Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes

Abstract

The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG) has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE), serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.

The Role of Secondary Metabolites on Gynecologic Cancer Therapy: Some Pathways and Mechanisms

“…Gray, and Acacia berlandieri Benth., was shown to possess anti-proliferative activity and display anticarcinogenic potential by inducing apoptosis. 7,[65][66][67] Fisetin inhibited the invasion and migration of cervical cancer cells by dose-dependently supressing the expression and activity of urokinase plasminogen activator and decreased p38 MAPK phosphorylation. Fisetin affected the nuclear translocation of NF-κB and inhibited tTPA (tetradecanoylphorbol-13-acetate)-enhanced migration and invasion.…”

BacHBerry: BACterial Hosts for production of Bioactive phenolics from bERRY fruits

“…Fisetin is a potent anti-inflammatory, anti-cancer, and anti-oxidant compound (Suh et al 2008;FunakoshiTago et al 2011;Jash and Mondal 2014). Moreover, it has been demonstrated to have a neuroprotective effect and also to limit the complications of type I diabetes (Maher 2009;Maher et al 2011). Based on the molecular structure of this compound, we hypothesized that its biosynthesis should follow the general pathway of flavonol biosynthesis (Figs.…”

Glyoxalase 1 and glyoxalase 2 activities in blood and neuronal tissue samples from experimental animal models of obesity and type 2 diabetes mellitus

“…Previous studies have shown that the glyoxalase system is modified in the tissues of streptozotocin-induced diabetic rats [7], and altered blood Glo1 activity is associated with late diabetic complications [8][9][10]. Moreover, it has been shown that enhancement of the glyoxalase pathway along with a decrease in methylglyoxal-dependent protein glycation prevents the development of several indices of late complications in diabetic mice [11]. However, the factors responsible for the variable susceptibility to diabetic complications and the role of the glyoxalase system in the development of vascular complications in diabetes and obesity are not clear.…”