The role of glucose, lipids, iron and physical activity
- Author
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Thomas Haider, Max Gassmann, Markus Thiersch, E.R. Swenson, University of Zurich, and Thiersch, M
- Subjects
0301 basic medicine ,Iron ,Cancer mortality ,Carbohydrate metabolism ,Biology ,Environment ,medicine.disease_cause ,Bioinformatics ,1307 Cell Biology ,03 medical and health sciences ,Hypoxia/metabolism ,Diabetes mellitus ,Exercise/physiology ,High altitude ,medicine ,Glucose/metabolism ,Animals ,Humans ,purl.org/pe-repo/ocde/ford#1.06.01 [https] ,Hypoxia ,Exercise ,Ecology ,Cancer ,Cell Biology ,Hypoxia (medical) ,medicine.disease ,10081 Institute of Veterinary Physiology ,Obesity ,Lipids ,Metabolism ,030104 developmental biology ,Glucose ,10076 Center for Integrative Human Physiology ,Cancer cell ,570 Life sciences ,biology ,medicine.symptom ,Carcinogenesis ,Iron/metabolism ,Drug metabolism - Abstract
Residency at high altitude (HA) demands adaptation to challenging environmental conditions with hypobaric hypoxia being the most important one. Epidemiological and experimental data suggest that chronic exposure to HA reduces cancer mortality and lowers prevalence of metabolic disorders like diabetes and obesity implying that adaption to HA modifies a broad spectrum of physiological, metabolic and cellular programs with a generally beneficial outcome for humans. However, the complexity of multiple, potentially tumor-suppressive pathways at HA impedes the understanding of mechanisms leading to reduced cancer mortality. Many adaptive processes at HA are tightly interconnected and thus it cannot be ruled out that the entirety or at least some of the HA-related alterations act in concert to reduce cancer mortality. In this review we discuss tumor formation as a concept of competition between healthy and cancer cells with improved fitness - and therefore higher competitiveness - of healthy cells at high altitude. We discuss HA-related changes in glucose, lipid and iron metabolism that may have an impact on tumorigenesis. Additionally, we discuss two parameters with a strong impact on tumorigenesis, namely drug metabolism and physical activity, to underpin their potential contribution to HA-dependent reduced cancer mortality. Future studies are needed to unravel why cancer mortality is reduced at HA and how this knowledge might be used to prevent and to treat cancer patients.
- Published
- 2017
20. The hypoxic transcriptome of the retina: identification of factors with potential neuroprotective activity
- Author
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Patricia R. Blank, Wolfgang Raffelsberger, Christian Grimm, Enrico Frigg, Marijana Samardzija, Olivier Poch, Markus Thiersch, University of Zurich, Anderson, R E, Thiersch, M, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), and Peney, Maité
- Subjects
Retinal degeneration ,MESH: Cell Death ,Time Factors ,Light ,MESH: Mice, Mutant Strains ,MESH: Anoxia ,Apoptosis ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,MESH: Mice, Knockout ,Photoreceptor cell ,Transcriptome ,Mice ,0302 clinical medicine ,MESH: Animals ,Hypoxia ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Mice, Inbred BALB C ,0303 health sciences ,Cell Death ,MESH: Retina ,MESH: Enzyme-Linked Immunosorbent Assay ,Intermittent hypoxia ,MESH: Neuroprotective Agents ,MESH: Gene Expression Regulation ,Neuroprotective Agents ,medicine.anatomical_structure ,10076 Center for Integrative Human Physiology ,Identification (biology) ,10018 Ophthalmology Clinic ,MESH: Mice, Inbred BALB C ,Enzyme-Linked Immunosorbent Assay ,610 Medicine & health ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Neuroprotection ,Retina ,03 medical and health sciences ,MESH: Gene Expression Profiling ,1300 General Biochemistry, Genetics and Molecular Biology ,medicine ,Animals ,MESH: Mice ,030304 developmental biology ,Gene Expression Profiling ,MESH: Apoptosis ,MESH: Time Factors ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,medicine.disease ,Mice, Mutant Strains ,MESH: Light ,Ophthalmology clinic ,Gene Expression Regulation ,MESH: Oligonucleotide Array Sequence Analysis ,570 Life sciences ,biology ,Neuroscience ,030217 neurology & neurosurgery - Published
- 2008
21. A Comprehensive Insight and In Silico Analysis of CircRNAs in Hepatocellular Carcinoma: A Step toward ncRNA-Based Precision Medicine.
- Author
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Youness RA, Hassan HA, Abaza T, Hady AA, El Magdoub HM, Ali M, Vogel J, Thiersch M, Gassmann M, Hamdy NM, and Aboouf MA
- Subjects
- Humans, Computer Simulation, Gene Expression Regulation, Neoplastic, Computational Biology methods, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular metabolism, Liver Neoplasms genetics, Liver Neoplasms pathology, Liver Neoplasms metabolism, RNA, Circular genetics, RNA, Circular metabolism, Precision Medicine methods, RNA, Untranslated genetics, RNA, Untranslated metabolism
- Abstract
Circular RNAs (circRNAs) are cardinal players in numerous physiological and pathological processes. CircRNAs play dual roles as tumor suppressors and oncogenes in different oncological contexts, including hepatocellular carcinoma (HCC). Their roles significantly impact the disease at all stages, including initiation, development, progression, invasion, and metastasis, in addition to the response to treatment. In this review, we discuss the biogenesis and regulatory functional roles of circRNAs, as well as circRNA-protein-mRNA ternary complex formation, elucidating the intricate pathways tuned by circRNAs to modulate gene expression and cellular processes through a comprehensive literature search, in silico search, and bioinformatics analysis. With a particular focus on the interplay between circRNAs, epigenetics, and HCC pathology, the article sets the stage for further exploration of circRNAs as novel investigational theranostic agents in the dynamic realm of HCC., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2024
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22. Myoglobin in Brown Adipose Tissue: A Multifaceted Player in Thermogenesis.
- Author
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Aboouf MA, Gorr TA, Hamdy NM, Gassmann M, and Thiersch M
- Subjects
- Humans, Animals, Mice, Obesity, Adipose Tissue, Brown, Cell Membrane, Fatty Acids, Myoglobin, Adiposity
- Abstract
Brown adipose tissue (BAT) plays an important role in energy homeostasis by generating heat from chemical energy via uncoupled oxidative phosphorylation. Besides its high mitochondrial content and its exclusive expression of the uncoupling protein 1, another key feature of BAT is the high expression of myoglobin (MB), a heme-containing protein that typically binds oxygen, thereby facilitating the diffusion of the gas from cell membranes to mitochondria of muscle cells. In addition, MB also modulates nitric oxide (NO•) pools and can bind C16 and C18 fatty acids, which indicates a role in lipid metabolism. Recent studies in humans and mice implicated MB present in BAT in the regulation of lipid droplet morphology and fatty acid shuttling and composition, as well as mitochondrial oxidative metabolism. These functions suggest that MB plays an essential role in BAT energy metabolism and thermogenesis. In this review, we will discuss in detail the possible physiological roles played by MB in BAT thermogenesis along with the potential underlying molecular mechanisms and focus on the question of how BAT-MB expression is regulated and, in turn, how this globin regulates mitochondrial, lipid, and NO• metabolism. Finally, we present potential MB-mediated approaches to augment energy metabolism, which ultimately could help tackle different metabolic disorders.
- Published
- 2023
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23. Voluntary exercise does not always suppress lung cancer progression.
