32 results on '"Thornalley, Paul J."'
Search Results
2. Glycation marker glucosepane increases with the progression of osteoarthritis and correlates with morphological and functional changes of cartilage in vivo
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Legrand, Catherine, Ahmed, Usman, Anwar, Attia, Rajpoot, Kashif, Pasha, Sabah, Lambert, Cécile, Davidson, Rose K., Clark, Ian M., Thornalley, Paul J., Henrotin, Yves, and Rabbani, Naila
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- 2018
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Catalog
3. Dicarbonyl stress in clinical obesity
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Masania, Jinit, Malczewska-Malec, Malgorzata, Razny, Urszula, Goralska, Joanna, Zdzienicka, Anna, Kiec-Wilk, Beata, Gruca, Anna, Stancel-Mozwillo, Julita, Dembinska-Kiec, Aldona, Rabbani, Naila, and Thornalley, Paul J. more...
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- 2016
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4. Mass spectrometric determination of early and advanced glycation in biology
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Rabbani, Naila, Ashour, Amal, and Thornalley, Paul J
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- 2016
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5. Dicarbonyls and glyoxalase in disease mechanisms and clinical therapeutics
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Rabbani, Naila, Xue, Mingzhan, and Thornalley, Paul J.
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- 2016
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6. Study of an Unusual Advanced Glycation End-Product (AGE) Derived from Glyoxal Using Mass Spectrometry
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Lopez-Clavijo, Andrea F., Duque-Daza, Carlos A., Romero Canelon, Isolda, Barrow, Mark P., Kilgour, David, Rabbani, Naila, Thornalley, Paul J., and O’Connor, Peter B.
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- 2014
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7. Analysis of Serum Advanced Glycation Endproducts Reveals Methylglyoxal-Derived Advanced Glycation MG-H1 Free Adduct Is a Risk Marker in Non-Diabetic and Diabetic Chronic Kidney Disease.
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Rabbani, Naila, Adaikalakoteswari, Antonysunil, Larkin, James R., Panagiotopoulos, Sianna, MacIsaac, Richard J., Yue, Dennis K., Fulcher, Gregory R., Roberts, Matthew A., Thomas, Merlin, Ekinci, Elif, and Thornalley, Paul J. more...
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CHRONIC kidney failure ,BLOOD serum analysis ,KIDNEY physiology - Abstract
Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2–4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2–4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD. [ABSTRACT FROM AUTHOR] more...
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- 2023
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8. Effect of Irbesartan treatment on plasma and urinary markers of protein damage in patients with type 2 diabetes and microalbuminuria
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Rabbani, Naila, Adaikalakoteswari, Antonysunil, Rossing, Kasper, Rossing, Peter, Tarnow, Lise, Parving, Hans-Henrik, and Thornalley, Paul J.
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- 2012
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9. Methylglyoxal, glyoxalase 1 and the dicarbonyl proteome
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Rabbani, Naila and Thornalley, Paul J.
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- 2012
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10. Glycation free adduct accumulation in renal disease: the new AGE
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Thornalley, Paul J.
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- 2005
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11. Molecular characteristics of methylglyoxal-modified bovine and human serum albumins. Comparison with glucose-derived advanced glycation endproduct-modified serum albumins
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Westwood, Marie E. and Thornalley, Paul J.
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- 1995
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12. Glyoxalase 1 Modulation in Obesity and Diabetes.
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Rabbani, Naila and Thornalley, Paul J.
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GLYOXALASE , *OBESITY , *TYPE 2 diabetes , *FATTY liver , *PYRUVALDEHYDE - Abstract
Significance: Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression. Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down-regulation of glyoxalase 1 (Glo1)—which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression—Glo1 inducers—exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial. Critical Issues: tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases. Future Directions: Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes. [ABSTRACT FROM AUTHOR] more...
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- 2019
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13. Methylglyoxal-induced dicarbonyl stress in aging and disease: first steps towards glyoxalase 1-based treatments.
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Rabbani, Naila, Mingzhan Xue, and Thornalley, Paul J.
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PYRUVALDEHYDE ,GLYOXALASE ,AGE factors in disease ,GLUTATHIONE ,DISEASE prevalence - Abstract
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. [ABSTRACT FROM AUTHOR] more...
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- 2016
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14. Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease.
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Rabbani, Naila and Thornalley, Paul J.
