Involvement Of Advanced Glycation End-products Research Articles

Alcoholic Liver Disease Is Associated with Elevated Plasma Levels of Novel Advanced Glycation End-Products: A Preliminary Study.

Elucidating the biochemical mechanisms associated with the progression of alcoholic liver disease (ALD) to more advanced stages such as alcoholic hepatitis (AH) remains an important clinical and scientific challenge. Several hypotheses point to the involvement of advanced glycation end-products (AGEs) in alcohol-associated liver injuries. Recently, we determined the structure of a synthetic, melibiose-derived AGE (MAGE), which was an analog of the novel AGE subgroup AGE10. The primary objective of our study was to determine whether AGE10 was associated with alcoholic hepatitis. The secondary objective was to provide a diagnostic accuracy of AGE10 in AH. To achieve this objective, we examined the plasma levels of AGE10 in 65 healthy individuals and 65 patients with AH. The AGE10 level was measured using a competitive ELISA. Our study confirmed that patients with AH had significantly higher plasma concentrations of AGE10 compared with healthy controls (184.5 ± 71.1 μg/mL and 123.5 ± 44.9 μg/mL, respectively; p < 0.001). In addition, AGE10 showed an acceptable performance as a diagnostic marker of AH, with an AUC of 0.78. In conclusion, AH was associated with elevated levels of novel advanced glycation end-product AGE10.

High-fructose intake as risk factor for neurodegeneration: Key role for carboxy methyllysine accumulation in mice hippocampal neurons

Several studies indicate the involvement of advanced glycation end-products (AGEs) in neurodegenerative diseases. Moreover, the rising consumption of fructose in industrialized countries has been related to cognitive impairment, but the impact of fructose-derived AGEs on hippocampus has never been investigated.The present study aimed to evaluate in the hippocampus of C57Bl/6 mice fed a standard (SD) or a 60% fructose (HFRT) diet for 12weeks the production of the most studied AGEs, carboxy methyllysine (CML), focusing on the role of the glutathione-dependent enzyme glyoxalase (Glo-1), the main AGEs-detoxifying system, in relation to early signs of neuronal impairment.HFRT diet evoked CML accumulation in the cell body of pyramidal neurons, followed by RAGE/NFkB signaling activation. A widespread reactive gliosis and altered mitochondrial respiratory complexes activity have been evidenced in HFRT hippocampi, paralleled by oxidative stress increase due to impaired activity of Nrf2 signaling. In addition, a translocation of Glo-1 from axons toward cell body of pyramidal neurons has been observed in HFRT mice, in relation to CML accumulation. Despite increased expression of dimeric Glo-1, its enzymatic activity was not upregulated in HFRT hippocampi, due to reduced glutathione availability, thus failing to prevent CML accumulation. The prevention of CML production by administration of the specific inhibitor pyridoxamine was able to prevent all the fructose-induced hippocampal alterations. In conclusion, a high-fructose consumption, through CML accumulation and Glo-1 impairment, induces in the hippocampus the same molecular and metabolic alterations observed in early phases of neurodegenerative diseases, and can thus represent a risk factor for their onset.

Special edition of Amino Acids of selected papers from the eleventh international symposium on the Maillard reaction, September 16–20, 2012

We introduce this special edition of Amino Acids with selected papers from the eleventh international symposium on the Maillard reaction held in Nancy, France, September 16–20, 2012. Glycation of proteins occurs by a complex series of sequential and parallel reactions called collectively the Maillard reaction—named after the leading pioneer of glycation research, Louis Camille Maillard (1978–1936). Glycation researchers gathered at the symposium in 2012 organised by the International Maillard Reaction Society to commemorate the centennial of Maillard reaction research and review achievements and current standing of glycation research. In this special edition there are selected papers from this meeting. Subjects of study include: the involvement of advanced glycation endproducts (AGEs) in complications of diabetes, association of AGEs with insulin secretion, enzymatic metabolism of early glycation adducts, absorption into the body of early and advanced glycation endproducts (AGEs) of dietary origin, association of AGEs in dietary protein with chronic disease, the study of the effect of AGEs on bacterial growth and inhibition of AGE formation by natural products. The Centennial Maillard Symposium began with a presentation by Nobel laureate Jean-Marie Lehn (University of Strasbourg, France) on ‘‘Towards a chemistry of complex matter’’. The Maillard reaction exemplifies how a relatively simple chemical reaction of a reducing sugar or sugar derivative with an amino group becomes highly complex through multiple parallel and sequential reactions. In recent decades there has also been increasing awareness of dicarbonyl compounds and metabolites reacting with guanidino groups in the Maillard reaction. This expands the locus of glycation adduct formation from N-terminal and lysine side chain amino groups in amino acids and proteins to guanidino groups of arginine and arginine residues in proteins. Indeed, arginine-derived AGEs are now considered to be quantitatively major AGEs in physiological systems. In 100 years the Maillard reaction has seen applications in chemistry, food, nutrition, health and disease, microbiology and clinical diagnostics and repeated, on-going development of applications in pharmacology and therapeutics. We celebrate the achievements of Louis Camille Maillard in glycation research and suggest that, if he was here today, he would marvel at the advances and development that led from his earlier studies.

