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Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11-7082, parthenolide and dimethyl fumarate

M. Ghashghaeinia, D. Giustarini, P. Koralkova, M. Köberle, K. Alzoubi, R. Bissinger, Z. Hosseinzadeh, P. Dreischer, I. Bernhardt, F. Lang, M. Toulany, T. Wieder, R. Mojzikova, R. Rossi, U. Mrowietz,

. 2016 ; 6 (-) : 28754. [pub] 20160629

Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc18025358

In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11-7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11-7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11-7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach "Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target" (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity.

Citace poskytuje Crossref.org

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$a Pharmacological targeting of glucose-6-phosphate dehydrogenase in human erythrocytes by Bay 11-7082, parthenolide and dimethyl fumarate / $c M. Ghashghaeinia, D. Giustarini, P. Koralkova, M. Köberle, K. Alzoubi, R. Bissinger, Z. Hosseinzadeh, P. Dreischer, I. Bernhardt, F. Lang, M. Toulany, T. Wieder, R. Mojzikova, R. Rossi, U. Mrowietz,
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$a In mature erythrocytes, glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) yield NADPH, a crucial cofactor of the enzyme glutathione reductase (GR) converting glutathione disulfide (GSSG) into its reduced state (GSH). GSH is essential for detoxification processes in and survival of erythrocytes. We explored whether the anti-inflammatory compounds Bay 11-7082, parthenolide and dimethyl fumarate (DMF) were able to completely deplete a common target (GSH), and to impair the function of upstream enzymes of GSH recycling and replenishment. Treatment of erythrocytes with Bay 11-7082, parthenolide or DMF led to concentration-dependent eryptosis resulting from complete depletion of GSH. GSH depletion was due to strong inhibition of G6PDH activity. Bay 11-7082 and DMF, but not parthenolide, were able to inhibit the GR activity. This approach "Inhibitors, Detection of their common target that is completely depleted or inactivated when pharmacologically relevant concentrations of each single inhibitor are applied, Subsequent functional analysis of upstream enzymes for this target" (IDS), can be applied to a broad range of inhibitors and cell types according to the selected target. The specific G6PDH inhibitory effect of these compounds may be exploited for the treatment of human diseases with high NADPH and GSH consumption rates, including malaria, trypanosomiasis, cancer or obesity.
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$a Giustarini, Daniela $u Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Via A Moro 2, 53100, Siena, Italy.
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$a Koralkova, Pavla $u Department of Biology, Faculty of Medicine and Dentistry Palacky University, Hnevotinska 3, 77515 Olomouc, Czech Republic.
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$a Köberle, Martin $u Department of Dermatology and Allergy, Biedersteinerstr. 29, Technische Universität München, 80802 München, Germany.
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$a Alzoubi, Kousi $u Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
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$a Bissinger, Rosi $u Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
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$a Hosseinzadeh, Zohreh $u Centre for Ophthalmology, Institute for Ophthalmic Research, Eberhard-Karls-University Tübingen, Frondsbergstr. 23, 72076 Tübingen, Germany.
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$a Dreischer, Peter $u Institute of Physiology II, Keplerstr. 15, Eberhard Karls University of Tübingen, 72074 Tübingen, Germany.
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$a Bernhardt, Ingolf $u Laboratory of Biophysics, Saarland University, Campus A2.4, 66123 Saarbrücken, Germany.
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$a Lang, Florian $u Department of Cardiology, Vascular Medicine and Physiology, University of Tübingen, Gmelinstr. 5, 72076, Tübingen, Germany.
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$a Toulany, Mahmoud $u Division of Radiobiology and Molecular Environmental Research, Department of Radiation Oncology, Roentgenweg 11, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
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$a Wieder, Thomas $u Department of Dermatology; Eberhard Karls University, Tübingen, Germany.
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$a Mojzikova, Renata $u Department of Biology, Faculty of Medicine and Dentistry Palacky University, Hnevotinska 3, 77515 Olomouc, Czech Republic.
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$a Rossi, Ranieri $u Department of Life Sciences, Laboratory of Pharmacology and Toxicology, University of Siena, Via A Moro 2, 53100, Siena, Italy.
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$a Mrowietz, Ulrich $u Psoriasis-Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Schittenhelmstr. 7, Kiel, 24105, Germany.
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