- Author
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Leimbacher AC, Villiger P, Desboeufs N, Aboouf MA, Nanni M, Armbruster J, Ademi H, Flüchter P, Ruetten M, Gantenbein F, Haider TJ, Gassmann M, and Thiersch M
- Abstract
Physical exercise can lower lung cancer incidence. However, its effect on lung cancer progression is less understood. Studies on exercising mice have shown decreased ectopic lung cancer growth through the secretion of interleukin-6 from muscles and the recruitment of natural killer (NK) cells to tumors. We asked if exercise suppresses lung cancer in an orthotopic model also. Single-housed C57Bl/6 male mice in cages with running wheels were tail vein-injected with LLC1.1 lung cancer cells, and lung tumor nodules were analyzed. Exercise did not affect lung cancer. Therefore, we also tested the effect of exercise on a subcutaneous LLC1 tumor and a tail vein-injected B16F10 melanoma model. Except for one case of excessive exercise, tumor progression was not influenced. Moderately exercising mice did not increase IL-6 or recruit NK cells to the tumor. Our data suggest that the exercise dose may dictate how efficiently the immune system is stimulated and controls tumor progression., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Authors.)
- Published
- 2023
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24. The Brain at High Altitude: From Molecular Signaling to Cognitive Performance.
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Aboouf MA, Thiersch M, Soliz J, Gassmann M, and Schneider Gasser EM
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- Humans, Hypoxia metabolism, Oxygen, Brain metabolism, Cognition, Altitude, Acclimatization physiology
- Abstract
The brain requires over one-fifth of the total body oxygen demand for normal functioning. At high altitude (HA), the lower atmospheric oxygen pressure inevitably challenges the brain, affecting voluntary spatial attention, cognitive processing, and attention speed after short-term, long-term, or lifespan exposure. Molecular responses to HA are controlled mainly by hypoxia-inducible factors. This review aims to summarize the cellular, metabolic, and functional alterations in the brain at HA with a focus on the role of hypoxia-inducible factors in controlling the hypoxic ventilatory response, neuronal survival, metabolism, neurogenesis, synaptogenesis, and plasticity.
- Published
- 2023
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25. Endogenous myoglobin expression in mouse models of mammary carcinoma reduces hypoxia and metastasis in PyMT mice.
- Author
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Aboouf MA, Armbruster J, Guscetti F, Thiersch M, Boss A, Gödecke A, Winning S, Padberg C, Fandrey J, Kristiansen G, Bicker A, Hankeln T, Gassmann M, and Gorr TA
- Subjects
- Animals, Mice, Biopsy, Disease Models, Animal, Hypoxia genetics, Mice, Knockout, Myoglobin genetics, Carcinoma
- Abstract
Myoglobin (MB) is expressed in different cancer types and may act as a tumor suppressor in breast cancer. The mechanisms by which basal MB expression level impacts murine mammary tumorigenesis are unclear. We investigated how MB expression in breast cancer influences proliferation, metastasis, tumor hypoxia, and chemotherapy treatment in vivo. We crossed PyMT and WapCreTrp53
flox mammary cancer mouse models that differed in tumor grade/type and onset of mammary carcinoma with MB knockout mice. The loss of MB in WapCre;Trp53flox mice did not affect tumor development and progression. On the other hand, loss of MB decreased tumor growth and increased tissue hypoxia as well as the number of lung metastases in PyMT mice. Furthermore, Doxorubicin therapy prevented the stronger metastatic propensity of MB-deficient tumors in PyMT mice. This suggests that, although MB expression predicts improved prognosis in breast cancer patients, MB-deficient tumors may still respond well to first-line therapies. We propose that determining the expression level of MB in malignant breast cancer biopsies will improve tumor stratification, outcome prediction, and personalized therapy in cancer patients., (© 2023. The Author(s).)- Published
- 2023
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26. Association of serum hepcidin with prostate-specific antigen levels in men from high Andean cities of Peru.
- Author
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Alcantara-Zapata DE, Thiersch M, and Gonzales GF
- Abstract
Objective: The prostate-specific antigen (PSA) is the primary biomarker to diagnose prostate cancer. Hepcidin has been reported as an alternative for this diagnosis; however, it is unclear how PSA and hepcidin function at high altitude (HA). This study aims to assess the association between hepcidin with PSA in HA residents chronically exposed to hypobaric hypoxia., Methods: We retrospectively examined data of 70 healthy males (aged 18-65-years-old) from four different altitudes cities in Peru: Lima (<150 m), Huancayo (2380 m), Puno (3800 m), and Cerro de Pasco (4320 m). Serum hepcidin, testosterone, and PSA were analyzed by chemiluminescence immunoassay. HA parameters (hemoglobin [Hb], pulse oxygen saturation [SpO
2 ], and chronic mountain sickness [CMS] score) were also included in the study. Bivariate analyses and a multivariate linear mixed model were used to evaluate the association between hepcidin and PSA, adjusted by HA parameters, age, and body mass index (BMI)., Results: Cases of excessive erythrocytosis (EE) (Hb >21 g/dL) were observed in the three highest cities. Hepcidin was positively correlated with Hb, CMS score, and BMI ( P ≤ 0.05). Hepcidin was higher in Huancayo with respect to Puno, while PSA was lower in Cerro de Pasco in regard to Puno and Lima ( P ≤ 0.05). Neither hepcidin nor PSA was increased by altitude in each city ( P > 0.05). We did not find an association between hepcidin and PSA, even adjusted by age, BMI, Hb, and SpO2 ( P ≤ 0.05)., Conclusion: These findings showed no association between hepcidin and PSA levels in healthy residents at HA., (Copyright: © International Journal of Health Sciences.)- Published
- 2023
27. Iron- and erythropoietin-resistant anemia in a spontaneous breast cancer mouse model.
- Author
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Bregolat NF, Ruetten M, Da Silva MC, Aboouf MA, Ademi H, Büren NV, Armbruster J, Stirn M, Altamura S, Marques O, Rodriguez JMM, Samillan VJ, Singh RP, Wielockx B, Muckenthaler MU, Gassmann M, and Thiersch M
- Subjects
- Animals, Erythropoiesis, Female, Hepcidins genetics, Humans, Inflammation complications, Interleukin-6 genetics, Iron therapeutic use, Mice, Anemia drug therapy, Anemia etiology, Anemia pathology, Breast Neoplasms complications, Erythropoietin pharmacology, Erythropoietin therapeutic use, Iron Deficiencies
- Abstract
Anemia of cancer (AoC) with its multifactorial etiology and complex pathology is a poor prognostic indicator for cancer patients. One of the main causes of AoC is cancer-associated inflammation that activates mechanisms, commonly observed in anemia of inflammation, whereby functional iron deficiency and iron-restricted erythropoiesis are induced by increased hepcidin levels in response to raised levels of interleukin-6. So far only a few AoC mouse models have been described, and most of them did not fully recapitulate the interplay of anemia, increased hepcidin levels and functional iron deficiency in human patients. To test if the selection and the complexity of AoC mouse models dictates the pathology or if AoC in mice per se develops independently of iron deficiency, we characterized AoC in Trp53floxWapCre mice that spontaneously develop breast cancer. These mice developed AoC associated with high levels of interleukin-6 and iron deficiency. However, hepcidin levels were not increased and hypoferremia coincided with anemia rather than causing it. Instead, an early shift in the commitment of common myeloid progenitors from the erythroid to the myeloid lineage resulted in increased myelopoiesis and in the excessive production of neutrophils that accumulate in necrotic tumor regions. This process could not be prevented by either iron or erythropoietin treatment. Trp53floxWapCre mice are the first mouse model in which erythropoietin-resistant anemia is described and may serve as a disease model to test therapeutic approaches for a subpopulation of human cancer patients with normal or corrected iron levels who do not respond to erythropoietin.