KCa3.1 channels mediate the increase of cell migration and proliferation by advanced glycation endproducts in cultured rat vascular smooth muscle cells.

The mechanisms underlying the involvement of advanced glycation endproducts (AGEs) in diabetic atherosclerosis are not fully understood. The present study was designed to investigate whether intermediate-conductance Ca(2+)-activated K(+) channels (K(Ca)3.1 channels) are involved in migration and proliferation induced by AGEs in cultured rat vascular smooth muscle cells (VSMCs) using approaches of whole-cell patch voltage-clamp, cell proliferation and migration assay, and western blot analysis. It was found that the current density and protein level of K(Ca)3.1 channels were enhanced in cells incubated with AGE-BSA (bovine serum albumin), and the effects were reversed by co-incubation of AGE-BSA with anti-RAGE (anti-receptors of AGEs) antibody. The ERK1/2 inhibitors PD98059 and U0126, the P38-MAPK inhibitors SB203580 and SB202190, or the PI3K inhibitors LY294002 and wortmannin countered the K(Ca)3.1 channel expression by AGE-BSA. In addition, AGE-BAS increased cell migration and proliferation, and the effects were fully reversed with anti-RAGE antibody, the K(Ca)3.1 channel blocker TRAM-34, or K(Ca)3.1 small interfering RNA. These results demonstrate for the first time that AGEs-induced increase of migration and proliferation is related to the upregulation of K(Ca)3.1 channels in rat VMSCs, and the intracellular signals ERK1/2, P38-MAPK and PI3K are involved in the regulation of K(Ca)3.1 channel expression.

Involvement of advanced glycation end-products, pentosidine and N ɛ-(carboxymethyl)lysine, in doxorubicin-induced cardiomyopathy in rats

In the pathogenesis of doxorubicin (DXR)-induced cardiomyopathy, oxidative stress appears to play an important role. It has been reported that pentosidine and N ɛ-(carboxymethyl)lysine (CML), advanced glycation end-products (AGEs), are formed by the combined processes of glycation and oxidation and play a significant role in the process of complications of diabetic mellitus. We investigated the potential involvement of AGE formation in DXR-induced cardiomyopathy in rats. Male Crl:CD(SD) rats received intravenous injection of DXR at 2 mg/kg or saline once weekly for 8 weeks, with or without daily treatment with the AGE formation inhibitors, aminoguanidine (AG, 25 mg/kg/day, i.p.) and pyridoxamine (PM, 60 mg/kg/day, i.p.). Time-course experiments revealed significantly increased pentosidine and CML in the heart in the DXR group from Week 6. These findings coincided with a decrease in fractional shortening (FS), an index of cardiac function, and the development of cardiomyopathy characterized by vacuolated hypertrophic myocardial fibers. There was a significant correlation between the myocardial AGEs and FS or plasma cardiac troponin-I. Immunohistochemical staining showed localization of pentosidine to the cytoplasm of vacuolated myocardial cells. In DXR-treated rats, oxidative stress was enhanced prior to any observed increase in pentosidine and CML levels in the heart. Hyperglycemia was not observed throughout the study period. Intervention by AG or PM treatment ameliorated the functional and morphological changes induced by DXR in the heart, in addition to lowered myocardial pentosidine and CML levels. These results suggested that DXR accelerates the formation of pentosidine and CML in the heart through enhanced oxidative stress and that AGE formation is involved in DXR-induced cardiomyopathy. The findings may enable development of novel preventive therapies and predictive biomarkers of DXR-induced cardiomyopathy.

Possible Involvement of Advanced Glycation End-Products (AGEs) in the Pathogenesis of Alzheimers Disease

