Pyridoxamine: the many virtues of a maillard reaction inhibitor.
ABSTRACT Pyridoxamine (PM) is one of three natural forms of vitamin B6. It is a critical transient intermediate in catalysis of transamination reactions by vitamin B6-dependent enzymes. The discovery eight years ago that PM can inhibit the Maillard reaction stimulated new interest in this B6 vitamer as a prospective pharmacological agent for treatment of complications of diabetes. PM application in diabetic nephropathy has now progressed to a phase III clinical trial. Investigation of the PM mechanism of action demonstrated that PM inhibits post-Amadori steps of the Maillard reaction by sequestering catalytic metal ions and blocking oxidative degradation of Amadori intermediate. PM also has the capacity to scavenge toxic carbonyl products of sugar and lipid degradation, and to inhibit reactive oxygen species. These multiple activities position PM as a promising drug candidate for treatment of multifactorial chronic conditions in which oxidative reactions and/or carbonyl compounds confer pathogenicity.
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ABSTRACT: Diabetic foot disease is an important complication of diabetes. The development and outcome of foot ulcers are related to the interplay between numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and microvascular and/or macrovascular disease.The formation of advanced glycation end products (AGEs) has been recognized as an important pathophysiological mechanism in the development of diabetic complications. Several mechanisms have been proposed by which AGEs lead to diabetic complications such as the accumulation of AGEs in the extracellular matrix causing aberrant cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and activation of key cell signalling pathways with subsequent modulation of gene expression, and intracellular AGE formation leading to quenching of nitric oxide and impaired function of growth factors. In the last decade, many experimental studies have shown that these effects of AGE formation may play a role in the pathogenesis of micro- and macrovascular complications of diabetes, diabetic neuropathy and impaired wound healing. In recent years also, several clinical studies have shown that glycation is an important pathway in the pathophysiology of those complications that predispose to the development of foot ulcers. Currently, there are a number of ways to prevent or decrease glycation and glycation-induced tissue damage. Although not in the area of neuropathy or wound healing, recent clinical studies have shown that the AGE-breakers may be able to decrease adverse vascular effects of glycation with few side effects.Diabetes/Metabolism Research and Reviews 24 Suppl 1:S19-24. · 3.37 Impact Factor
Article: Carbonylation contributes to SERCA2a activity loss and diastolic dysfunction in a rat model of type 1 diabetes.[show abstract] [hide abstract]
ABSTRACT: Approximately 25% of children and adolescents with type 1 diabetes will develop diastolic dysfunction. This defect, which is characterized by an increase in time to cardiac relaxation, results in part from a reduction in the activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), the ATP-driven pump that translocates Ca(2+) from the cytoplasm to the lumen of the sarcoplasmic reticulum. To date, mechanisms responsible for SERCA2a activity loss remain incompletely characterized. The streptozotocin (STZ)-induced murine model of type 1 diabetes, in combination with echocardiography, high-speed video detection, confocal microscopy, ATPase and Ca(2+) uptake assays, Western blots, mass spectrometry, and site-directed mutagenesis, were used to assess whether modification by reactive carbonyl species (RCS) contributes to SERCA2a activity loss. After 6-7 weeks of diabetes, cardiac and myocyte relaxation times were prolonged. Total ventricular SERCA2a protein remained unchanged, but its ability to hydrolyze ATP and transport Ca(2+) was significantly reduced. Western blots and mass spectroscopic analyses revealed carbonyl adducts on select basic residues of SERCA2a. Mutating affected residues to mimic physio-chemical changes induced on them by RCS reduced SERCA2a activity. Preincubating with the RCS, methylglyoxal (MGO) likewise reduced SERCA2a activity. Mutating an impacted residue to chemically inert glutamine did not alter SERCA2a activity, but it blunted MGO's effect. Treating STZ-induced diabetic animals with the RCS scavenger, pyridoxamine, blunted SERCA2a activity loss and minimized diastolic dysfunction. These data identify carbonylation as a novel mechanism that contributes to SERCA2a activity loss and diastolic dysfunction during type 1 diabetes.Diabetes 02/2011; 60(3):947-59. · 8.29 Impact Factor
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ABSTRACT: Carbonylation of proteins is an irreversible oxidative damage, often leading to a loss of protein function, which is considered a widespread indicator of severe oxidative damage and disease-derived protein dysfunction. Whereas moderately carbonylated proteins are degraded by the proteasomal system, heavily carbonylated proteins tend to form high-molecular-weight aggregates that are resistant to degradation and accumulate as damaged or unfolded proteins. Such aggregates of carbonylated proteins can inhibit proteasome activity. Alarge number of neurodegenerative diseases are directly associated with the accumulation of proteolysis-resistant aggregates of carbonylated proteins in tissues. Identification of specific carbonylated protein(s) functionally impaired and development of selective carbonyl blockers should lead to the definitive assessment of the causative, correlative or consequential role of protein carbonylation in disease onset and/or progression, possibly providing new therapeutic approaches.Journal of Cellular and Molecular Medicine 10(2):389-406. · 4.13 Impact Factor