Multi-disciplinary, working in the field of disease mechanisms - particularly in the study of damage to the proteome by glycation, oxidation and nitration, related enzymatic countermeasures and other metabolic dysfunction. Diseases under current investigation are: vascular complications of diabetes, renal failure and ageing. Therapeutic problems under current investigation are: high dose thiamine therapy for the prevention of diabetic nephropathy, dialysis renal replacement therapy, antistress gene response activators for prevention of vascular disease and healthy ageing, and glyoxalase 1-mediated multidrug resistance. Novel diagnostics under investigation are: biomarkers for vascular and metabolic health, joint health, and healthy ageing.
My PhD studies and initial post-doctoral research was on oxidative stress and free radical mediated processes in cellular and pharmacological processes. Since then I have worked for over 25 years on processes of protein glycation involved in the development of microvascular complications in diabetes, renal failure and ageing, publishing a total of 229 peer-reviewed articles and 154 conference papers with h-factor 52. I have also filed 7 patents. I have a career-long interest in protein glycation by physiological dicarbonyl compounds ‒ particularly methylglyoxal (MG) ‒ and its suppression in physiological systems by the glyoxalase system. MG is now viewed as one of the most important precursors of advanced glycation endproducts (AGEs) in physiological systems and causes of spontaneous modifications to the proteome. In initial studies, my team developed and published biochemical methods for characterising MG metabolism by the glyoxalase system: activity, protein, genotype measurements of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2); concentrations of metabolites MG, S-D-lactoylglutathione and D-lactate; molecular characteristics of human Glo1 and Glo2; and prototype cell permeable Glo1 inhibitor. These remain standard reference methods. I pioneered studies on the link of increased formation of MG in diabetes and the link to microvascular disease ‒ now viewed as important dysfunctional biochemical pathway linked to diabetic complications. I organised the first international symposium on 'Glyoxalase in Health and Disease' in 1992.
I led studies on the mechanism of protein glycation by dicarbonyl compounds, identifying the major adducts formed ‒ arginine-derived hydroimidazolones. I developed liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for comprehensive quantitative screening of protein damage by glycation, oxidation and nitration ‒ providing for the first time a near complete profile of protein damage in diabetes, renal failure and other diseases. Thereby I discovered the widespread occurrence of endogenous dicarbonyl glycation of both cellular and extracellular proteins, export of proteolytic debris of dicarbonyl modified proteins from cells ‒ 'glycation free adducts' ‒ into plasma and other body fluids and efficient renal clearance and excretion of glycation free adducts in urine. I found profound plasma accumulation of glycation free adducts in diabetes and renal failure and identified glycation free adducts as the major form by which the body excretes protein glycation damage. Dialysis clears the same products in renal replacement therapy.
I introduced the concepts of 'dicarbonyl proteome' and 'enzymatic defence against glycation'. The dicarbonyl proteome are proteins susceptible to functional impairment by dicarbonyl glycation. Important examples are type IV collagen (modification leading to endothelial cell anoikis) and cytochrome c1 (modification linked to increased reactive oxygen species formation). The enzymatic defence against glycation are enzymes protective against glycation damage. Glo1 is a key member of the anti-glycation defence ‒ together with fructosamine 3-phosphokinase and aldoketo reductases. I organised the first international meeting on this topic in 2003.
I have collaborated widely with leading international research teams on vascular complications of diabetes, renal failure, arthritis and ageing to disclose the role of dicarbonyl glycation and Glo1 in disease processes and ageing. For example, reporting recently the increased lifespan of Caenorhabditis elegans achieved by overexpression of Glo1 and decreased lifespan by Glo1 silencing. Other studies have revealed: down-regulation of Glo1 by activation of the receptor for AGEs (RAGE) and increased dicarbonyl tissue injury in arthritis and other inflammatory disorders; and importance of Glo1 in neurological disorders ‒ further research areas to be fully explored for clinical benefit.
Other recent achievements and activities are:
(i) I led studies on high dose thiamine therapy for the prevention of diabetic nephropathy ‒ an intervention decreasing MG formation in diabetes. I discovered tissue-specific thiamine deficiency in experimental and clinical diabetes. I designed, coordinated and reported the first pilot intervention trial of high dose thiamine therapy in type 2 diabetic patients with early stage nephropathy. Thiamine therapy reversed early stage nephropathy and improved renal function in all patients treated. (ii) Collaborative research revealed that MG is the precursor of major endogenous DNA damage adducts (imidazopurinones) and the Glo1 gene is amplified in ca. 10% of human tumours conferring associated multidrug resistance.
(iii) I and my colleague, Dr Naila Rabbani, are co-founding editors of the first peer-review journal for glycation research ‒ Amino Acids-Glycation (Springer).
Dr Naila Rabbani and I currently co-direct our research team recognised as an international authority and research activity hub on protein damage in human disease, collaborating with leading international outreach partners.