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CARBONYL compounds , *PROTEIN analysis , *ENZYME metabolism , *CELL-mediated cytotoxicity , *AGE factors in disease - Abstract
Dicarbonyl stress is the abnormal accumulation of dicarbonyl metabolites leading to increased protein and DNA modification contributing to cell and tissue dysfunction in ageing and disease. Enzymes metabolising dicarbonyls, glyoxalase 1 and aldoketo reductases, provide an efficient and stress-response enzyme defence against dicarbonyl stress. Dicarbonyl stress is produced by increased formation and/or decreased metabolism of dicarbonyl metabolites, and by exposure to exogenous dicarbonyls. It contributes to ageing, disease and activity of cytototoxic chemotherapeutic agents. [ABSTRACT FROM AUTHOR] more...
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- 2015
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15. Assay of methylglyoxal and glyoxal and control of peroxidase interference.
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Thornalley, Paul J. and Rabbani, Naila
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PYRUVALDEHYDE , *PEROXIDASE regulation , *BODY fluid analysis , *GLYOXAL , *METABOLIC models - Abstract
Methylglyoxal and glyoxal are endogenous a-oxoaldehyde metabolites and substrates of the glyoxalase system. These and related a-oxoaldehydes are often determined in cell, tissue and body fluid samples by derivatization with 1,2-diaminobenzene and similar compounds. Peroxidase activity in physiological tissues is a potential interference in estimation of methylglyoxal and glyoxal as it catalyses the conversion of 1,2-diaminobenzene into trace amounts of these dicarbonyl metabolites. Residual peroxidase activity in deproteinized extracts is found to cause significant interference in methylglyoxal and glyoxal estimations. This interference is blocked by the addition of sodium azide in the derivatizing buffer. Estimates of methylglyoxal concentration thereby obtained are in keeping with those predicted by systems modelling of methylglyoxal glycation kinetics in situ. Blocking sample peroxidase activity is important to avoid overestimation in the measurement of glyoxal and methylglyoxal. A dicarbonyl assay protocol resistant to interferences is described in the present article. [ABSTRACT FROM AUTHOR] more...
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- 2014
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16. Possible role of methylglyoxal and glyoxalase in arthritis.
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Ahmed, Usman, Thornalley, Paul J., and Rabbani, Naila
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PYRUVALDEHYDE , *GLYOXALASE , *TREATMENT of arthritis , *OSTEOARTHRITIS treatment , *ADVANCED glycation end-products , *DISEASE progression - Abstract
OA (osteoarthritis) and RA (rheumatoid arthritis) lead to deterioration of the joints. Early OA is associated with loss of bone due to increased bone remodelling. A role for inflammation is thought to be integral to the pathology. RA is a chronic inflammatory disease of the synovium, a membrane lining the non-weightbearing surfaces of the joint. The mainstay of RA diagnostic testing is for autoantibodies. Rheumatoid factor has been a primary diagnostic test; however, sensitivity is approximately 75%, but specificity is limited. Recently, detection of antibodies against cyclic citrullinated peptide, identified as a screening marker and marker of disease progression, has been proposed. Studies of glycation in arthritis have focused mostly on levels of AGEs (advanced glycation end-products), Ne-carboxymethyl-lysine and pentosidine. There was a weak correlation of skin and urinary pentosidine with joint damage in early-stage OA. RAGE (receptor for AGEs) is a cell-surface receptor in the synovial tissue of patients with OA and RA. The RAGE agonist S100A12 is increased in RA and OA. Activation of RAGE may decrease expression of Glo1 (glyoxalase I). Conflict between RAGE-activated inflammatory signalling and Nrf2 (nuclear factor-erythroid 2-related factor 2) regulation of basal and inducible expression of Glo1 may be involved. Thereby glyoxal- and methylglyoxalderived AGEs may be increased in OA and RA. Further studies are now required to investigate the role of glyoxalase and dicarbonyl glycation in OA and RA for early-stage diagnosis and potential novel preventive therapy. [ABSTRACT FROM AUTHOR] more...
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- 2014
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17. Dicarbonyl proteome and genome damage in metabolic and vascular disease.
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Rabbani, Naila and Thornalley, Paul J.