- Published
- 2022
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28. Pro-Apoptotic and Anti-Invasive Properties Underscore the Tumor-Suppressing Impact of Myoglobin on a Subset of Human Breast Cancer Cells.
- Author
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Aboouf MA, Armbruster J, Thiersch M, Guscetti F, Kristiansen G, Schraml P, Bicker A, Petry R, Hankeln T, Gassmann M, and Gorr TA
- Subjects
- Cell Line, Tumor, Cyclins metabolism, Doxorubicin pharmacology, Epithelial-Mesenchymal Transition, Female, Humans, Oxygen metabolism, Tumor Suppressor Protein p53 genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Myoglobin metabolism
- Abstract
The expression of myoglobin (MB), well known as the oxygen storage and transport protein of myocytes, is a novel hallmark of the luminal subtype in breast cancer patients and correlates with better prognosis. The mechanisms by which MB impacts mammary tumorigenesis are hitherto unclear. We aimed to unravel this role by using CRISPR/Cas9 technology to generate MB-deficient clones of MCF7 and SKBR3 breast cancer cell lines and subsequently characterize them by transcriptomics plus molecular and functional analyses. As main findings, loss of MB at normoxia upregulated the expression of cell cyclins and increased cell survival, while it prevented apoptosis in MCF7 cells. Additionally, MB-deficient cells were less sensitive to doxorubicin but not ionizing radiation. Under hypoxia, the loss of MB enhanced the partial epithelial to mesenchymal transition, thus, augmenting the migratory and invasive behavior of cells. Notably, in human invasive mammary ductal carcinoma tissues, MB and apoptotic marker levels were positively correlated. In addition, MB protein expression in invasive ductal carcinomas was associated with a positive prognostic value, independent of the known tumor suppressor p53. In conclusion, we provide multiple lines of evidence that endogenous MB in cancer cells by itself exerts novel tumor-suppressive roles through which it can reduce cancer malignancy.
- Published
- 2022
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29. Erythropoietin receptor regulates tumor mitochondrial biogenesis through iNOS and pAKT.
- Author
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Aboouf MA, Guscetti F, von Büren N, Armbruster J, Ademi H, Ruetten M, Meléndez-Rodríguez F, Rülicke T, Seymer A, Jacobs RA, Schneider Gasser EM, Aragones J, Neumann D, Gassmann M, and Thiersch M
- Abstract
Erythropoietin receptor (EPOR) is widely expressed in healthy and malignant tissues. In certain malignancies, EPOR stimulates tumor growth. In healthy tissues, EPOR controls processes other than erythropoiesis, including mitochondrial metabolism. We hypothesized that EPOR also controls the mitochondrial metabolism in cancer cells. To test this hypothesis, we generated EPOR-knockdown cancer cells to grow tumor xenografts in mice and analyzed tumor cellular respiration via high-resolution respirometry. Furthermore, we analyzed cellular respiratory control, mitochondrial content, and regulators of mitochondrial biogenesis in vivo and in vitro in different cancer cell lines. Our results show that EPOR controls tumor growth and mitochondrial biogenesis in tumors by controlling the levels of both, pAKT and inducible NO synthase (iNOS). Furthermore, we observed that the expression of EPOR is associated with the expression of the mitochondrial marker VDAC1 in tissue arrays of lung cancer patients, suggesting that EPOR indeed helps to regulate mitochondrial biogenesis in tumors of cancer patients. Thus, our data imply that EPOR not only stimulates tumor growth but also regulates tumor metabolism and is a target for direct intervention against progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aboouf, Guscetti, von Büren, Armbruster, Ademi, Ruetten, Meléndez-Rodríguez, Rülicke, Seymer, Jacobs, Schneider Gasser, Aragones, Neumann, Gassmann and Thiersch.)
- Published
- 2022
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30. Myoglobin, expressed in brown adipose tissue of mice, regulates the content and activity of mitochondria and lipid droplets.
- Author
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Aboouf MA, Armbruster J, Thiersch M, Gassmann M, Gödecke A, Gnaiger E, Kristiansen G, Bicker A, Hankeln T, Zhu H, and Gorr TA
- Subjects
- Adipocytes, Brown metabolism, Adipose Tissue, Brown metabolism, Animals, Apoptosis Regulatory Proteins genetics, Disease Models, Animal, Energy Metabolism genetics, Humans, Mice, Mice, Knockout, Mitochondria genetics, Muscle, Skeletal metabolism, Myoglobin metabolism, PPAR alpha genetics, Palmitates metabolism, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha genetics, Proteins genetics, Thermogenesis genetics, Uncoupling Protein 1 genetics, Lipid Droplets metabolism, Mitochondria metabolism, Myoglobin genetics, Oxygen metabolism
- Abstract
The identification of novel physiological regulators that stimulate energy expenditure through brown adipose tissue (BAT) activity in substrate catalysis is of utmost importance to understand and treat metabolic diseases. Myoglobin (MB), known to store or transport oxygen in heart and skeletal muscles, has recently been found to bind fatty acids with physiological constants in its oxygenated form (i.e., MBO
2 ). Here, we investigated the in vivo effect of MB expression on BAT activity. In particular, we studied mitochondrial function and lipid metabolism as essential determinants of energy expenditure in this tissue. We show in a MB-null (MBko) mouse model that MB expression in BAT impacts on the activity of brown adipocytes in a twofold manner: i) by elevating mitochondrial density plus maximal respiration capacity, and through that, by stimulating BAT oxidative metabolism along with the organelles` uncoupled respiration; and ii) by influencing the free fatty acids pool towards a palmitate-enriched composition and shifting the lipid droplet (LD) equilibrium towards higher counts of smaller droplets. These metabolic changes were accompanied by the up-regulated expression of thermogenesis markers UCP1, CIDEA, CIDEC, PGC1-α and PPAR-α in the BAT of MB wildtype (MBwt) mice. Along with the emergence of the "browning" BAT morphology, MBwt mice exhibited a leaner phenotype when compared to MBko littermates at 20 weeks of age. Our data shed novel insights into MB's role in linking oxygen and lipid-based thermogenic metabolism. The findings suggest potential new strategies of targeting the MB pathway to treat metabolic disorders related to diminishing energy expenditure., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2021
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31. Erythropoietin promotes hippocampal mitochondrial function and enhances cognition in mice.
- Author
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Jacobs RA, Aboouf MA, Koester-Hegmann C, Muttathukunnel P, Laouafa S, Arias-Reyes C, Thiersch M, Soliz J, Gassmann M, and Schneider Gasser EM
- Subjects
- Animals, Hippocampus physiology, Mice, Mice, Transgenic, Mitochondria metabolism, Neurons metabolism, Random Allocation, Cognition drug effects, Erythropoietin administration & dosage, Hippocampus drug effects, Mitochondria drug effects, Neurons drug effects
- Abstract
Erythropoietin (EPO) improves neuronal mitochondrial function and cognition in adults after brain injury and in those afflicted by psychiatric disorders. However, the influence of EPO on mitochondria and cognition during development remains unexplored. We previously observed that EPO stimulates hippocampal-specific neuronal maturation and synaptogenesis early in postnatal development in mice. Here we show that EPO promotes mitochondrial respiration in developing postnatal hippocampus by increasing mitochondrial content and enhancing cellular respiratory potential. Ultrastructurally, mitochondria profiles and total vesicle content were greater in presynaptic axon terminals, suggesting that EPO enhances oxidative metabolism and synaptic transmission capabilities. Behavioural tests of hippocampus-dependent memory at early adulthood, showed that EPO improves spatial and short-term memory. Collectively, we identify a role for EPO in the murine postnatal hippocampus by promoting mitochondrial function throughout early postnatal development, which corresponds to enhanced cognition by early adulthood., (© 2021. The Author(s).)
