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Advanced glycation end products diabetes and ageing,eat this not that magazine pdf,easy diet recipes for lunch,family dinner recipes blog - Try Out

Increasing evidence demonstrates that advanced glycation end products (AGEs) play a pivotal role in the development and progression of diabetic vascular damage. Advanced glycation end products (AGEs) are modifications of proteins or lipids that become nonenzymatically glycated and oxidized after contact with aldose sugars.
Schematic representation of the formation of some common advanced glycation end products (AGEs). It must also be kept in mind that AGEs can be absorbed through diet.8 In this regard, foods high in protein and fat, such as meat, cheese, and egg yolk, are rich in AGEs, whereas those high in carbohydrates have the lowest amount of AGEs. It has to be kept in mind, however, that RAGEs also bind ligands other than AGEs.5-7 Shortly after its discovery, structural analysis of the ligand- RAGE interaction revealed that the receptor recognized three-dimensional structures, such as Гў sheets and fibrils, rather than specific amino acid sequences (ie, primary structures). RAGE is expressed in many tissues and is most abundant in the heart, lung, skeletal muscle, and vessel wall. The most important pathological consequence of RAGE interaction with its ligands is the activation of several intracellular pathways, leading to the induction of oxidative stress and a broad spectrum of signaling mechanisms, schematically represented in Figure 4.
It has long been recognized that increased HbA1c (a precursor of AGEs) levels are associated with a higher incidence of vascular complications and reduced life expectancy in diabetic patients. Serum levels of AGEs in patients with type 2 diabetes and coronary heart disease are higher than those in patients without heart disease and correlate with the severity of the coronary syndrome.3,4,20 Furthermore, AGE levels are higher in type 2 diabetic patients with peripheral artery occlusive disease compared with those without it. In terms of relationship with life expectancy, it has been reported that increased serum levels of AGE predicted increased total cardiovascular and coronary mortality in women with type 2 diabetes during a follow-up period of 18 years.24 AGE level remained a strong predictor of survival even after adjustment for confounding factors, including C-reactive protein. Obviously, direct intervention on the AGE-RAGE system might lead to new and more targeted therapeutic approaches. A molecule which is being actively studied is 4,5-dimethyl-3- phenacylthiozolium chloride (ALT-711, or alagebrium), a compound that breaks the crosslinks of AGEs.46 Diabetic rats treated for 4 months with ALT-711 showed reduced collagen III, increased collagen solubility, and reduced RAGE mRNA expression compared with placebo.
Accelerated chemical modification of proteins and lipids during hyperglycemia leads to the formation of AGEs. When AGEs form in the skin, they activate a receptor site and form a complex known as Receptor-AGE (R-AGE) that signals cellular processes related to inflammation and subsequent disease.
While free radical formation and the activation of Matrix Metalloproteinase enzymes have been studied quite extensively over the past decade, the formation of Advanced Glycation End-products is now one of the hottest areas of research for understanding not only how the skin ages, but for determining the mechanism of disease formation in the human body. Then, via pathways also involving receptor-dependent signals, they promote the development and progression of cardiovascular disease. In other words, they are the result of a chain of chemical reactions which follow an initial glycation reaction. Alternatively, fructoselysine decays and releases its carbohydrate moiety either as glucose or as the more reactive hexoses, such as 3-deoxyglucosone, which themselves may modify proteins. In this way, AGEs alter the properties of the large matrix proteins collagen, vitronectin, and laminin.
In addition, increased cooking temperatures, through broiling and frying, and increased cooking times lead to an increased amount of AGEs. The human RAGE gene is on chromosome 6 in the major histocompatibility complex between genes for class II and class III.
In addition, forms of RAGE lacking both the cytosolic and the transmembrane domains have been described. As a matter of fact,RAGEs bind amyloid-â peptide (which accumulates in Alzheimer’s disease) and amyloid A (which accumulates in systemic amyloidosis).
The interactions lead to prolonged inflammation, mainly as a result of the RAGE-dependent expression of proinflammatory cytokines and chemokines. Fewer macrophages, T cells, and HLA-DR–expressing cells were noted in the lesions of these subjects.
