Diversity of advanced glycation end products in the bovine milk proteome.

Milk processing relies on thermal treatments warranting microbiologically safe products with extended shelf life. However, elevated temperatures favor also Maillard reactions yielding the structurally diverse advanced glycation end products (AGEs). AGEs may alter protein functions and immunogenicity and also decrease the nutritional value of milk products. Furthermore, dietary AGEs contribute to the circulating AGE pool with potentially harmful effects. Here, 14 types of protein-derived AGEs present in raw milk or produced during processing/storage of regular and lactose-free milk products were identified by nanoRP-UPLC-ESI-MS/MS. In total, 132 peptides (118 modification sites in 62 proteins) were modified by at least one studied AGE. Amide-AGEs were the most abundant group with formyllysine being the main type. Most lysine- and arginine-derived AGEs and their modification sites have not been reported before. The number of AGE modification sites increased with the harsher processing conditions of regular milk, but remained stable during storage. This was further supported by quantitative data.

Advanced glycation end products (AGEs) and cardiovascular dysfunction: focus on high molecular weight AGEs.

Advanced glycation end products (AGEs) are a group of proteins and lipids becoming glycated and oxidized after persistent contact with reducing sugars or short-chain aldehydes with amino group and/or high degree of oxidative stress. The accumulation of AGEs in the body is a natural process that occurs with senescence, when the turnover rate of proteins is reduced. However, increased circulating AGEs have been described to arise at early lifetime and are associated with adverse outcome and survival, in particular in settings of cardiovascular diseases. AGEs contribute to the development of cardiac dysfunction by two major mechanisms: cross-linking of proteins or binding to their cell surface receptor. Recently, growing evidence shows that high-molecular weight AGEs (HMW-AGEs) might be as important as the characterized low-molecular weight AGEs (LMW-AGEs). Here, we point out the targets of AGEs in the heart and the mechanisms that lead to heart failure with focus on the difference between LMW-AGEs and the less characterized HMW-AGEs. As such, this review is a compilation of relevant papers in the form of a useful resource tool for researchers who want to further investigate the role of HMW-AGEs on cardiac disorders and need a solid base to start on this specific topic.

Two soluble isoforms of receptors for advanced glycation end products (RAGE) in carotid atherosclerosis: the difference of soluble and endogenous secretory RAGE.

BACKGROUND: Advanced glycation end products (AGEs) promote atherosclerosis through binding to their receptor, RAGE. Since soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) may suppress AGEs-RAGE signaling, we examined the usefulness of sRAGE and esRAGE as biomarkers of early-stage atherosclerosis. METHODS: Serum sRAGE and esRAGE levels were measured in 284 subjects with no history of atherothrombotic diseases. The subjects were divided into high-sRAGE and low-sRAGE groups and high-esRAGE and low-esRAGE groups based on respective median values. We investigated the relationships between these parameters and the following factors: number of metabolic components, maximum intima-media thickness of the common carotid artery (IMT Cmax), carotid plaque calcification, and asymptomatic cerebral white matter lesions. RESULTS: The low-sRAGE and low-esRAGE groups exhibited significantly more components of metabolic syndrome than the high-sRAGE and high-esRAGE groups, respectively. IMT Cmax was significantly higher in the low-sRAGE and low-esRAGE groups. Low-sRAGE levels were significantly associated with carotid plaque calcification. Multiple linear regression analysis identified body mass index (BMI), age, and high-sensitivity C-reactive protein as determinants of sRAGE, whereas only BMI was identified as a determinant of esRAGE. CONCLUSIONS: We demonstrated that sRAGE and esRAGE are associated with atherosclerotic risk factors in early-stage atherosclerosis, suggesting that their levels evolve in correlation with those of metabolic components and inflammation. Interestingly, low-sRAGE and esRAGE levels are associated with high IMT Cmax, but only low-sRAGE levels were associated with carotid plaque calcification. Thus, sRAGE and esRAGE may reflect different aspects of atherosclerosis in its early stage.