- Published
- 2021
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32. HIF-2: an important player in neuronal response to ischemia.
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Schneider Gasser EM, Gassmann M, and Thiersch M
- Subjects
- Basic Helix-Loop-Helix Transcription Factors, Humans, Ischemia, Neurons
- Published
- 2021
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33. Iron Regulation in Elderly Asian Elephants ( Elephas maximus ) Chronically Infected With Mycobacterium tuberculosis .
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Ruetten M, Steinmetz HW, Thiersch M, Kik M, Vaughan L, Altamura S, Muckenthaler MU, and Gassmann M
- Abstract
Restriction of nutrients to pathogens (nutritional immunity) is a critical innate immune response mechanism that operates when pathogens such as Mycobacterium tuberculosis have the potential to evade humoral immunity. Tuberculosis is of growing concern for zoological collections worldwide and is well-illustrated by infections of Asian and African elephants, where tuberculosis is difficult to diagnose. Here, we investigated hematological parameters and iron deposition in liver, lung, and spleen of three Asian elephants ( Elephas maximus ) infected with Mycobacterium tuberculosis . For reference purposes, we analyzed tissue samples from control M. tuberculosis -negative elephants with and without evidence of inflammation and/or chronic disease. Molecular analyses of bacterial lesions of post mortally collected tissues confirmed M. tuberculosis infection in three elephants. DNA sequencing of the bacterial cultures demonstrated a single source of infection, most likely of human origin. In these elephants, we observed moderate microcytic anemia as well as liver (mild), lung (moderate) and spleen (severe) iron accumulation, the latter mainly occurring in macrophages. Macrophage iron sequestration in response to infection and inflammation is caused by inhibition of iron export via hepcidin-dependent and independent mechanisms. The hepatic mRNA levels of the iron-regulating hormone hepcidin were increased in only one control elephant suffering from chronic inflammation without mycobacterial infection. By contrast, all three tuberculosis-infected elephants showed low hepcidin mRNA levels in the liver and low serum hepcidin concentrations. In addition, hepatic ferroportin mRNA expression was high. This suggests that the hepcidin/ferroportin regulatory system aims to counteract iron restriction in splenic macrophages in M. tuberculosis infected elephants to provide iron for erythropoiesis and to limit iron availability for a pathogen that predominantly proliferates in macrophages. Tuberculosis infections appear to have lingered for more than 30 years in the three infected elephants, and decreased iron availability for mycobacterial proliferation may have forced the bacteria into a persistent, non-proliferative state. As a result, therapeutic iron substitution may not have been beneficial in these elephants, as this therapy may have enhanced progression of the infection., (Copyright © 2020 Ruetten, Steinmetz, Thiersch, Kik, Vaughan, Altamura, Muckenthaler and Gassmann.)
- Published
- 2020
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34. A Single 60.000 IU Dose of Erythropoietin Does Not Improve Short-Term Aerobic Exercise Performance in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial.
- Author
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Haider T, Diaz V, Albert J, Alvarez-Sanchez M, Thiersch M, Maggiorini M, Hilty MP, Spengler CM, and Gassmann M
- Abstract
Erythropoietin (EPO) boosts exercise performance through increase in oxygen transport capacity following regular administration of EPO but preclinical study results suggest that single high dose of EPO also may improve exercise capacity. Twenty-nine healthy subjects (14 males/15 females; age: 25 ± 3 years) were included in a randomized, double-blind, placebo-controlled crossover study to assess peak work load and cardiopulmonary variables during submaximal and maximal cycling tests following a single dose of 60.000 IU of recombinant erythropoietin (EPO) or placebo (PLA). Submaximal exercise at 40%/60% of peak work load revealed no main effect of EPO on oxygen uptake (27.9 ± 8.7 ml min
-1 ⋅kg-1 / 37.1 ± 13.2 ml min-1 ⋅kg-1 ) versus PLA (25.2 ± 3.7 ml min-1 ⋅kg-1 / 33.1 ± 5.3 ml min-1 ⋅kg-1 ) condition ( p = 0.447/ p = 0.756). During maximal exercise peak work load (PLA: 3.5 ± 0.6 W⋅kg-1 vs. EPO: 3.5 ± 0.6 W kg-1 , p = 0.892) and peak oxygen uptake (PLA: 45.1 ± 10.4 ml⋅min-1 kg-1 vs. EPO: 46.1 ± 14.2 ml⋅min-1 kg-1 , p = 0.344) reached comparable values in the two treatment conditions. Other cardiopulmonary variables (ventilation, cardiac output, heart rate) also reached similar levels in the two treatment conditions. An interaction effect was found between treatment condition and sex resulting in higher peak oxygen consumption ( p = 0.048) and ventilation ( p = 0.044) in EPO-treated males. In conclusion, in a carefully conducted study using placebo-controlled design the present data failed to support the hypothesis that a single high dose of EPO has a measurable impact on work capacity in healthy subjects., (Copyright © 2020 Haider, Diaz, Albert, Alvarez-Sanchez, Thiersch, Maggiorini, Hilty, Spengler and Gassmann.)- Published
- 2020
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35. High-Altitude Cognitive Impairment Is Prevented by Enriched Environment Including Exercise via VEGF Signaling.
- Author
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Koester-Hegmann C, Bengoetxea H, Kosenkov D, Thiersch M, Haider T, Gassmann M, and Schneider Gasser EM
- Abstract
Exposure to hypobaric hypoxia at high altitude (above 2500 m asl) causes cognitive impairment, mostly attributed to changes in brain perfusion and consequently neuronal death. Enriched environment and voluntary exercise has been shown to improve cognitive function, to enhance brain microvasculature and neurogenesis, and to be neuroprotective. Here we show that high-altitude exposure (3540 m asl) of Long Evans rats during early adulthood (P48-P59) increases brain microvasculature and neurogenesis but impairs spatial and visual memory along with an increase in neuronal apoptosis. We tested whether enriched environment including a running wheel for voluntary exercise (EE) can prevent cognitive impairment at high-altitude and whether apoptosis is prevented. We found that EE retained spatial and visual memory at high altitude, and prevented neuronal apoptosis. Further, we tested whether vascular endothelial growth factor (VEGF) signaling is required for the EE-mediated recovery of spatial and visual memory and the reduction in apoptosis. Pharmacological inhibition of VEGF signaling by oral application of a tyrosine kinase inhibitor (Vandetanib) prevented the recovery of spatial and visual memory in animals housed in EE, along with an increase in apoptosis and a reduction in neurogenesis. Surprisingly, inhibition of VEGF signaling also caused impairment in spatial memory in EE-housed animals reared at low altitude, affecting mainly dentate gyrus microvasculature but not neurogenesis. We conclude that EE-mediated VEGF signaling is neuroprotective and essential for the maintenance of cognition and neurogenesis during high-altitude exposure, and for the maintenance of spatial memory at low altitude. Finally, our data also underlines the potential risk of cognitive impairment and disturbed high altitude adaption from the use of VEGF-signaling inhibitors for therapeutic purposes.
