Glycation

Plant extracts have been suggested as a rich as yet unexplored source of potentially useful anti-diabetic drugs. Recent scientific investigations have confirmed the efficacy of many of these preparations, as effective antioxidants; able to regenerate functional pancreatic beta cells and has a hypoglycemic potential. In this study, the exotic rambutan (Nephelium lappaceum L.) fruit's rind has been shown to be effective in inhibiting the carbohydrate hydrolyzing enzymes, alpha glucosidase (EC 50 = 2.7 μg/mL) and alpha amylase (EC 50 = 70.8 μg/mL), at a much more significant level than the drug acarbose (EC 50 = 3500 μg/mL; alpha glucosidase; EC 50 =12 μg/mL; alpha amylase). In addition, the geraniin-enriched ethanolic extracts were able to inhibit the key enzyme in the polyol pathway, aldol reductase (EC 50 = 0.04 μg/mL) and prevent the formation of advanced glycation end-products (AGE) by 43%. These findings indicate that the geraniinstandardized N. lappaceum rind may be a potential source of an anti-hyperglycemic agent.

Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying amino-groups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD. Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder affecting 5–10 per 100 000 individuals 1–3. Its clinical features include progressive motor dysfunction, cognitive impairment, and psychiatric disturbance and dementia 4. HD is caused by a CAG triplet repeat expansion in exon 1 of the HTT gene, which encodes a polyglutamine (polyQ) stretch in huntingtin (HTT) protein. The number of CAG repeats varies from 16 to 35 in healthy individuals, while expansions of > 35 CAG repeats are found in HD patients 1. The length of the polyQ tract in the protein modulates HTT aggregation, thereby causing cytotoxicity by mechanisms that are still not fully understood, with medium spiny neurons in the striatum particularly affected 5. Glucose is the major energy supply of neurons and is essential for their survival. However, impaired glucose metabolism can also damage neurons and lead to neurodegeneration. For example, diabetic patients who neglect their circulating glucose levels frequently develop severe neuropathy that results in the amputation of limbs 6,7. Glucose metabolism drives the formation of by-products that are highly reactive with free amino-groups of proteins. This non-enzymatic reaction, named glycation, induces the formation of advanced glycation end-products (AGEs) that frequently have deleterious effects on proteins 8,9. For example, glycation has been reported in several neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, where it potentiates the aggregation and toxicity of proteins such as amyloid-β (Aβ) and α-synuclein, respectively 8,9. Methylglyoxal (MGO) is an unavoidable by-product of glycolysis and the most reactive glycation agent. It is mainly produced by the non-enzymatic decomposition of the phosphate group of the triose phosphates (glycer-aldeyde 3-phosphate and dihydroxyacetone phosphate) 8. MGO can also arise from the interconversion between

The non enzymatic reaction between the carbonyl group of sugars and amino group of proteins, lipids and nucleic acids is termed as glycation. It has been linked to various diseases such as diabetes, cataract, Alzheimer's, dialysis related amyloidosis, atherosclerosis, Parkinson's as well as physiological ageing. In the present study, the progress of glycation was assessed, using methods for the measurement of browning, periodate, fructosamine and carbonyl content. It was found that phenolic acids (gallic acid, cinnamic acid and ferulic acid) caused a decrease in the production of amadori products and carbonyl content and had no significant effect on browning of glucose-lysine mixture, standard glycation reaction. When the effect of gallic acid was checked on the glycated DNA sample, it caused the DNA damage alone and did not enhance the damage of glycated DNA sample. This study is significant as far as understanding the mechanism of phenolic acids on in vitro glycation is concerned.

In a recent study, we were able to show that the intermediate filament protein vimentin aggregates in human dermal fibroblasts because of modification by the advanced glycation endproduct carboxymethyllysine (CML). In this work, we investigated the formation of intracellular CML in relation to the concentration of glucose in the culture medium. The natural degradation product of glucose, methylglyoxal, was able to induce the aggregation of vimentin. This dicarbonyl leads to the formation of the modifications MG-H1 and carboxyethyllysine (CEL) as a result of the reaction with arginine and lysine residues of proteins. Furthermore, we found that the protein vimentin was modified, not only by CML and CEL, but also by pentosidine and pyrraline. These findings underline the special position of vimentin as a preferential target of the Maillard reaction in human skin.

Diabetes and its associated complications are major known health disorders. Diabetes mellitus increases the risk of cardiovascular morbidity and mortality by promoting cardiomyopathy. It appears to arise as a result of the diabetic state, at times independent of vascular or valvular pathology. It manifests initially as asymptomatic diastolic dysfunction, which progresses to symptomatic heart failure. The compliance of the heart wall is decreased and contractile function is impaired. The pathophysiology of diabetic cardiomyopathy is incompletely understood but appears to be multifactorial in origin. Several hypotheses have been proposed, including oxidative stress, inflammation, endothelial dysfunction, metabolic derangements, abnormalities in ion homeostasis, alterations in structural proteins, and interstitial fibrosis. Amongst these various mechanisms, an increase in reactive oxygen species, leading to oxidative stress, has received significant experimental support. This review focuses on the role of oxidative stress in the pathogenesis of diabetic cardiomyopathy and the potential of antioxidant therapy.