Molecules under investigation for possible clinical use can be roughly subdivided into two main groups: those that prevent the formation of AGEs and those that degrade existing AGEs. In addition, ALT-711 has been shown to improve left ventricular function, to reduce ventricular collagen, and to lengthen survival in diabetic animals. AGEs contribute to the development and progression of diabetic vascular complications through a number of mechanisms, including interaction with their receptors, RAGEs. Increased serum levels of advanced glycation endproducts predict total, cardiovascular and coronary mortality in women with type 2 diabetes: a population-based 18 year follow-up study.
After my Photodamage and Aging class, I feel like I am on my way to being a far more educated professional. Age-related skin changes are the result of genetically programmed changes (intrinsic factors) and environmental wear-and-tear on the skin (extrinsic factors). Manifestations of photoaging include an increase in wrinkle formation, a loss of tension and elasticity, degeneration of the vascular supply and skin thickness, hyperpigmentation and other skin discoloration, dilated capillaries (telangiectasis) and a reduction in the water-binding properties of the skin. ROS are generally very small molecules and are highly reactive due to the presence of unpaired electrons. Then, following the interaction with receptors for advanced glycation end products (RAGEs), a series of events leading to vessel damage are elicited and perpetuated, which include oxidative stress, increased inflammation, and enhanced extracellular matrix accumulation.
These compounds interact with receptors, such as RAGEs (receptors for advanced glycation end products), to induce oxidative stress, increase inflammation by promoting nuclear factor-ГЄB (NFГЄB) activation, and enhance extracellular matrix accumulation.5-7 These biological effects translate into accelerated plaque formation and increased cardiac fibrosis, with consequent effects on cardiac function.
The intermediate products are known as Schiff base, Amadori, and Maillard products, after the researchers who first described them. In addition, it has recently been found that glucose can auto-oxidize to form reactive carbonyl compounds (glyoxal and methylglyoxal) which can react with proteins to form glycoxidation products (Figure 2). AGE cross-linking on type I collagen and elastin causes an increase in the area of ECM, resulting in increased stiffness of the vasculature.
It is composed of 11 exons and a 3_UTR region, and common variants have been described.12 For example, the Gly82Ser polymorphism in exon 3 is located in the ligand- binding V-domain of RAGE (see below), and has been studied to assess its role in subjects with vascular disease.
These forms of RAGE are, therefore, secreted extracellularly, can be detected in circulating blood, and are called soluble receptors for advanced glycation end products (sRAGEs).5-7 This is of importance since sRAGEs can bind their ligands in the circulation, thus preventing the adverse intracellular events of the AGE-RAGE axis (see below). For example, aminoguanidine is a hydrazine compound that prevents AGE formation by interacting with derivatives of early glycation products that are not bound to proteins.


A cascade of dramatic events follows this interaction, which include oxidative stress and activation of inflammatory pathways that all cause proatherosclerotic changes and induce vessel damage.
The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes. Receptor for advanced glycation end products and the cardiovascular complications of diabetes and beyond: lessons from AGEing. Receptor for advanced glycation endproducts and atherosclerosis: From basic mechanisms to clinical implications. Advanced glycosylation end products and nutrition—a possible relation with diabetic atherosclerosis and how to prevent it. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy.
Diet-derived advanced glycation end products are major contributors to the body’s AGE pool and induce inflammation in healthy subjects. Identification of polymorphisms in the receptor for advanced glycation end products (RAGE) gene: prevalence in type 2 diabetes and ethnic groups. Coregulation of neurite outgrowth and cell survival by amphoterin and S100 proteins through receptor for advanced glycation end products (RAGE) activation. Roles of the receptor for advanced glycation endproducts in diabetes-induced vascular injury. Increased serum concentrations of advanced glycation end products: a marker of coronary artery disease activity in type 2 diabetic patients. Serum levels of advanced glycation end products are associated with left ventricular diastolic function in patients with type 1 diabetes.
Advanced glycation end products and antioxidant status in type 2 diabetic patients with and without peripheral artery disease.
Serum levels of advanced glycation end products are associated with in-stent restenosis in diabetic patients. Increased accumulation of the glycoxidation product Nepsilon-(carboxymethyl) lysine in hearts of diabetic patients: generation and characterisation of a monoclonal anti-CML antibody.