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GLYOXAL , *METABOLIC disorders , *PYRUVALDEHYDE , *VASCULAR diseases , *PROTEOMICS , *DNA damage , *GENOMICS , *GENETICS - Abstract
Methylglyoxal is a potent protein-glycating agent. It is an arginine-directed glycating agent and often modifies functionally important sites in proteins. Glycation forms mainly MG-H1 [Nd-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine] residues. MG-H1 content of proteins is quantified by stable isotopic dilution analysis-MS/MS and also by immunoblotting with specific monoclonal antibodies. Methylglyoxal-modified proteins undergo cellular proteolysis and release MG-H1 free adduct for excretion. MG-H1 residues have been found in proteins of animals, plants, bacteria, fungi and protoctista. MG-H1 is often the major advanced glycation end-product in proteins of tissues and body fluids, increasing in diabetes and associated vascular complications, renal failure, cirrhosis, Alzheimer's disease, arthritis, Parkinson's disease and aging. Proteins susceptible to methylglyoxal modification with related functional impairment are called the DCP (dicarbonyl proteome). The DCP includes albumin, haemoglobin, transcription factors, mitochondrial proteins, extracellular matrix proteins, lens crystallins and others. DCP component proteins are linked to mitochondrial dysfunction in diabetes and aging, oxidative stress, dyslipidaemia, cell detachment and anoikis and apoptosis. Methylglyoxal also modifies DNA where deoxyguanosine residues are modified to imidazopurinone MGdG {3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6/7-methylimidazo-[2,3-b]purine-9(8)one} isomers. MGdG was the major quantitative adduct detected in vivo. It was linked to frequency of DNA strand breaks and increased markedly during apoptosis induced by a cell-permeant glyoxalase I inhibitor. Glyoxalase I metabolizes >99% methylglyoxal and thereby protects the proteome and genome. Gene deletion of GLO1 is embryonically lethal and GLO1 silencing increases methylglyoxal concentration, MG-H1 and MGdG, premature aging and disease. Studies of methylglyoxal glycation have importance for human health, longevity and treatment of disease. [ABSTRACT FROM AUTHOR] more...
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- 2014
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18. Glyoxalase Centennial conference: introduction, history of research on the glyoxalase system and future prospects.
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Rabbani, Naila and Thornalley, Paul J.
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GLYOXALASE , *BIOCHEMISTRY , *PYRUVALDEHYDE , *GLYCOLYSIS , *HISTORY , *CONFERENCES & conventions - Abstract
On 27-29 November 2013, researchers gathered at the University of Warwick, Coventry, U.K., to celebrate the centennial of the discovery of the glyoxalase pathway. The glyoxalase system was discovered and reported in papers by Carl Neuberg and by Henry Drysdale Dakin and Harold Ward Dudley in 1913. All three were leading extraordinary investigators in the pioneering years of biochemistry. Neuberg proposed glyoxalase as the pathway of mainstream glycolysis and Gustav Embden correctly discounted this, later confirmed by Otto Meyerhof. Albert Szent-Gyö rgyi proposed glyoxalase I as the regulator of cell growth and others discounted this. In the meantime, molecular, structural and mechanistic properties of the enzymatic components of the system, glyoxalase I and glyoxalase II, have been characterized. The physiological function of the glyoxalase pathway of enzymatic defence against dicarbonyl glycation, particularly by endogenous methylglyoxal, now seems secure. We are now in an era of investigation of the regulation of the glyoxalase system where a role in aging and disease, physiological stress and drug resistance and development of healthier foods and new pharmaceuticals is emerging. The history of glyoxalase research illustrates the scientific process of hypothesis proposal, testing and rejection or acceptance with further investigation, standing testament to the need for intuition guided by experience and expertise, as well as indefatigable experimentation. [ABSTRACT FROM AUTHOR] more...
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- 2014
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19. Assay of methylglyoxal-derived protein and nucleotide AGEs.
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Rabbani, Naila, Shaheen, Fozia, Anwar, Attia, Masania, Jinit, and Thornalley, Paul J.