TAGE (toxic AGEs) hypothesis in various chronic diseases.

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, in aging, and in neurodegenerative diseases. However, it is still not clear which AGEs subtypes play a pathogenetic role and which of several AGEs receptor mediate AGEs effects on cells. We have provided direct immunochemical evidence for the existence of six distinct AGEs structures (AGEs-1 to -6) within the AGEs-modified proteins and peptides that circulate in the serum of diabetic patients. Recently we demonstrated for the first time that glyceraldehyde-derived AGEs (AGEs-2) and glycolaldehyde-derived AGEs (AGE-3) have diverse biological activities on vascular wall cells, mesangial cells, Schwann cells, malignant melanoma cells and cortical neurons. We also demonstrated for the first time that acetaldehyde (AA)-derived AGEs (AA-AGE) have cytotoxic activity on cortical neurons and the AA-AGE epitope was detected in human brain of alcoholics. These results indicate that of the various types of AGEs structures that can form in vivo, the toxic AGEs (TAGE) structures (AGEs 2, 3, and AA-AGE), but not non-toxic AGEs (N-carboxymethyllysine, pentosidine, pyrraline etc.) are likely to play an important role in the pathophysiological processes associated with AGEs formation.

Alternative routes for the formation of glyceraldehyde-derived AGEs (TAGE) in vivo.

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, and in Alzheimer's disease (AD). Recently we have provided direct immunochemical evidence for the existence of six distinct AGEs structures, designated AGEs-1 to -6, within the AGEs-modified proteins and peptides that circulate in the serum of diabetic patients. We found for the first time that glyceraldehyde-derived AGEs (AGE-2), which comprise main structure of TAGE (toxic AGEs), in the serum of diabetic patients have diverse biological activities on vascular wall cells and cortical neurons. These results suggest a causal role for AGE-2 in the pathogenesis of diabetic complications and AD in vivo. In AD brains, AGE-2 epitope was mainly present in the cytosol of neurons in the hippocampus and para-hipocampal gyrus. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, by: (i) glycolytic pathway, (ii) polyol pathway, and (iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of AGE-2 at both intracellular and extracellular region.

Cell activation by glycated proteins. AGE receptors, receptor recognition factors and functional classification of AGEs.

Proteins modified by advanced glycation endproducts (AGE) bind to cell surface receptors and other AGE binding proteins. AGE-binding receptors are: scavenger receptors types I and II, the receptor for advanced glycation endproducts (RAGE), oligosaccharyl transferase-48 (OST-48, AGE-R1), 80K-H phosphoprotein (AGE-R2) and galectin-3 (AGE-R3). AGE receptors are found in monocytes, macrophages, endothelial cells, pericytes, podocytes, astrocytes and microglia. AGE-modified proteins also bind to lysozyme and lactoferrin. A critical review of the evidence for receptors binding AGE-modified protein binding in vivo is presented. Scavenger receptors have only been shown to bind proteins modified by AGE to a much higher extent than found in vivo. 80K-H phosphoprotein is involved in FGFR3 signal transduction to MAP kinase, and may be involved in AGE-receptor signal transduction. Whether all of these proteins bind AGE-modified proteins in vivo is not yet clear. Cell activation in response to AGE-modified proteins is associated with increased expression of extracellular matrix proteins, vascular adhesion molecules, cytokines and growth factors. Depending on the cell type and concurrent signaling, this is associated with chemotaxis, angiogenesis, oxidative stress, cell proliferation or programmed cell death (PCD). Receptor recognition factors for agonism at the AGE receptor have been little studied but to date hydroimidazolones appear to be the most likely candidates. Pharmacologic inhibition of AGE receptor-mediated cell activation with specific antagonists may provide the basis for therapeutic intervention in diseases where AGE accumulation is a suspected etiological factor vascular complications of diabetes, macrovascular disease, renal insufficiency and Alzheimer's disease.