The receptor RAGE as a progression factor amplifying arachidonate-dependent inflammatory and proteolytic response in human atherosclerotic plaques: role of glycemic control. Suppression of RAGE as a basis of simvastatin- dependent plaque stabilization in type 2 diabetes. Plasma levels of soluble receptor for advanced glycation end products and coronary artery disease in nondiabetic men. Decreased endogenous secretory advanced glycation end product receptor in type 1 diabetic patients: its possible association with diabetic vascular complications. Plasma level of endogenous secretory RAGE is associated with components of the metabolic syndrome and atherosclerosis. Low circulating endogenous secretory receptor for AGEs predicts cardiovascular mortality in patients with end-stage renal disease.
Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein. Association between serum levels of soluble receptor for advanced glycation end products and circulating advanced glycation end products in type 2 diabetes. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Metformin reduces endothelial cell expression of both the receptor for advanced glycation end products and lectin-like oxidized receptor 1. Effect of metformin administration on plasma advanced glycation end product levels in women with polycystic ovary syndrome. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin.
Advanced glycation end products increase, through a protein kinase C-dependent pathway, vascular endothelial growth factor expression in retinal endothelial cells.
Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products: inhibitory effect of gliclazide.
Antiglycation effect of gliclazide on in vitro AGE formation from glucose and methylglyoxal. Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy.
Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. Effects of pyridoxamine in combined phase 2 studies of patients with type 1 and type 2 diabetes and overt nephropathy. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes.
Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes.
A neutralizing antibody against receptor for advanced glycation end products (RAGE) reduces atherosclerosis in uremic mice. While both influence the skin’s structure and function, extrinsic factors cause more pronounced changes.
Collagenase is really a group of enzymes that are responsible for breaking down the different types of collagen and elastin. We now know that collagen and elastin proteins are highly susceptible to an internal chemical reaction within the body called glycation. Because we now know that inflammation is the catalyst critical to the aging process and many diseases.


While it may seem like these three biochemical phenomena are isolated occurrences in the skin, it is important to note their connection and the influence they have on each other. Whereas targeting glycemic control and treating additional risk factors, such as obesity, dyslipidemia, and hypertension, are mandatory to reduce chronic complications and prolong life expectancy in diabetic patients, drug therapy tailored to reducing the deleterious effects of the AGE-RAGE interaction is being actively investigated and showing signs of promise. In this article, we will deal with the biology of AGEs and RAGEs, with particular emphasis on their role in diabetes.
Initially, glycation involves covalent reactions between free amino groups of amino acids, such as lysine, arginine, or protein terminal amino acids and sugars (glucose, fructose, ribose, etc), to create, first, the Schiff base and then Amadori products, of which the best known are HbA1c (Figure 1) and fructosamine (fructoselysine). Glycation results in increased synthesis of type III collagen, type V collagen, type VI collagen, laminin, and fibronectin in the ECM, most likely via upregulation of transforming growth factor-Гў pathways. The V domain in the N-terminus is important in ligand binding, and the cytosolic tail is critical for RAGE-induced intracellular signaling.
In the cases of diabetes, inflammation, and atherosclerosis, there is marked induction of RAGE due to the action of its ligands and to several mediators from activated inflammatory cells.5-7,16,17 In turn, the binding of ligands to RAGE induces further upregulation of the receptor (positive feedback), leading to a vicious circle. In addition, in endothelial cells, mitochondrial sources of ROS are also involved, following the AGE-RAGE interaction. Additional findings from plaques retrieved from type 2 diabetic patients include larger necrotic cores and a correlation between RAGE expression on macrophages and apoptotic smooth muscle cells.25-29 Altogether, the findings indicate that the AGE-RAGE axis may compromise cell survival and, thereby, promote mechanisms linked to plaque destabilization.