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PYRUVALDEHYDE ,PROTEOLYSIS ,DNA damage ,ADVANCED glycation end-products ,CHEMICAL adducts ,OXIDATIVE stress ,NUCLEOSIDES - Abstract
Glyoxalase- and methylglyoxal-related research has required the development of quantitative and reliable techniques for the measurement of methylglyoxal-derived glycation adducts of protein and DNA. There are also other glycation adducts, oxidation adducts and nitration adducts of proteins and oxidation adducts of DNA. Proteolysis of protein releases glycation, oxidation and nitration free adducts (glycated, oxidized and nitrated amino acids) in plasma and nuclease digestion of DNA releases glycated and oxidized nucleosides into plasma and other body fluids for excretion in urine. The gold standard method for quantifying these adducts is stable isotopic dilution analysis LC-MS/MS. Protein and DNA adduct residues are determined by assay of enzymatic hydrolysates of protein and DNA extracts prepared using cocktails of proteases and nucleases respectively. Free adducts are determined by analysis of ultrafiltrates of plasma, urine and other physiological fluids. Protein damage markers (13 glycation adducts, five oxidation adducts and 3- nitrotyrosine) and DNA damage markers (three glycation adducts and one oxidation adduct) are quantified using 25 µg of protein, 10 µg of DNA or 5 µl of physiological fluid. Protein and nucleotide AGE (advanced glycation end-product) assay protocols resistant to interferences is described. [ABSTRACT FROM AUTHOR] more...
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- 2014
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20. Measurement of glyoxalase gene expression.
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Mingzhan Xue, Rabbani, Naila, and Thornalley, Paul J.
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GLYOXALASE ,GENE expression ,PYRUVALDEHYDE ,PROTEOLYSIS ,REVERSE transcriptase polymerase chain reaction ,WESTERN immunoblotting - Abstract
The glyoxalase system is an important component of the enzymatic defence against glycation, preventing particularly quantitatively and functionally important glycation of protein and DNA by methylglyoxal. Expression of genes encoding Glo1 (glyoxalase I) and Glo2 (glyoxalase II) may be induced or suppressed, and rates of proteolysis of Glo1 and Glo2 proteins may change in health and disease. Quantitative assessment of glyoxalase gene expression at the mRNA and protein levels has become a key part of glyoxalase system characterization. For mRNA, there is the common technique of real-time RT (reverse transcription)- PCR and direct quantification of mRNA copy number by the Nanostring™ method. For glyoxalase protein quantification, there is the commonly used Western blotting, and also immunoassay and, in proteome-wide studies, quantitative proteomics and proteome dynamics. We provide protocols for the common methods below and briefly review their application. [ABSTRACT FROM AUTHOR] more...
- Published
- 2014
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21. Transcriptional control of glyoxalase 1 by Nrf2 provides a stress-responsive defence against dicarbonyl glycation.
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Mingzhan XUE, RABBANI, Naila, MOMIJI, Hiroshi, IMBASI, Precious, ANWAR, M. Maqsud, KITTERINGHAM, Neil, PARK, B. Kevin, SOUMA, Tomokazu, MORIGUCHI, Takashi, YAMAMOTO, Masayuki, and THORNALLEY, Paul J.
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GLYOXALASE ,AGING ,GENES ,MUTAGENESIS ,ERYTHROCYTE membranes - Abstract
Abnormal cellular accumulation of the dicarbonyl metabolite MG (methylglyoxal) occurs on exposure to high glucose concentrations, inflammation, cell aging and senescence. It is associated with increased MG-adduct content of protein and DNA linked to increased DNA strand breaks and mutagenesis, mitochondrial dysfunction and ROS (reactive oxygen species) formation and cell detachment from the extracellular matrix. MG-mediated damage is countered by glutathione-dependent metabolism by Glo1 (glyoxalase 1). It is not known, however, whether Glo1 has stress-responsive up-regulation to counter periods of high MG concentration or dicarbonyl stress. We identified a functional ARE (antioxidant-response element) in the 5'-untranslated region of exon 1 of the mammalian Glo1 gene. Transcription factor Nrf2 (nuclear factor-erythroid 2 p45 subunitrelated factor 2) binds to this ARE, increasing basal and inducible expression of Glo1. Activators of Nrf2 induced increased Glo1 mRNA, protein and activity. Increased expression of Glo1 decreased cellular and extracellular concentrations of MG, MG-derived protein adducts, mutagenesis and cell detachment. Hepatic, brain, heart, kidney and lung Glo1 mRNA and protein were decreased in Nrf2-/- mice, and urinary excretion of MG protein and nucleotide adducts were increased approximately 2-fold. We conclude that dicarbonyl stress is countered by upregulation ofGlo1 in the Nrf2 stress-responsive system, protecting protein and DNA from increased damage and preserving cell function. [ABSTRACT FROM AUTHOR] more...