- Published
- 2019
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36. Coping with Hypoxia at High Altitude: How Lung, Blood, and Brain Respond and Cross Talk 5th International Atacama-Leh Symposium in San Pedro de Atacama, March 4-9, 2018, Chile.
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Schneider Gasser EM, Fabregas Bregolat N, and Thiersch M
- Subjects
- Brain physiopathology, Brain Diseases physiopathology, Hematocrit, Hemoglobins metabolism, Humans, Hypoxia blood, Hypoxia complications, Hypoxia therapy, Lung physiopathology, Lung Diseases physiopathology, Polycythemia etiology, Adaptation, Physiological, Altitude, Brain Diseases etiology, Hypoxia physiopathology, Lung Diseases etiology
- Published
- 2018
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37. High Altitude and Cancer Mortality.
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Thiersch M and Swenson ER
- Subjects
- Altitude Sickness complications, Animals, Humans, Neoplasms complications, Neoplasms physiopathology, Oxygen Consumption physiology, Reactive Oxygen Species metabolism, Acclimatization physiology, Altitude, Altitude Sickness physiopathology, Neoplasms mortality
- Abstract
Thiersch, Markus, and Erik R. Swenson. High altitude and cancer mortality. High Alt Med Biol 19:116-123, 2018.-Humans living at high altitude (HA) are exposed to chronic (hypobaric) hypoxia. Despite the permanent stress of hypoxic exposure, humans populating HA areas have reduced cancer mortality over a broad spectrum of cancer types. In fact, the majority of the physiological adaptive processes at HA occurring in response to hypoxia might be the driving force for reduced cancer mortality at HA. In this review, we summarize epidemiological and animal studies that compare cancer incidence and cancer mortality between HA and low altitude or between hypoxia and normoxia, respectively. We discuss the potential role of oxygen-independent and oxygen-dependent mechanisms that might contribute to reduced cancer mortality at HA. Reactive oxygen species and their detoxification as well as the hypoxia-inducible factors are especially promising targets and may be related to why cancer mortality is reduced at HA. In addition, we briefly discuss two aspects with a proven impact on tumorigenesis, namely the immune system and tumor surveillance as well as HA-induced metabolic changes. Further animal and clinical studies are clearly needed to explain why cancer mortality is reduced at HA and to decide whether HA or hypoxia-based therapeutic approaches could be implemented for cancer treatment. However, exposure to HA activates multiple adaptive mechanisms (oxygen independent and oxygen dependent) sharing common pathways as well as activating counteracting pathways, which complicate the identification of specific HA-induced mechanisms of tumor suppression.
- Published
- 2018
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38. Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation.
- Author
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Maxwell P, Melendez-Rodríguez F, Matchett KB, Aragones J, Ben-Califa N, Jaekel H, Hengst L, Lindner H, Bernardini A, Brockmeier U, Fandrey J, Grunert F, Oster HS, Mittelman M, El-Tanani M, Thiersch M, Schneider Gasser EM, Gassmann M, Dangoor D, Cuthbert RJ, Irvine A, Jordan A, Lappin T, Thompson J, and Neumann D
- Subjects
- Amino Acid Sequence, Animals, Chemistry Techniques, Synthetic methods, Flow Cytometry methods, Fluorescent Antibody Technique, Gene Silencing, Humans, Immunoprecipitation, Mice, Molecular Sequence Data, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Rats, Receptors, Erythropoietin genetics, Receptors, Erythropoietin metabolism, Risk Assessment methods, Terminology as Topic, Tumor Cells, Cultured metabolism, Antibodies, Monoclonal biosynthesis, Neoplasm Proteins immunology, Receptors, Erythropoietin immunology
- Abstract
Recombinant human erythropoietin (rHuEPO) is an effective treatment for anaemia but concerns that it causes disease progression in cancer patients by activation of EPO receptors (EPOR) in tumour tissue have been controversial and have restricted its clinical use. Initial clinical studies were flawed because they used polyclonal antibodies, later shown to lack specificity for EPOR. Moreover, multiple isoforms of EPOR caused by differential splicing have been reported in cancer cell lines at the mRNA level but investigations of these variants and their potential impact on tumour progression, have been hampered by lack of suitable antibodies. The EpoCan consortium seeks to promote improved pathological testing of EPOR, leading to safer clinical use of rHuEPO, by producing well characterized EPOR antibodies. Using novel genetic and traditional peptide immunization protocols, we have produced mouse and rat monoclonal antibodies, and show that several of these specifically recognize EPOR by Western blot, immunoprecipitation, immunofluorescence, flow cytometry and immunohistochemistry in cell lines and clinical material. Widespread availability of these antibodies should enable the research community to gain a better understanding of the role of EPOR in cancer, and eventually to distinguish patients who can be treated safely by rHuEPO from those at increased risk from treatment., (© 2014 John Wiley & Sons Ltd.)
- Published
- 2015
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39. The angiogenic response to PLL-g-PEG-mediated HIF-1α plasmid DNA delivery in healthy and diabetic rats.
- Author
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Thiersch M, Rimann M, Panagiotopoulou V, Öztürk E, Biedermann T, Textor M, Lühmann TC, and Hall H
- Subjects
- Amino Acid Sequence, Animals, COS Cells, Capillaries metabolism, Capillaries pathology, Chlorocebus aethiops, Diabetes Mellitus, Experimental pathology, Diabetes Mellitus, Type 1 pathology, Diabetes Mellitus, Type 1 therapy, Fibrin metabolism, Gene Expression Regulation, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypoxia-Inducible Factor 1, alpha Subunit therapeutic use, Molecular Sequence Data, Polylysine chemistry, Rats, Rats, Sprague-Dawley, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor A metabolism, Wound Healing, DNA metabolism, Diabetes Mellitus, Experimental therapy, Gene Transfer Techniques, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Neovascularization, Physiologic, Plasmids metabolism, Polyethylene Glycols chemistry, Polylysine analogs & derivatives
- Abstract
Impaired angiogenesis is a major clinical problem and affects wound healing especially in diabetic patients. Improving angiogenesis is a reasonable strategy to increase diabetes-impaired wound healing. Recently, our lab described a system of transient gene expression due to pegylated poly-l-lysine (PLL-g-PEG) polymer-mediated plasmid DNA delivery in vitro. Here we synthesized peptide-modified PLL-g-PEG polymers with two functionalities, characterized them in vitro and utilized them in vivo via a fibrin-based delivery matrix to induce dermal wound angiogenesis in diabetic rats. The two peptides were 1) a TG-peptide to covalently bind these nanocondensates to the fibrin matrix (TG-peptide) for a sustained release and 2) a polyR peptide to improve cellular uptake of these nanocondensates. In order to induce angiogenesis in vivo we condensed modified and non-modified polymers with plasmid DNA encoding a truncated form of the therapeutic candidate gene hypoxia-inducible transcription factor 1α (HIF-1α). HIF-1α is the primarily oxygen-dependent regulated subunit of the heterodimeric transcription factor HIF-1, which controls angiogenesis among other physiological pathways. The truncated form of HIF-1α lacks the oxygen-dependent degradation domain (ODD) and therefore escapes degradation under normoxic conditions. PLL-g-PEG polymer-mediated HIF-1α-ΔODD plasmid DNA delivery was found to lead to a transiently induced gene expression of angiogenesis-related genes Acta2 and Pecam1 as well as the HIF-1α target gene Vegf in vivo. Furthermore, HIF-1α gene delivery was shown to enhance the number endothelial cells and smooth muscle cells - precursors for mature blood vessels - during wound healing. We show that - depending on the selection of the therapeutic target gene - PLL-g-PEG nanocondensates are a promising alternative to viral DNA delivery approaches, which might pose a risk to health., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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40. Normoxic activation of hypoxia-inducible factors in photoreceptors provides transient protection against light-induced retinal degeneration.
