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27. On the inhibition of 5-lipoxygenase product formation by tryptanthrin: mechanistic studies and efficiency in vivo

Author

Pergola C, Jazzar B, Northoff H, Hamburger M, Werz O., ROSSI, ANTONIETTA, SAUTEBIN, LIDIA, Pergola, C, Jazzar, B, Rossi, Antonietta, Northoff, H, Hamburger, M, Sautebin, Lidia, and Werz, O.

Abstract

BACKGROUND AND PURPOSE:Leukotrienes (LTs) are pro-inflammatory mediators produced by 5-lipoxygenase (5-LO). Currently available 5-LO inhibitors either lack efficacy or are toxic and novel approaches are required to establish a successful anti-LT therapy. Here we provide a detailed evaluation of the effectiveness of the plant-derived alkaloid tryptanthrin as an inhibitor of LT biosynthesis. EXPERIMENTAL APPROACH: We analysed LT formation and performed mechanistic studies in human neutrophils stimulated with pathophysiologically relevant stimuli (LPS and formyl peptide), as well as in cell-free assays (neutrophil homogenates or recombinant human 5-LO) and in human whole blood. The in vivo effectiveness of tryptanthrin was evaluated in the rat model of carrageenan-induced pleurisy. KEY RESULTS: Tryptanthrin potently reduced LT-formation in human neutrophils (IC(50) = 0.6µM). However, tryptanthrin is not a redox-active compound and did not directly interfere with 5-LO activity in cell-free assays. Similarly, tryptanthrin did not inhibit the release of arachidonic acid, the activation of MAPKs, or the increase in [Ca(2+) ](i) , but it modified the subcellular localization of 5-LO. Moreover, tryptanthrin potently suppressed LT formation in human whole blood (IC(50) = 10µM) and reduced LTB(4) levels in the rat pleurisy model after a single oral dose of 10mg·kg(-1) . CONCLUSIONS AND IMPLICATIONS: Our data reveal that tryptanthrin is a potent natural inhibitor of cellular LT biosynthesis with proven efficacy in whole blood and is effective in vivo after oral administration. Its unique pharmacological profile supports further analysis to exploit its pharmacological potential.

Published
2012

28. Book reviews

Author

Seifried, E., TeVelde, J., Bunjes, D., Northoff, H., Stange, E. F., Brudler, O., Kabelitz, D., Lechner, K., Fauser, A. A., Mueller-Eckhardt, C., Beck, E. A., Anger, G., Malberg, K., Binder, T., Weinzel, H., and Heene, D. L.

Published
1985
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32. Basic research and clinical applications of non-hematopoietic stem cells, 4–5 April 2008, Tübingen, Germany

Author

Schäfer, R., Dominici, M., Müller, I., Horwitz, E., Asahara, T., Bulte, Jwm, Bieback, K., Blanc, K Le, Bühring, Hj, Capogrossi, Mc, Dazzi, F., Gorodetsky, R., Henschler, R., Handgretinger, R., Kajstura, J., Kluger, Pj, Lange, C., Luettichau, I von, Mertsching, H., Schrezenmeier, H., Sievert, Kd, Strunk, D., Verfaillie, C., and Northoff, H.

Published
2009
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34. In vitro desensitization to lipopolysaccharide suppresses tumour necrosis factor, interleukin-1 and interleukin-6 gene expression in a similar fashion

Author

Ziegler-Heitbrock, H W, Blumenstein, M, Käfferlein, E, Kieper, D, Petersmann, I, Endres, S, Flegel, W A, Northoff, H, Riethmüller, G, and Haas, J G

Subjects
Lipopolysaccharides, Antigens, Bacterial, Staphylococcus aureus, Desensitization, Immunologic, Interleukin-6, Tumor Necrosis Factor-alpha, Gene Expression, Humans, Muramidase, Cells, Cultured, Research Article, Cell Line, Interleukin-1
Abstract

Like blood monocytes, the human monocytic cell line Mono Mac 6 can be stimulated by lipopolysaccharide (LPS) at 1 microgram/ml to produce high levels of cytokines. When Mono Mac 6 cells are stimulated for 4-6 hr at 1 x 10(6)/ml, supernatants contain tumour necrosis factor (TNF) at an average of 60 U/ml and interleukin-6 (IL-6) at an average of 1000 U/ml. IL-1 is not detected in the supernatant, but after three freeze-thaw cycles cell-associated IL-1 can be detected (100 U/ml) and with similar amounts of IL-alpha and -beta. Preculture of Mono Mac 6 cells with LPS at 10 ng/ml for 3 days results in cells refractory to subsequent stimulation by LPS at 1 microgram/ml. In the refractory desensitized cells, production of all three cytokines is down-regulated, with a more than 10-fold reduction in protein production. For all three cytokines, this desensitization appears to be regulated at the transcript level, with a strong reduction in specific mRNA as detected by Northern blot analysis. Furthermore, Mono Mac 6 cells can be stimulated by Staphylococcus aureus (LPS contamination less than 10 pg/ml) to produce cytokines. This type of stimulus is unable to overcome desensitization, in that the secretion of TNF in LPS-precultured Mono Mac 6 cells was 10- to 100-fold lower than in Mono Mac 6 cells without LPS preculture. These data show that desensitization in Mono Mac 6 cells affects all three cytokines tested and that it extends to other activating signals, such as staphylococci.