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- 2012
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22. Protein damage in diabetes and uremia-identifying hotspots of proteome damage where minimal modification is amplified to marked pathophysiological effect.
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Thornalley, Paul J. and Rabbani, Naila
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DIABETES , *UREMIA , *PROTEINS , *POST-translational modification , *GENE amplification , *PATHOLOGICAL physiology , *OXIDATION , *NITRATION - Abstract
Increased protein glycation, oxidation and nitration are found in diabetes and renal failure. Steady state levels of glycated, oxidized and nitrated proteins are generally low, yet often have significant physiological effects-particularly linked to development and progression of vascular complications, including often fatal cardiovascular disease. Identification of sites activated toward damaging modifications or 'hotspots' in functional domains within proteins appears key to assessing targets of functional impairment. Disease progression is likely linked to instances where change in low level of hotspot damage influences metabolic control or physiological function. Examples discussed are: type IV collagen modification leading to endothelial cell detachment and anoikis, mitochondrial protein modification leading to oxidative stress and apolipoprotein B100 modification in low density lipoprotein leading to vascular retention and atherosclerosis. The role of mathematical systems biology, bioinformatics and proteome dynamics in future investigations is discussed. [ABSTRACT FROM AUTHOR] more...
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- 2011
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23. Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress.
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Rabbani, Naila and Thornalley, Paul J.
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OXIDATIVE stress , *PROTEINS , *REACTIVE oxygen species , *NEMATODES , *CAENORHABDITIS elegans - Abstract
Protection of mitochondrial proteins from glycation by endogenous dicarbonyl compounds, methylglyoxal and glyoxal, was found recently to prevent increased formation of reactive oxygen species and oxidative and nitrosative damage to the proteome during aging and produce life extension in the nematode Caenorhabditis elegans. This suggests that dicarbonyl glycation damage to the mitochondrial proteome may be a preceding event to mitochondrial dysfunction leading to oxidative stress. Future research will address the functional charges in mitochondrial proteins that are the targets for dicarbonyl glycation. [ABSTRACT FROM AUTHOR] more...
- Published
- 2008
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24. The Dicarbonyl Proteome.
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Rabbani, Naila and Thornalley, Paul J.
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PROTEIN analysis , *GLYOXAL , *ARGININE , *AGING , *DEGENERATION (Pathology) , *METABOLIC disorders , *MITOCHONDRIAL pathology , *VASCULAR diseases , *LIPOPROTEINS - Abstract
Reactive, physiological, dicarbonyl, glycating agents, glyoxal and methylglyoxal, are arginine-directed glycating agents forming mainly hydroimidazolone residues. Arginine residues have high-frequency occurrence in sites of protein–protein, enzyme substrate and protein–nucleotide binding sites. There is emerging evidence that functionally important arginine residues in proteins are often activated toward dicarbonyl glycation—leading to functional impairment. When uncontrolled, this is associated with aging, degenerative diseases, and metabolic disorders where dicarbonyl glycation may be viewed as damage to the proteome. The glyoxalase system, particularly glyoxalase 1, is the vanguard against dicarbonyl glycation in physiological systems. Functional regulation of glyoxalase 1 suggests a role for dicarbonyl glycation in cell signaling. Although extents of modification are usually low, the dicarbonyl proteome is a critical feature of the impact of glycation on physiological function—particularly in mitochondrial dysfunction, vascular disease, and potentially in disorders of lipoprotein metabolism. [ABSTRACT FROM AUTHOR] more...
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- 2008
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25. High-Dose Thiamine Therapy Counters Dyslipidemia and Advanced Glycation of Plasma Protein in Streptozotocin-Induced Diabetic Rats.
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KARACHALIAS, NIKOLAOS, BABAEI‐JADIDI, ROYA, KUPICH, CHRISTIAN, AHMED, NAILA, and THORNALLEY, PAUL J.