- Author
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Lange C, Heynen SR, Tanimoto N, Thiersch M, Le YZ, Meneau I, Seeliger MW, Samardzija M, Caprara C, and Grimm C
- Subjects
- Aging pathology, Animals, Aryl Hydrocarbon Receptor Nuclear Translocator genetics, Cell Death physiology, Cell Death radiation effects, Female, Fibroblast Growth Factor 2 genetics, Genotype, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Ischemic Preconditioning, Light adverse effects, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Retinal Degeneration pathology, Transcription Factors genetics, Von Hippel-Lindau Tumor Suppressor Protein genetics, Von Hippel-Lindau Tumor Suppressor Protein metabolism, Aryl Hydrocarbon Receptor Nuclear Translocator metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Retinal Degeneration physiopathology, Retinal Rod Photoreceptor Cells pathology, Retinal Rod Photoreceptor Cells physiology, Retinal Rod Photoreceptor Cells radiation effects, Transcription Factors metabolism
- Abstract
Purpose: Hypoxic preconditioning activates hypoxia-inducible transcription factors (HIFs) in the retina and protects photoreceptors from light-induced retinal degeneration. The authors tested whether photoreceptor-specific activation of HIFs in normoxia is sufficient for protection., Methods: Rod-specific Vhl knockdown mice were generated using the Cre-lox system with the rod opsin promoter controlling expression of CRE recombinase to stabilize HIF transcription factors in normoxic rods. Cell death was induced by light exposure and quantified by ELISA. Rhodopsin was quantified by spectrophotometry. Gene expression was analyzed by real-time PCR, and levels of proteins were determined by Western blotting. Morphology was investigated by light microscopy and retinal function tested by ERG., Results: The rod-specific Vhl knockdown stabilized HIF-α proteins and induced expression of HIF target genes in retinas of 10-week-old mice under normoxic conditions. Retinal morphology and function were normal. At 36 hours after exposure to excessive light, Vhl knockdowns showed significantly less photoreceptor cell death than did wild-type controls. Ten days after light exposure, however, photoreceptor degeneration in Vhl knockdowns was similar to that of control animals. Vhl knockdowns expressed Fgf2 at higher basal levels before light exposure. After light exposure, however, expression of Fgf2 was not significantly different from that of wild-type controls., Conclusions: Artificial activation of HIF transcription factors in normoxic photoreceptors results in an increased basal expression of Fgf2 that may contribute to a transient protection of rods against light damage. Full photoreceptor protection may require a hypoxia-like response in additional retinal cell types and/or the differential regulation of additional mechanisms.
- Published
- 2011
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41. HIF1A is essential for the development of the intermediate plexus of the retinal vasculature.
- Author
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Caprara C, Thiersch M, Lange C, Joly S, Samardzija M, and Grimm C
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors metabolism, Blotting, Western, DNA Primers chemistry, Down-Regulation, Erythropoietin genetics, Fluorescent Antibody Technique, Indirect, Mice, Mice, Knockout, Retinal Vessels metabolism, Reverse Transcriptase Polymerase Chain Reaction, Vascular Endothelial Growth Factor A genetics, Hypoxia-Inducible Factor 1, alpha Subunit physiology, Neovascularization, Physiologic physiology, Retinal Vessels growth & development
- Abstract
Purpose: HIF1A is one of the major transcription factors that regulate tissue response to low oxygen tension. It controls expression of a large number of genes involved in cell survival, proliferation, angiogenesis, and other cellular processes. HIF1A is present at increased levels in the early postnatal retina. In this study its potential function during postnatal development of the mouse retina and retinal vasculature was analyzed., Methods: A mouse line was generated with a Cre-mediated Hif1a knockdown in the peripheral retina. Retinal morphology and vasculature were analyzed in sections and flat mount preparations. Gene and protein expression were determined by real-time PCR and Western blot analysis., Results: The Cre-mediated knockdown caused a significant reduction in Hif1a gene expression and HIF1A protein levels in the early postnatal retina. Retinal morphology was normal but the Hif1a knockdown prevented the formation of the intermediate vascular plexus in the peripheral retina. The primary plexus and the outer plexus were less affected. The Hif1a knockdown did not affect expression of such angiogenesis-related genes as vascular endothelial growth factor (Vegf) but strongly induced expression of erythropoietin (Epo). At the protein level, EPAS1 (HIF2A) was stabilized in the Hif1a knockdown mice., Conclusions: The results suggest that HIF1A may be directly or indirectly required for normal development of the retinal vasculature, especially of the intermediate plexus. EPO but not VEGF may play a significant role in the development of this phenotype. HIF1A may not be the main factor that regulates Vegf expression during retinal development in the mouse.
- Published
- 2011
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42. LIF-dependent JAK3 activation is not essential for retinal degeneration.
- Author
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Lange C, Thiersch M, Samardzija M, Bürgi S, Joly S, and Grimm C
- Subjects
- Animals, Blotting, Western, Enzyme Activation physiology, Eye, Fluorescent Antibody Technique, Hypoxia metabolism, Injections, Janus Kinase 3 genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Microglia physiology, Photoreceptor Cells, Vertebrate physiology, Recombinant Proteins pharmacology, Retina pathology, Retinal Degeneration pathology, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction physiology, Up-Regulation physiology, Janus Kinase 3 metabolism, Leukemia Inhibitory Factor physiology, Retinal Degeneration enzymology
- Abstract
Retinal degeneration causes the induction of a leukemia inhibitory factor (LIF)-controlled survival pathway which includes Janus kinase/signal transducer and activator of transcription signaling. Lack of LIF prevents activation of this signaling cascade and accelerates disease progression leading to a fast loss of photoreceptor cells. In this study, we show that expression of Janus kinase 3 (Jak3), but not of the other members of the family of Janus kinases, is induced in four different models of retinal degeneration and that LIF is essential and sufficient to activate Jak3 gene expression. We also show that the induction of Jak3 and Lif may not depend directly on cell death but rather on the retinal stress during photoreceptor degeneration. However, despite its dependence on LIF, JAK3 is not essential for LIF-mediated photoreceptor protection or gene expression. Also, absence of JAK3 in knockout mice did not affect immune-related responses in the degenerating retina. JAK3 may therefore play a different, yet unknown, role in the retinal response to photoreceptor injury.
- Published
- 2010
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43. Retinal neuroprotection by hypoxic preconditioning is independent of hypoxia-inducible factor-1 alpha expression in photoreceptors.