Alzheimer's disease (AD) is the most common cause of dementia in developed countries. AD is characterized pathologically by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the major constituents of which are amyloid betaprotein and tau protein, respectively. Advanced glycation end-products (AGEs), senescent macroprotein derivatives formed at an accelerated rate under normal aging, can be identified immunohistochemically in both SPs and NFTs in AD patients. Further, recent clinical evidence has suggested diabetes mellitus as one of the risk factors for the development and progression of AD. Continuous hyperglycemia is a causative factor for diabetic vascular complications, and it enhances the generation of AGEs through the non-enzymatic glycation, thereby being involved in the pathogenesis of AD as well. Moreover, there is a growing body of evidence to show that the interaction of AGEs with a receptor for AGEs (RAGE) elicits reactive oxygen species generation and vascular inflammation, and subsequently alters various gene expressions in numerous types of cells, all of which could contribute to the pathological changes of diabetic vascular complications and AD. Indeed, we have recently found that glyceraldehyde-derived AGEs (Glycer-AGE) induce apoptotic cell death in cultured cortical neuronal cells. In addition, we also found that neurotoxic effect of diabetic serum on neuronal cells was blocked by neutralizing antibody raised against Glycer-AGE. In human AD brains, Glycer-AGE are actually detected in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. These observations suggest that Glycer-AGE play a role in the pathogenesis of AD. In this review, we discuss the pathophysiological role for AGEs in the development and progression of AD, especially focusing on Glycer-AGE.

Involvement of Advanced Glycation End-products (AGEs) in Alzheimers Disease

The advanced stage of the glycation process (one of the post-translational modifications of proteins) leads to the formation of advanced glycation end-products (AGEs) and plays an important role in the pathogenesis of angiopathy in diabetic patients. It has recently become clear that AGEs also influence physiological aging and neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Recently we have provided direct immunochemical evidence for the existence of six distinct AGE structures within the AGE-modified proteins and peptides that circulate in the serum of diabetic patients on hemodialysis (DM-HD). We showed a direct toxic effect of the synthetic AGE-2 (glyceraldehyde-derived AGEs) on cortical neuronal cells and provided evidence for a toxic effect of AGE-2 present in DM-HD serum. These results indicate that of the various types of AGE structures that can form in vivo, the AGE-2 structure is likely to play an important role in the pathophysiological processes associated with AGE formation. In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hippocampal gyrus. Protein cross-linking by AGE structures results in the formation of protease-resistant aggregates. Such protein aggregates may interfere with both axonal transport and intracellular protein traffic in neuron. In this review, we provide an outline of AGEs formation in vivo and propose that the novel structural epitope AGE-2 is an important toxic moiety for neuronal cells in AD.

The involvement of advanced glycation endproducts (AGEs) in renal injury of diabetic glomerulosclerosis: association with phenotypic change in renal cells and infiltration of immune cells.

Glycation of proteins is regarded as one of the major causes of the progression of diabetic nephropathy (DN) and of the phenotypic changes in glomerular mesangial cells (MC) and the cellular infiltration that occurs in MC from DN. It thus is very important to study the interrelationships and interaction between these causes. The localization of advanced glycation endproducts (AGEs), cytoskeletal proteins, and immune cell infiltration was evaluated by immunohistochemical study in patients with DN. N(Epsilon)-(carboxymethyl)lysine (CML), Alpha-smooth muscle actin (SMA), and low-molecular-weight caldesmon (L-CLD) were localized in the mesangial area in DN. The intensity of mesangial SMA and L-CLD expression was significantly correlated with the index of diabetic glomerulosclerosis (IDGS), while the expression of pentosidine was correlated with the IDGS and with 24-h urinary protein. Pentosidine was localized in glomerular basement membrane (GBM) only in DN and had a significant correlation with the mesangial expression of SMA and L-CLD. Pyrraline deposition on the tubular basement membrane, and the expression of SMA and L-CLD, and the infiltration of immune cells were observed in interstitial areas in DN. The intensity of L-CLD expression had a close relationship with pyrraline deposition and immune cell infiltration. The expression of SMA and L-CLD in interstitial areas was significantly correlated with the percent interstitial volume. AGEs are involved in renal injury in DN, and their effect is, at least in part, exercised via phenotypic changes in intrinsic renal cells and by the infiltration of immune cells.

Possible involvement of advanced glycation end-products in bone resorption.

Advanced glycation end-products (AGEs) are formed in long-lived matrix proteins by a non-enzymatic reaction with sugar. We recently demonstrated the presence of AGEs in amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits. This suggested a potential link of AGEs in bone resorption and led us to investigate whether AGEs enhance bone resorption. An immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in bone tissues from elderly subjects. AGE-modified proteins were shown to stimulate monocyte/macrophage to secrete bone-resorbing cytokines such as interleukin-1 beta, interleukin-6 and tumour necrosis factor- alpha. AGE-modified proteins enhanced net calcium efflux in cultured neonatal mouse calvariae to a much greater extent than unmodified proteins. Furthermore, when mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, AGE-modified proteins increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts or those modified with the early glycation products did not. These findings suggest that AGEs enhance bone resorption by osteoclasts. The modification of bone matrices with AGEs might, therefore, play a pathophysiological role not only in the remodelling of senescent bone matrix tissues, but also in dialysis-related amyloidosis or osteoporosis associated with diabetes and ageing.