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STREPTOZOTOCIN ,VITAMIN B1 ,KIDNEY diseases ,CARBOHYDRATE intolerance ,BLOOD proteins - Abstract
The streptozotocin-induced (STZ) diabetic rat experimental model of diabetes on insulin maintenance therapy exhibits dyslipidemia, mild thiamine deficiency, and increased plasma protein advanced glycation end products (AGEs). The reversal of thiamine deficiency by high-dose thiamine and Sbenzoylthiamine monophosphate (benfotiamine) prevented the development of incipient nephropathy. Recently, we reported that high-dose thiamine (but not benfotiamine) countered diabetic dyslipidemia. To understand further the differences between the effects of thiamine and benfotiamine therapy, we quantified the levels of the AGEs in plasma protein. We found hydroimidazolone AGE residues derived from glyoxal and methylglyoxal, G-H1 and MG-H1, were increased 115% and 68% in STZ diabetic rats, with respect to normal controls, and were normalized by both thiamine and benfotiamine; whereas Ncarboxymethyl- lysine (CML) and N-carboxyethyl-lysine (CEL) residues were increased 74% and 118% in STZ diabetic rats and were normalized by thiamine only. The lack of effect of benfotiamine on plasma CML and CEL residue concentrations suggests there may be important precursors of plasma protein CML and CEL residues other than glyoxal and methylglyoxal. These are probably lipid-derived aldehydes. [ABSTRACT FROM AUTHOR] more...
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- 2005
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26. Peptide Mapping of Human Serum Albumin Modified Minimally by Methylglyoxal in Vitro and in Vivo.
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AHMED, NAILA and THORNALLEY, PAUL J.
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AMINO acids ,PROTEINS ,ARGININE ,HIGH-lysine diet ,BLOOD plasma ,BLOOD proteins - Abstract
Methylglyoxal is a potent glycating agent and important precursor of advanced glycation end products (AGEs) in physiological systems. Unlike glucose, methylglyoxal is predominantly an arginine-directed glycating agent. Methylglyoxal reacts with proteins to form mainly the arginine-derived hydroimidazolone AGE, N
8 -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1), argpyrimidine, the lysine-derived AGEs, Nε -(1-carboxyethyl)lysine (CEL), and methylglyoxal-derived lysine dimer (MOLD). Sites within proteins susceptible to modification by methylglyoxal have not been identified. Here we show that modification of human serum albumin by methylglyoxal forms mainly hydroimidazolone MG-H1 residues. The location of MG-H1 residues was identified by mass spectrometric peptide mapping. This method identified a hot spot of hydroimidazolone formation at Arg-410, with other minor MGH1 modifications at Arg-114, Arg-186, Arg-218, and Arg-428. Other extracellular and intracellular proteins are modified by methylglyoxal in physiological systems. Modification of arginine residues by methylglyoxal may be particularly damaging because arginine residues have a high frequency of occurrence in ligand and substrate recognition sites in receptor and enzyme active sites. [ABSTRACT FROM AUTHOR] more...- Published
- 2005
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27. Dicarbonyl Intermediates in the Maillard Reaction.
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THORNALLEY, PAUL J.
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MAILLARD reaction ,CHEMICAL reactions ,AMINO acids ,PROTEINS ,GENOMES - Abstract
The complexity of the Maillard reaction arises partly from multiple fragmentation reactions of the sugar moiety, constituting branch points in the reaction progress and establishing many parallel reaction pathways. Reactive intermediates produced by these processes are often α-oxoaldehydes. The formation of α-oxoaldehydes enhances and redirects glycating activity in the Maillard reaction since α-oxoaldehydes are up to 20,000-fold more reactive than glucose in glycation processes and are predominantly arginine-directed glycating agents. α-Oxoaldehydes bypass a requirement for a fructosamine precursor in the formation of advanced glycation end products (AGEs) since α-- oxoaldehydes react with proteins (also nucleotides and basic phospholipids) to form AGEs directly. The major AGE formed from α-oxoaldehydes is generally a hydroimidazolone with other products—although for glyoxal, Nω-carboxymethylarginine is a major product. α-Oxoaldehyde formation also occurs in the absence of an amine substrate, particularly during heat processing of sugar solutions and lipid peroxidation processes—in the latter case, the glycation adducts are advanced lipoxidation products (ALEs). Hydroimidazolones are quantitatively important AGEs in cellular and extracellular proteins in physiological systems. Hydroimidazolone free adducts are liberated by cellular proteolysis and digestion. They are released into blood plasma for urinary excretion. Modification of arginine residues by α-oxoaldehydes may be particularly damaging since arginine residues have high-frequency occurrence in ligand and substrate recognition sites in receptor and enzyme active sites. Along with fructosamine formation, α-oxoaldehyde intermediates of the Maillard reaction represent a major source of damage to the proteome and genome. [ABSTRACT FROM AUTHOR] more...