CURRENT RESEARCH PROJECTS
BIOmarkers of Robustness of Metabolic Homeostasis for Nutrigenomics-derived Health CLAIMS Made on Food (BIOCLAIMS), Funded by: EU FP7,
Project Start Date:
01/03/2010
Project End Date:
28/02/2015
Effect of glyoxalase 1 silencing and gene deletion on development of diabetic nephropathy, with Dr Naila Rabbani, University of Warwick, Dr Naila Rabbani, Funded by: Saudi Arabian Ministry of Education,
Project Start Date:
01/01/2011
Project End Date:
31/12/2014
Anti-stress gene response in cell and tissue ageing: role of transcription factor NF-E2-related factor-2 and effect of dietary activators, Funded by: BBSRC-Unilever,
Project Start Date:
01/03/2010
Project End Date:
28/02/2014
Effect of dicarbonyl glycation of pancreatic beta-cell function, with Dr Paul Squires, Life Sciences, Funded by: BBSRC,
Project Start Date:
01/10/2010
Project End Date:
30/09/2013
Mechanism of increased renal clearance of thiamine in hyperglycaemia associated with diabetes., with Dr Naila Rabbani, Funded by: Diabetes UK,
Project Start Date:
01/10/2008
Project End Date:
31/03/2012
Murphy, M. P., Holmgren, A., Larsson, N. -G., Halliwell, B., Chang, C. J., Kalyanaraman, B., Rhee, S. G., Thornalley, P. J., Partridge, L., Gems, D., Nyström, T., Belousov, V., Schumacker, P. T. and Winterbourn, C. C.(2011) 'Unraveling the biological roles of reactive oxygen species'
Cell Metabolism (Print Edition)
13
(4), 361 - 366 (1550-4131)
Thornalley, P. J. and Rabbani, N.(2011) 'Protein damage in diabetes and uremia?identifying hotspots of proteome damage where minimal modification is amplified to marked pathophysiological effect'
Free Radical Research
45
(1), 89 - 100 (1071-5762)
Rabbani, N. and Thornalley, P.J.(2011) 'Emerging role of thiamine therapy for prevention and treatment of early stage diabetic nephropathy.'
Diabetes Obesity And Metabolism
In press
(1462-8902)
Rabbani, N. and Thornalley, P.J.(2011) 'Glyoxalase in diabetes, obesity and related disorders.'
Seminars In Cell And Developmental Biology
In press
(1084-9521)
Xue, M., Rabbani, N. and Thornalley, P. J.(2011) 'Glyoxalase in ageing'
Seminars In Cell And Developmental Biology
In press
(1084-9521)
Effect of dicarbonyl glycation on the development of diabetic complications, Date of Completion:
2014
Anti-stress gene response in cell and tissue ageing: role of transcription factor NF-E2-related factor-2 and effect of dietary activators, Date of Completion:
2014
Effect of dicarbonyl glycation of pancreatic beta-cell function, Date of Completion:
2013
Dicarbonyl glycation and endoethial dysfunction in hyperglycaemia associated with diabetes, Date of Completion:
2012
Mechanism of increased renal clearance of thiamine in hyperglycaemia associated with diabetes, Date of Completion:
2012
Biomarkers of protein damage in athritis, Date of Completion:
2011
The role of the kidney in diabetic thiamine defciency, Date of Completion:
2010
Preparation and measurement of dicarbonyl glycation adducts of deoxyguanosine in diabetes and multidrug resistance associated with glyoxalase 1, Date of Completion:
2009
Glycation of human serum albumin, haemoglobin and lens crystallins and capsule collagen by methylglyoxal and other alpha-oxoaldehydes in vivo, Date of Completion:
2009
Methylglyoxal as a downstream mediator of antitumour drug cytotoxicity and link to glyoxalase 1 - associated multidrug resistance, Date of Completion:
2008
Pharmacokinetics and pharmacodynamics of high dose therapy with thiamine and Benfotiamine in diabetes, Date of Completion:
2007
Preparation and measurement of dicarbonyl glycation adducts of deoxyguanosine., Date of Completion:
2007
Studies of the prevention of diabetic nephropathy by thiamine. Protein damage studies., Date of Completion:
2007
Induction of antioxidant response element - linked gene expression by dietary isothiocyanates, Date of Completion:
2007
Glycation of collagen in health and disease - structural and functional studies, Date of Completion:
2007
Studies of the prevention of diabetic nephropathy by thiamine. Protein kinase C studies, Date of Completion:
2003
Studies on the formation, metabolism and glycation reactions of endogenous and exogenous alpha-oxoaldehydes in uraemia, Date of Completion:
2003
Study on the chromatographic analysis of glycation adducts, Date of Completion:
2002
Thiamine metabolism associated with biochemical dysfunction in diabetes mellitus and triosephosphate isomerase deficiency, Date of Completion:
2001