Published
1992

35. Blutersatzlösungen.

Author

Weinstock, C., Dinkelmann, S., and Northoff, H.

Abstract

Copyright of Transfusionsmedizin und Immunhämatologie is the property of Springer Nature / Books and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2011
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36. Survival, neuron-like differentiation and functionality of mesenchymal stem cells in neurotoxic environment: the critical role of erythropoietin.

Author

Danielyan, L., Schäfer, R., Schulz, A., Ladewig, T., Lourhmati, A., Buadze, M., Schmitt, A. L., Verleysdonk, S., Kabisch, D., Koeppen, K., Siegel, G., Proksch, B., Kluba, T., Eckert, A., Köhle, C., Schöneberg, T., Northoff, H., Schwab, M., and Gleiter, C. H.

Subjects
STEM cells, ERYTHROPOIETIN, HEMATOPOIETIC growth factors, HYPOXEMIA, CENTRAL nervous system, NEURODEGENERATION
Abstract

Mesenchymal stem cells (MSCs) can ameliorate symptoms in several neurodegenerative diseases. However, the toxic environment of a degenerating central nervous system (CNS) characterized by hypoxia, glutamate (Glu) excess and amyloid beta (Abeta) pathology may hamper the survival and regenerative/replacing capacities of engrafted stem cells. Indeed, human MSC (hMSC) exposed to hypoxia were disabled in (i) the capacity of their muscarinic receptors (mAChRs) to respond to acetylcholine (ACh) with a transient increase in intracellular [Ca2+], (ii) their capacity to metabolize Glu, reflected by a strong decrease in glutamine synthetase activity, and (iii) their survival on exposure to Glu. Cocultivation of MSC with PC12 cells expressing the amyloid precursor protein gene (APPsw-PC12) increased the release of IL-6 from MSC. HMSC exposed to erythropoietin (EPO) showed a cholinergic neuron-like phenotype reflected by increased cellular levels of choline acetyltransferase, ACh and mAChR. All their functional deficits observed under hypoxia, Glu exposure and APPsw-PC12 cocultivation were reversed by the application of EPO, which increased the expression of Wnt3a. EPO also enhanced the metabolism of Abeta in MSC by increasing their neprilysin content. Our data show that cholinergic neuron-like differentiation of MSC, their functionality and resistance to a neurotoxic environment is regulated and can be improved by EPO, highlighting its potential for optimizing cellular therapies of the CNS. [ABSTRACT FROM AUTHOR]

Published
2009
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37. Antioxidant intervention does not affect the response of plasma erythropoietin to short-term normobaric hypoxia in humans.

Author

Niess, A.M., Fehrenbach, E., Lorenz, I., Müller, A., Northoff, H., Dickhuth, H.-H., and Schneider, E.M.

Subjects
ACTIVE oxygen in the body, BLOOD plasma, ERYTHROPOIETIN, PEROXIDES, OXYGEN in the body, ANTIOXIDANTS
Abstract

Investigates the role of reactive oxygen species (ROS) in the response of plasma erythropoietin (Epo) to short-term normobaric hypoxia in humans. Finding that plasma peroxide levels were lower under antioxidant treatment but not affected by hypoxia; Conclusion that individual variability of Epo in response to hypoxia was not related to the individual degree of hypoxemia during hypoxia.

Published
2004
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43. Die Akkumulation von Laktat im Rahmen der Wundheilung stimuliert die Expression von Schlüsselgenen für das Homing mesenchymaler Stammzellen.

Author

Zieker, D., Löffler, M., Königsrainer, I., Löb, S., Glatzle, J., Königsrainer, A., Hunt, T.K., Northoff, H., and Beckert, S.