- Published
- 2005
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28. Protein glycation, oxidation and nitration adduct residues and free adducts of cerebrospinal fluid in Alzheimer's disease and link to cognitive impairment.
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Ahmed, Naila, Ahmed, Usman, Thornalley, Paul J., Hager, Klaus, Fleischer, Gerd, and Münch, Gerald
- Subjects
ALZHEIMER'S disease ,COGNITION disorders ,AMINO acids ,LYSINE ,CEREBROSPINAL fluid ,CELL death ,NITRATION ,PROTEIN metabolism ,REGRESSION analysis - Abstract
Increased damage to proteins by glycation, oxidation and nitration has been implicated in neuronal cell death leading to Alzheimer's disease (AD). Protein glycation, oxidation and nitration adducts are consequently formed. Quantitative screening of these adducts in CSF may provide a biochemical indicator for the diagnosis of AD. To assess this, we measured 11 glycation adducts, three oxidation adducts and a nitration adduct, determining both protein adduct residues and free adducts, in CSF samples of age-matched normal healthy subjects (n = 18) and subjects with Alzheimer's disease (n = 32). In CSF protein, the concentrations of 3-nitrotyrosine,N
ℇ -carboxymethyl-lysine, 3-deoxyglucosone-derived hydroimidazolone andN-formylkynurenine residues were increased in subjects with Alzheimer's disease. In CSF ultrafiltrate, the concentrations of 3-nitrotyrosine, methylglyoxal-derived hydroimidazolone and glyoxal-derived hydroimidazolone free adducts were also increased. The Mini-Mental State Examination (MMSE) score correlated negatively with 3-nitrotyrosine residue concentration (p < 0.05), and the negative correlation with fructosyl-lysine residues just failed to reach significance (p = 0.052). Multiple linear regression gave a regression model of the MMSE score on 3-nitrotyrosine, fructosyl-lysine andNℇ -carboxyethyl-lysine residues withp-values of 0.021, 0.031 and 0.052, respectively. These findings indicate that protein glycation, oxidation and nitration adduct residues and free adducts were increased in the CSF of subjects with Alzheimer's disease. A combination of nitration and glycation adduct estimates of CSF may provide an indicator for the diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR] more...- Published
- 2005
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29. Preparation of Nucleotide Advanced Glycation Endproducts—Imidazopurinone Adducts Formed by Glycation of Deoxyguanosine with Glyoxal and Methylglyoxal.
- Author
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Fleming, Thomas, Rabbani, Naila, and Thornalley, Paul J.
- Subjects
NUCLEOTIDES ,DNA ,TANDEM mass spectrometry ,HUMAN cell culture ,LIQUID chromatography ,ISOTOPE dilution analysis ,OXIDATION ,DEAMINATION ,MUTAGENESIS ,GLYOXAL - Abstract
An analytical procedure was developed for nucleotide advanced glycation endproducts formed by the reaction of glyoxal and methylglyoxal with deoxyguanosine under physiological conditions. For this, the imidazopurinone derivatives, 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one (dG-G) and 3-(2′-deoxyribosyl)-6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one (dG-MG), were prepared. Authentic standard and stable isotope-substituted standard adducts were prepared and an isotopic dilution analysis assay methodology was developed using liquid chromatography with tandem mass spectrometry and optimized DNA extraction and nuclease digestion procedures. Analysis of dG-G, dG-MG, and the oxidative marker 8-hydroxydeoxyguanosine in the DNA of cultured human cells and mononuclear leukocytes showed that nucleotide advanced glycation endproducts are major markers of DNA damage in human cells. [ABSTRACT FROM AUTHOR] more...
- Published
- 2008
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30. Reversal of Hyperglycemia-Induced Angiogenesis Deficit of Human Endothelial Cells by Overexpression of Glyoxalase 1.
- Author
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Ahmed, Usman, Dobler, Darin, Larkin, Sarah J., Rabbani, Naila, and Thornalley, Paul J.