- Author
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Thiersch M, Lange C, Joly S, Heynen S, Le YZ, Samardzija M, and Grimm C
- Subjects
- Animals, Autocrine Communication genetics, Autocrine Communication radiation effects, Down-Regulation genetics, Gene Expression Regulation genetics, Gene Expression Regulation radiation effects, Hypoxia physiopathology, Hypoxia therapy, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Light adverse effects, Mice, Mice, Knockout, Mice, Transgenic, Photic Stimulation, Photoreceptor Cells, Vertebrate pathology, Photoreceptor Cells, Vertebrate radiation effects, RNA, Messenger metabolism, Retinal Degeneration physiopathology, Retinal Degeneration therapy, Cytoprotection physiology, Hypoxia metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Ischemic Preconditioning methods, Photoreceptor Cells, Vertebrate metabolism, Retinal Degeneration metabolism
- Abstract
Hypoxic preconditioning stabilizes hypoxia-inducible factor (HIF) 1 alpha in the retina and protects photoreceptors against light-induced cell death. HIF-1 alpha is one of the major transcription factors responding to low oxygen tension and can differentially regulate a large number of target genes. To analyse whether photoreceptor-specific expression of HIF-1 alpha is essential to protect photoreceptors by hypoxic preconditioning, we knocked down expression of HIF-1 alpha specifically in photoreceptor cells, using the cyclization recombinase (Cre)-lox system. The Cre-mediated knockdown caused a 20-fold reduced expression of Hif-1 alpha in the photoreceptor cell layer. In the total retina, RNA expression was reduced by 65%, and hypoxic preconditioning led to only a small increase in HIF-1 alpha protein levels. Accordingly, HIF-1 target gene expression after hypoxia was significantly diminished. Retinas of Hif-1 alpha knockdown animals did not show any pathological alterations, and tolerated hypoxic exposure in a comparable way to wild-type retinas. Importantly, the strong neuroprotective effect of hypoxic preconditioning against light-induced photoreceptor degeneration persisted in knockdown mice, suggesting that hypoxia-mediated survival of light exposure does not depend on an autocrine action of HIF-1 alpha in photoreceptor cells. Hypoxia-mediated stabilization of HIF-2 alpha and phosphorylation of signal transducer and activator of transcription 3 (STAT 3) were not affected in the retinas of Hif-1 alpha knockdown mice. Thus, these factors are candidates for regulating the resistance of photoreceptors to light damage after hypoxic preconditioning, along with several potentially neuroprotective genes that were similarly induced in hypoxic knockdown and control mice.
- Published
- 2009
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44. Nonessential role of beta3 and beta5 integrin subunits for efficient clearance of cellular debris after light-induced photoreceptor degeneration.
- Author
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Joly S, Samardzija M, Wenzel A, Thiersch M, and Grimm C
- Subjects
- Animals, Blotting, Western, Chemokine CCL2 metabolism, Dark Adaptation, Fluorescent Antibody Technique, Indirect, Focal Adhesion Protein-Tyrosine Kinases metabolism, Light, Macrophages physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Radiation Injuries, Experimental etiology, Retinal Degeneration etiology, Reverse Transcriptase Polymerase Chain Reaction, Up-Regulation, Integrin beta Chains physiology, Integrin beta3 physiology, Phagocytosis physiology, Photoreceptor Cells, Vertebrate radiation effects, Radiation Injuries, Experimental metabolism, Retinal Degeneration metabolism
- Abstract
Purpose: During light-induced photoreceptor degeneration, large amounts of cellular debris are formed that must be cleared from the subretinal space. The integrins alphavbeta5 and alphavbeta3 are involved in the normal physiological process of phagocytosis in the retina. This study was conducted to investigate the question of whether the lack of beta5 and/or beta3 integrin subunits might influence the course of retinal degeneration and/or clearance of photoreceptor debris induced by acute exposure to light., Methods: Wild-type, beta5(-/-) and beta3(-/-) single-knockout, and beta3(-/-)/beta5(-/-) Ccl2(-/-)/beta5(-/-) double-knockout mice were exposed to 13,000 lux of white light for 2 hours to induce severe photoreceptor degeneration. Real-time PCR and Western blot analysis were used to analyze gene and protein expression, light- and electron microscopy to judge retinal morphology, and immunofluorescence to study retinal distribution of proteins., Results: Individual or combined deletion of beta3 and beta5 integrin subunits did not affect the pattern of photoreceptor cell loss or the clearance of photoreceptor debris in mice compared with that in wild-type mice. Invading macrophages may contribute to efficient phagocytosis. However, ablation of the MCP-1 gene did not prevent macrophage recruitment. Several chemokines in addition to MCP-1 were induced after light-induced damage that may have compensated for the deletion of MCP-1., Conclusions: Acute clearance of a large amount of cellular debris from the subretinal space involves invading macrophages and does not depend on beta3 and beta5 integrins.
- Published
- 2009
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45. Analysis of the retinal gene expression profile after hypoxic preconditioning identifies candidate genes for neuroprotection.
- Author
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Thiersch M, Raffelsberger W, Frigg R, Samardzija M, Wenzel A, Poch O, and Grimm C
- Subjects
- Animals, Computational Biology, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Gene Expression Regulation, Enzymologic, Genome genetics, Light, Mice, Neuroprotective Agents, Oligonucleotide Array Sequence Analysis, Oxygen metabolism, Retinal Degeneration genetics, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Transcription, Genetic genetics, Gene Expression Profiling, Hypoxia genetics, Ischemic Preconditioning, Retina metabolism, Retina pathology
- Abstract
Background: Retinal degeneration is a main cause of blindness in humans. Neuroprotective therapies may be used to rescue retinal cells and preserve vision. Hypoxic preconditioning stabilizes the transcription factor HIF-1alpha in the retina and strongly protects photoreceptors in an animal model of light-induced retinal degeneration. To address the molecular mechanisms of the protection, we analyzed the transcriptome of the hypoxic retina using microarrays and real-time PCR., Results: Hypoxic exposure induced a marked alteration in the retinal transcriptome with significantly different expression levels of 431 genes immediately after hypoxic exposure. The normal expression profile was restored within 16 hours of reoxygenation. Among the differentially regulated genes, several candidates for neuroprotection were identified like metallothionein-1 and -2, the HIF-1 target gene adrenomedullin and the gene encoding the antioxidative and cytoprotective enzyme paraoxonase 1 which was previously not known to be a hypoxia responsive gene in the retina. The strongly upregulated cyclin dependent kinase inhibitor p21 was excluded from being essential for neuroprotection., Conclusion: Our data suggest that neuroprotection after hypoxic preconditioning is the result of the differential expression of a multitude of genes which may act in concert to protect visual cells against a toxic insult.
- Published
- 2008
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46. R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal.
- Author
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Samardzija M, von Lintig J, Tanimoto N, Oberhauser V, Thiersch M, Remé CE, Seeliger M, Grimm C, and Wenzel A
- Subjects
- Age of Onset, Animals, Carrier Proteins genetics, Eye Proteins genetics, Humans, Mice, Photoreceptor Cells metabolism, Point Mutation, Retinal Diseases epidemiology, Retinal Diseases genetics, cis-trans-Isomerases, Carrier Proteins metabolism, Eye Proteins metabolism, Mutation, Missense, Retinal Diseases metabolism, Retinaldehyde metabolism
- Abstract
RPE65 is a retinal pigment epithelial protein essential for the regeneration of 11-cis-retinal, the chromophore of cone and rod visual pigments. Mutations in RPE65 lead to a spectrum of retinal dystrophies ranging from Leber's congenital amaurosis to autosomal recessive retinitis pigmentosa. One of the most frequent missense mutations is an amino acid substitution at position 91 (R91W). Affected patients have useful cone vision in the first decade of life, but progressively lose sight during adolescence. We generated R91W knock-in mice to understand the mechanism of retinal degeneration caused by this aberrant Rpe65 variant. We found that in contrast to Rpe65 null mice, low but substantial levels of both RPE65 and 11-cis-retinal were present. Whereas rod function was impaired already in young animals, cone function was less affected. Rhodopsin metabolism and photoreceptor morphology were disturbed, leading to a progressive loss of photoreceptor cells and retinal function. Thus, the consequences of the R91W mutation are clearly distinguishable from an Rpe65 null mutation as evidenced by the production of 11-cis-retinal and rhodopsin as well as by less severe morphological and functional disturbances at early age. Taken together, the pathology in R91W knock-in mice mimics many aspects of the corresponding human blinding disease. Therefore, this mouse mutant provides a valuable animal model to test therapeutic concepts for patients affected by RPE65 missense mutations.