Abstract

Introduction: Surgical wounds are characterized by tissue lactate accumulation. A recent study was able to detect an increased stem cell count in experimental wounds treated with exogenous lactate. Nevertheless, it remains unclear whether these cells are locally activated stem cells or migrated stem cells from the blood circulation. Therefore, the aim of this study was to investigate the effect of lactate on genes involved in stem cell homing. Material and Methods: Human umbilical vein endothelial cells (HUVEC) and mesenchymal stem cells (MSC) were incubated with different concentrations of lactate. Gene expression analysis was conducted using oligonucleotid-microarrays. Differentially expressed genes of interest were additionally evaluated using qRT-PCR. Protein analysis was performed using FACS, Westernblot and ELISA. Results are given as mean ± SD or as fold-change to control. Results: Lactate induced gene expression of c-Kit (2,4-fold) and CXCR-4 (2,2-fold) in MSC. In HUVEC, gene expression of CXCL-12 (SDF-1) and SCF was enhanced. In lactate-stimulated MSC, FACS analysis confirmed a higher expression for c-Kit and westernblotting for CXCR-4. In the supernatant of lactatetreated HUVEC, ELISA detected higher concentrations of CXCL-12 (SDF-1) and SCF compared to their corresponding controls. Conclusion: Lactate enhances the expression of genes involved in mesenchymal stem cell homing. The association between lactate and stem cell homing provides new insights into the wound healing physiology. Hence, this data might serve for new treatment strategies. [ABSTRACT FROM AUTHOR]

Published
2010
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44. Die PGK1 Überexpression im Magenkarzinom induziert Metastasierung und peritoneale Tumoraussaat.

Author

Königsrainer, I., Beckert, S., Glatzle, J., Löffler, M., Northoff, H., M. Brücher, B.L.D., Königsrainer, A., and Zieker, D.

Abstract

Introduction: Peritoneal carcinomatosis and metastases is a frequent finding in diffuse gastric cancer patients and is associated with a poor prognosis. The enhanced expression of phosphoglycerate kinase 1 (PGK1) seems to play a crucial role in enabling diffuse primary gastric tumours to develop peritoneal dissemination. Material and Methods: A metastatic mouse model was established simulating human gastric cancer behaviour by orthotopic implantation of histologically intact tumor tissue with (n = 7) and without (n = 7) overexpression of PGK1 onto the serosa of nude mice. PET-MRTimaging was performed to evaluate peritoneal carcinomatosis and metastases in-vivo. Subsequent the animals were examined for tumor growth and metastases by histopathological evaluation and compared among each other. Results: Histopathological examinations revealed that overexpression of PGK1 significantly increased peritoneal carcinomatosis and metastases of human gastric cancer in nude mice. The mean tumorindex (tumorweight in relation to the body weight of the animals in %) in PGK1 overexpressed mice was 15.9 % and in the non-overexpressed mice by 8.4 % (p = 0.006). We were further able to confirm this findings in-vivo using PET-MRT-imaging, showing a strong correlation to the obtained histopathological alterations. Conclusion: The overexpression of PGK1 appears to be a crucial enzyme enabling gastric tumor cells to disseminate. Thus, PGK1 may serve in future as prognostic marker and/or be a potential therapeutic target to prevent peritoneal carcinomatosis and metastases in gastric cancer. [ABSTRACT FROM AUTHOR]

Published
2010
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48. <em>In vitro</em> desensitization to lipopolysaccharide suppresses tumour necrosis factor interleukin-1 and interleukin-6 gene expression in a similar fashion.

Author

Ziegler-Heitbrock, H. W. L., Blumenstein, M., Käfferlein, E., Kieper, D., Petersmann, I., Endres, S., Flegel, W. A., Northoff, H., Riethmüller, G., and Haas, J. G.

Subjects
MONOCYTES, CELL lines, CYTOKINES, CELLULAR immunity, TUMOR necrosis factors, MACROPHAGES, GENE expression, STAPHYLOCOCCUS aureus
Abstract

Like blood monocytes, the human monocytic cell line Mono Mac 6 can be stimulated by lipopolysaccharide (LPS) at 1 μg/ml to produce high levels of cytokines. When Mono Mac 6 cells are stimulated for 4-6 hr at I × 106/ml, supernatants contain tumour necrosis factor (TNF) at an average of 60 U/mi and interleukin-6 (IL-6) at an average of 1000 U/ml. IL-1 is not detected in the supernatant, but after three freeze-thaw cycles cell-associated IL-1 can be detected (100 U/mI) and with similar amounts of IL-α and-β. Preculture of Mono Mac 6 cells with LPS at 10 μg/ml for 3 days results in cells refractory to subsequent stimulation by LPS at 1 μg/mI. In the refractory desensitized cells, production of all three cytokines is down-regulated, with a more than 10-fold reduction in protein production. For all three cytokines, this desensitization appears to be regulated at the transcript level, with a strong reduction in specific mRNA as detected by Northern blot analysis. Furthermore, Mono Mac 6 cells can be stimulated by Staphylococcus aureus (LPS contamination <10 μg/mI) to produce cytokines. This type of stimulus is unable to overcome desensitization, in that the secretion of TNF in LPS-precultured Mono Mac 6 cells was 10- to 100-fold lower than in Mono Mac 6 cells without LPS preculture. These data show that desensitization in Mono Mac 6 cells affects all three cytokines tested and that it extends to other activating signals, such as staphylococci. [ABSTRACT FROM AUTHOR]

Published
1992

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