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HYPERGLYCEMIA ,NEOVASCULARIZATION ,ENDOTHELIUM ,CELLS ,GLYOXALASE ,ISOMERASES ,VASCULAR endothelial growth factors ,METALLOPROTEINASES ,DIABETES complications ,MICROCIRCULATION disorders - Abstract
Dicarbonyl glycation of RGD and GFOGER sites in type IV collagen has been associated with decreased angiogenesis. In this study, we investigated whether overexpression of glyoxalase 1 to decrease dicarbonyl glycation would prevent the angiogenesis deficit induced by hyperglycemia in vitro. Transfection of human microvascular endothelial cells resulted in a four-fold increase in glyoxalase 1 activity compared with controls. Incubation of human microvascular endothelial cells in model hyperglycemia produced a 32% decrease in formation of tube structures that was prevented by glyoxalase 1 overexpression. We conclude that increased protection against dicarbonyl glycation of endothelial cell protein protects hyperglycemia-induced angiogenesis deficit. [ABSTRACT FROM AUTHOR] more...
- Published
- 2008
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31. Protein Glycation in Plants—An Under-Researched Field with Much Still to Discover.
- Author
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Rabbani, Naila, Al-Motawa, Maryam, and Thornalley, Paul J.
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UNFOLDED protein response ,PLANT proteins ,ORNAMENTAL plants ,AMINO acid residues ,CALVIN cycle ,CROP growth ,GALACTOSE ,POST-translational modification - Abstract
Recent research has identified glycation as a non-enzymatic post-translational modification of proteins in plants with a potential contributory role to the functional impairment of the plant proteome. Reducing sugars with a free aldehyde or ketone group such as glucose, fructose and galactose react with the N-terminal and lysine side chain amino groups of proteins. A common early-stage glycation adduct formed from glucose is N
ε -fructosyl-lysine (FL). Saccharide-derived reactive dicarbonyls are arginine residue-directed glycating agents, forming advanced glycation endproducts (AGEs). A dominant dicarbonyl is methylglyoxal—formed mainly by the trace-level degradation of triosephosphates, including through the Calvin cycle of photosynthesis. Methylglyoxal forms the major quantitative AGE, hydroimidazolone MG-H1. Glucose and methylglyoxal concentrations in plants change with the developmental stage, senescence, light and dark cycles and also likely biotic and abiotic stresses. Proteomics analysis indicates that there is an enrichment of the amino acid residue targets of glycation, arginine and lysine residues, in predicted functional sites of the plant proteome, suggesting the susceptibility of proteins to functional inactivation by glycation. In this review, we give a brief introduction to glycation, glycating agents and glycation adducts in plants. We consider dicarbonyl stress, the functional vulnerability of the plant proteome to arginine-directed glycation and the likely role of methylglyoxal-mediated glycation in the activation of the unfolded protein response in plants. The latter is linked to the recent suggestion of protein glycation in sugar signaling in plant metabolism. The overexpression of glyoxalase 1, which suppresses glycation by methylglyoxal and glyoxal, produced plants resistant to high salinity, drought, extreme temperature and other stresses. Further research to decrease protein glycation in plants may lead to improved plant growth and assist the breeding of plant varieties resistant to environmental stress and senescence—including plants of commercial ornamental and crop cultivation value. [ABSTRACT FROM AUTHOR] more...- Published
- 2020
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32. Glyoxalase in ageing
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Xue, Mingzhan, Rabbani, Naila, and Thornalley, Paul J.
- Subjects
- *
GLYOXALASE , *AGING , *METABOLISM , *GLYOXAL , *GENOMES , *PROTEINS , *DNA damage , *GENE expression - Abstract
Abstract: The glyoxalase system has been studied since 1913. The biochemical function of this enzymatic system is the metabolism of reactive dicarbonyl metabolites, glyoxal and methylglyoxal, to less reactive products. In the last decade research has shown that methylglyoxal is the precursor of quantitatively important damage to the proteome and genome, forming mainly hydroimidazolone and imidazopurinone adducts in protein and DNA respectively. The aim of this article is to review the evidence of the involvement of the glyoxalase system in ageing and role of glyoxalase in future research into healthy ageing—mainly in mammalian systems for insights into consequences and interventions in human health. Protein and DNA damage by glyoxalase system substrates is linked to dysfunction of proteins susceptible to dicarbonyl modification—the dicarbonyl proteome, and DNA instability and mutation. A component of the glyoxalase system, glyoxalase 1, is a gene with expression influential on lifespan—increasing longevity being associated with increased expression of glyoxalase 1. The glyoxalase 1 gene is also a site of copy number variation in both transcribed and non-transcribed regions giving rise to population variation of expression. The glyoxalase system and Glo1 expression particularly is therefore likely linked to healthy ageing. [Copyright &y& Elsevier] more...
- Published
- 2011
- Full Text
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