In animal models of diabetes, aminoguanidine treatment increased arterial elasticity, decreased vascular AGE accumulation as well as the severity of atherosclerotic plaques, and, in addition, reduced accumulation of fibronectin and laminin in the extracellular membrane of streptozotocin-induced diabetic rats with diabetic nephropathy.46 In a placebo-controlled, randomized trial in patients with type 1 diabetes mellitus,47 aminoguanidine caused a slower reduction in glomerular filtration rate, diminished 24-hour urinary proteinuria and progression of retinopathy, but it did not attenuate the time-to-doubling of serum creatinine. In phase 2 trials involving diabetic patients with overt nephropathy,50 pyridoxamine significantly reduced the change in serum creatinine from baseline, with no differences in urinary albumin excretion. Reduction of blood glucose levels and correction of additional classic risk factors for cardiovascular disease remain the most appropriate ways to reduce vascular complications and prolong life expectancy in diabetic patients. This is a non-enzyme mediated reaction that takes place between free amino groups in proteins and a sugar such as glucose. For example, diabetics have characteristically high levels of sugar in their blood and suffer from numerous health issues (including cataracts, atherosclerosis, etc.), which emanate from the formation of AGEs in the body. Thus, AGEs can arise from glucose and lipids through several, partially intermingling reactions. Formation of AGEs on laminin results in reduced binding to type IV collagen, reduced polymer elongation, and lower binding of heparan sulfate proteoglycan.
Unsurprisingly, one of the locations where RAGE expression is enhanced is in the diabetic atherosclerotic plaque (particularly at the vulnerable regions of the plaque and in macrophages), where it colocalizes with cyclooxygenase 2, microsomal prostaglandin E2, and metalloproteases.
Experimental evidence demonstrates that RAGE dependent modulation of gene expression and cellular properties depends upon signal transduction. More targeted therapeutic approaches aimed at preventing the deleterious effects of the AGE-RAGE interaction have remarkable potential, and initial studies in humans show encouraging results.
This is known as oxidative stress, which is the major cause of degenerative disorders including aging and disease. The same glucose that provides energy for our cells can react with proteins (such as collagen), resulting in the formation of Advanced Glycation End-products and Reactive Oxygen Species; these contribute to cross-linking of protein fibers, the loss of elasticity and changes in the dermis associated with the aging process.
Hence, diabetes is considered a disease of accelerated aging due to the inflammation that arises from the formation of AGEs. Glycation of laminin and type I and type IV collagens, key molecules in the basement membrane, causes inhibited adhesion to endothelial cells for both matrix glycoproteins. In particular, one variant protein (N-truncated type) lacks the V-type immunoglobulin domain, but it is otherwise identical to full-length RAGE and is retained in the plasma membrane. Thus, RAGEs have a large repertoire of ligands, making this receptor crucial at the crossroad between diabetes, inflammation, and vascular disease. This activity makes the MMPs critical for the remodeling of connective tissue, which is an integral part of aging and wound healing. This is not restricted to diabetes; muscle weakness, heart disease and many diseases of the brain are associated with glycation. In addition, it has been suggested that AGE formation leads to a reduction in the binding of collagen and heparan to the adhesive matrix molecule vitronectin. Lipid peroxidation also results from ROS damage to cell membranes, leading to premature aging, skin cancer and cell death. Scientists now believe that reducing glycation is a means of slowing the aging process and disease formation. AGE-induced alterations of vitronectin and laminin may explain the reduction in binding of heparan sulfate proteoglycan, a stimulant of other matrix molecules in the vessel wall, to the diabetic basement membrane.
In human endothelial cells, RAGE activation enhances the expression of adhesion molecules, including VCAM-1, ICAM-1, and E-selectin. As for the role of lipids, glycated low-density lipoprotein (LDL) reduces nitric oxide (NO) production and suppresses uptake and clearance of LDL through its receptor on endothelial cells. AGE bound to RAGE on the endothelium also determines alterations to the surface antithrombotic properties of flowing blood, as shown by a reduction in thrombomodulin expression and the concomitant induction of tissue factor expression that confers procoagulant properties.
The interaction of AGEs with RAGEs in monocytes induces their activation to macrophages, which manifests with the induction of platelet-derived growth factor, insulin-like growth factor 1, and proinflammatory cytokines, such as IL-1 and TNF-ГЎ. In addition to all this, AGE-RAGE interaction promotes monocyte chemotaxis and, at the level of smooth muscle cells, is associated with increased cellular proliferation.
Viewed together, these findings indicate that the AGE-RAGE interaction elicits and potentiates inflammatory responses through the enhanced generation of reactive oxygen species, proinflammatory adhesion molecules, and cytokines, causing continued amplification of inflammatory events.



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