- Published
- 2008
- Full Text
- View/download PDF
47. The hypoxic transcriptome of the retina: identification of factors with potential neuroprotective activity.
- Author
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Thiersch M, Raffelsberger W, Frigg E, Samardzija M, Blank P, Poch O, and Grimm C
- Subjects
- Animals, Apoptosis radiation effects, Cell Death radiation effects, Enzyme-Linked Immunosorbent Assay, Hypoxia genetics, Light adverse effects, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Mutant Strains, Neuroprotective Agents administration & dosage, Oligonucleotide Array Sequence Analysis, Time Factors, Gene Expression Profiling, Gene Expression Regulation drug effects, Hypoxia metabolism, Neuroprotective Agents pharmacology, Retina drug effects
- Published
- 2008
- Full Text
- View/download PDF
48. Caspase-1 ablation protects photoreceptors in a model of autosomal dominant retinitis pigmentosa.
- Author
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Samardzija M, Wenzel A, Thiersch M, Frigg R, Remé C, and Grimm C
- Subjects
- Animals, Apoptosis, Blotting, Western, Chemokine CCL2 metabolism, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Enzymologic physiology, Genes, Dominant, Light, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Knockout, Neuroprotective Agents, Photoreceptor Cells, Vertebrate pathology, Radiation Injuries, Experimental prevention & control, Receptors, Interleukin-1 Type I metabolism, Retina radiation effects, Retinal Degeneration prevention & control, Retinitis Pigmentosa enzymology, Retinitis Pigmentosa genetics, Retinitis Pigmentosa pathology, Reverse Transcriptase Polymerase Chain Reaction, Caspase 1 physiology, Photoreceptor Cells, Vertebrate enzymology, Retinitis Pigmentosa prevention & control
- Abstract
Purpose: Caspase-1 gene expression has been reported to be upregulated during light-induced retinal degeneration and to be reduced after neuroprotective treatments. Thus, caspase-1 may be proapoptotic in the retina. To test directly the role of caspase-1 in photoreceptor apoptosis, three mouse models were analyzed for retinal degeneration in the presence or absence of caspase-1., Methods: Photoreceptor apoptosis was monitored in one model of induced (exposure to light) and in two models of inherited (rd1, VPP) retinal degeneration. Retinal degeneration was assessed qualitatively by light microscopy and quantitatively by the determination of free nucleosomes with ELISA or by rhodopsin measurements. Gene expression and protein levels were assessed by real-time RT-PCR and by Western blot analysis, respectively., Results: Levels of caspase-1 proenzyme increased in all models of retinal degeneration concomitantly with the onset of cell death. Maturation or classic activity of caspase-1 was not detected in the retina. Ablation of caspase-1 was protective in the model of adRP (VPP mouse), but not in the two other models. Ablation of interleukin-1 receptor type 1 was without effect. Expression of monocyte chemoattractant protein (MCP)-1 increased in the model protected by caspase-1 ablation., Conclusions: Increased retinal expression of caspase-1 proenzyme may be a common marker for photoreceptor degeneration. The differential effects of caspase-1 ablation suggests a modulatory role of caspase-1 for photoreceptor apoptosis in some but not all models. Such a modulatory activity may involve a caspase-1 function different from the classic activation of interleukin-1beta.
- Published
- 2006
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49. Differential role of Jak-STAT signaling in retinal degenerations.
- Author
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Samardzija M, Wenzel A, Aufenberg S, Thiersch M, Remé C, and Grimm C
- Subjects
- Animals, Apoptosis, Interleukin-6 metabolism, Light, Mice, Mice, Inbred BALB C, Photoreceptor Cells physiology, Protein-Tyrosine Kinases metabolism, Retinal Degeneration pathology, Signal Transduction, Retinal Degeneration physiopathology, STAT Transcription Factors physiology
- Abstract
Retinal degeneration is a major cause of severe visual impairment or blindness. Understanding the underlying molecular mechanisms is a prerequisite to develop therapeutic approaches for human patients. We show in three mouse models that induced and inherited retinal degeneration induces LIF and CLC as members of the interleukin (IL)-6 family of proteins, activates proteins of the Jak-STAT signaling pathway, and up-regulates suppressors of cytokine signaling as a negative feedback loop. Inhibition of Jak2 leads to protection of photoreceptors in a model of induced but not in a model of inherited retinal degeneration. Differential activation of Akt suggests alternative pathways for cell death and/or survival in different models. Proteins induced during photoreceptor degeneration are not mainly expressed in photoreceptors but in cells of other retinal layers. This suggests a model in which photoreceptor injury is signaled to cells of the inner retina, which in turn initiate a response either to support viability or accelerate death of injured cells.
- Published
- 2006
- Full Text
- View/download PDF
50. Pseudomonas putida KT2440 responds specifically to chlorophenoxy herbicides and their initial metabolites.
- Author
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Benndorf D, Thiersch M, Loffhagen N, Kunath C, and Harms H
- Subjects
- 2,4-Dichlorophenoxyacetic Acid analogs & derivatives, 2,4-Dichlorophenoxyacetic Acid toxicity, 2,4-Dinitrophenol toxicity, Catechols toxicity, Electrophoresis, Gel, Two-Dimensional, Fumarate Hydratase metabolism, Mixed Function Oxygenases metabolism, Oxidation-Reduction, Phosphorylation, Pseudomonas putida metabolism, Bacterial Proteins metabolism, Herbicides toxicity, Proteome metabolism, Pseudomonas putida drug effects
- Abstract
Pseudomonas putida KT2440 is often used as a model to investigate toxicity mechanisms and adaptation to hazardous chemicals in bacteria. The objective of this paper was to test the impact of the chlorophenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-(2,4-dichlorophenoxy)propanoic acid (DCPP) and their metabolites 2,4-dichlorophenol (DCP) and 3,5-dichlorocatechol (DCC), on protein expression patterns and physiological parameters. Both approaches showed that DCC has a different mode of action and induces different responses than DCPP, 2,4-D and DCP. DCC was the most toxic compound and was active as an uncoupler of oxidative phosphorylation. It repressed the synthesis of ferric uptake regulator (Fur)-dependent proteins, e.g. fumarase C and L-ornithine N5-oxygenase, which are involved in oxidative stress response and iron uptake. DCPP, 2,4-D and DCP were less toxic than DCC. They disturbed oxidative phosphorylation to a lesser extent by a yet unknown mechanism. Furthermore, they repressed enzymes of energy-consuming biosynthetic pathways and induced membrane transporters for organic substrates. A TolC homologue component of multidrug resistance transporters was found to be induced, which is probably involved in the removal of lipophilic compounds from membranes.
- Published
- 2006
- Full Text
- View/download PDF
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