Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in aging and disease. It is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites. MG (methylglyoxal) is a dicarbonyl metabolite of relatively high flux of formation and precursor of the most quantitatively and functionally important spontaneous modifications of protein and DNA clinically. Major MG-derived adducts are arginine-derived hydroimidazolones of protein and deoxyguanosine-derived imidazopurinones of DNA. These are formed non-oxidatively. The glyoxalase system provides an efficient and essential basal and stress-response-inducible enzymatic defence against dicarbonyl stress by the reduced glutathione-dependent metabolism of methylglyoxal by glyoxalase 1. The GLO1 gene encoding glyoxalase 1 has low prevalence duplication and high prevalence amplification in some tumours. Dicarbonyl stress contributes to aging, disease and activity of cytotoxic chemotherapeutic agents. It is found at a low, moderate and severe level in obesity, diabetes and renal failure respectively, where it contributes to the development of metabolic and vascular complications. Increased glyoxalase 1 expression confers multidrug resistance to cancer chemotherapy and has relatively high prevalence in liver, lung and breast cancers. Studies of dicarbonyl stress are providing improved understanding of aging and disease and the basis for rational design of novel pharmaceuticals: glyoxalase 1 inducers for obesity, diabetes and cardiovascular disease and glyoxalase 1 inhibitors for multidrug-resistant tumours. The first clinical trial of a glyoxalase 1 inducer in overweight and obese subjects showed improved glycaemic control, insulin resistance and vascular function.
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October 2016
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Targeted cancer treatment. In this issue, Gopal et al, review the molecular mechanisms of vascular complications of targeted cancer therapies. See pp. 1763–1779 for further details.
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August 23 2016
Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments
Naila Rabbani;
Naila Rabbani
*AGE-omics and Systems Biology Research Group, Warwick Systems Biology Centre, Coventry House, University of Warwick, Coventry CV4 7AL, U.K.
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Mingzhan Xue;
Mingzhan Xue
†Glyoxalase Research Group, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
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Paul J. Thornalley
*AGE-omics and Systems Biology Research Group, Warwick Systems Biology Centre, Coventry House, University of Warwick, Coventry CV4 7AL, U.K.
†Glyoxalase Research Group, Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
Correspondence: Professor Paul J. Thornalley (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 14 2016
Revision Received:
June 02 2016
Accepted:
June 03 2016
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Clin Sci (Lond) (2016) 130 (19): 1677–1696.
Article history
Received:
January 14 2016
Revision Received:
June 02 2016
Accepted:
June 03 2016
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Citation
Naila Rabbani, Mingzhan Xue, Paul J. Thornalley; Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments. Clin Sci (Lond) 1 October 2016; 130 (19): 1677–1696. doi: https://doi.org/10.1042/CS20160025
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