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Advanced Glycation Endproducts (AGEs) are the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. The literature is imprecise in usages of these terms. For example, Maillard reaction products are sometimes considered an intermediate step and other times as AGEs. Side products generated in the intermediate steps may be oxidizing agents such as hydrogen peroxide, and others, such as beta amyloid proteins.[1] Glycosylation is also sometimes used as a synonym for glycation in the literature, but is then usually referred to as 'non-enzymatic glycosylation.' Glycation is the result of a sugar-reducing molecule, such as fructose or glucose, bonding to a protein or lipid molecule without the controlling action of an enzyme. ...
An Amadori product is an intermediate in the production of an advanced glycation end-product (AGE) as a result of glycation. ...
a mixture of 4,4-diaminodiphenyl ether 1 (1. ...
The Maillard reaction is a chemical reaction between an amino acid and a reducing sugar, usually requiring the addition of heat. ...
Glycosylation is the process or result of addition of saccharides to proteins and lipids. ...
Glycation is the result of a sugar-reducing molecule, such as fructose or glucose, bonding to a protein or lipid molecule without the controlling action of an enzyme. ...
AGE formation
AGEs may be formed external to the body (exogenously) by heating (e.g. cooking) sugars with fats or proteins[2]; or, inside the body (endogenously) through normal metabolism and aging. Under certain pathologic conditions (e.g. oxidative stress due to hyperglycemia in patients with diabetes), AGE formation can be increased beyond normal levels. Exogenous (or exogeneous) (from the Greek words exo and gen, meaning outside and production) refers to an action or object coming from outside a system. ...
Look up Endogenous in Wiktionary, the free dictionary. ...
Hyperglycemia or High Blood Sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. ...
This article is about the disease that features high blood sugar. ...
AGE formation in diabetes In the pathogenesis of diabetes-related AGE formation, hyperglycemia results in higher cellular glucose levels in those cells unable to reduce glucose intake (e.g. endothelial cells).[3][4] This in turn results in increased levels of NADH and FADH, increasing the proton gradient beyond a particular threshold at which the complex III prevents further increase by stopping the electron transport chain.[citation needed] This results in mitochondrial production of reactive oxygen species, activating PARP1 by damaging DNA. PARP1 in turn, ADP-ribosylates GAPDH, a protein involved in glucose metabolism, leading to its inactivation and an accumulation of metabolites earlier in the metabolism pathway. These metabolites activate multiple pathogenic mechanisms, one of which includes increased production of AGEs. Nicotinamide adenine dinucleotide (NAD+) Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are two important coenzymes found in cells. ...
Riboflavin Flavin is a tricyclic heteronuclear organic ring whose biochemical source is the vitamin riboflavin. ...
An ion gradient is a concentration gradient of ions, it can be called an electrochemical potential gradient of ions across membranes. ...
schematic illustration of complex III reactions The coenzyme Q : cytochrome c — oxidoreductase, sometimes called the cytochrome bc1 complex, and at other times complex III, is the third complex in the electron transport chain (EC 1. ...
The Electron Transport Chain. ...
Reactive oxygen species (ROS) include oxygen ions, free radicals and peroxides both inorganic and organic. ...
RNA expression pattern Orthologs Human Mouse Entrez Ensembl na Uniprot na Refseq Location na Pubmed search Poly (ADP-ribose) polymerase family, member 1, also known as PARP1, is a human gene. ...
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH or G3PDH, although this is not really correct) (EC 1. ...
Examples of AGE modified sites are carboxymethyllysine (CML), carboxyethyllysine (CEL) and Argpyrimidine which is the most common epitope.
Effects AGEs may be less, or more, reactive than the initial sugars they were formed from. Foods may be up to 200 times more immunoreactive after cooking.[2] Many cells in the body (for example endothelial cells, smooth muscle or cells of the immune system) from tissue such as lung, liver, kidney or peripheral blood bear the Receptor for Advanced Glycation Endproducts (RAGE) that, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy or neuropathy. There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs.[5] The endothelium is the layer of thin, flat cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ...
Smooth muscle Layers of Esophageal Wall: 1. ...
A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ...
In biochemistry, a receptor is a protein on the cell membrane or within the cytoplasm or cell nucleus that binds to a specific molecule (a ligand), such as a neurotransmitter, hormone, or other substance, and initiates the cellular response to the ligand. ...
To meet Wikipedias quality standards, this article or section may require cleanup. ...
An abscess on the skin, showing the redness and swelling characteristic of inflammation. ...
Arthritis (from Greek arthro-, joint + -itis, inflammation; plural: arthritides) is a group of conditions where there is damage caused to the joints of the body. ...
The total state of oxidative and peroxidative stress on the healthy body, and the accumulation of AGE-related damage is proportional to the dietary intake of exogenous (preformed) AGEs, the consumption of sugars with a propensity towards glycation such as fructose and galactose.
AGEs affect nearly every type of cell and molecule in the body, are thought to be major factors in aging and age related chronic diseases. They are also believed to play a causative role in the vascular complications of diabetes mellitus. For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. ...
They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide, oxdising LDL,[6] binding cells including macrophage, endothelial and mesangial cells to induce the secretion of a variety of cytokines and enhancing oxidative stress[7][6] R-phrases , , , , S-phrases , , , Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references Nitric oxide or Nitrogen monoxide is a chemical compound with chemical formula NO. This gas is an important signaling molecule in the body of...
Clearance Cellular proteolysis of AGEs, produces AGE peptides and "AGE free adducts" (AGE adducts bound to single amino acids) which after being released into the plasma, can be excreted in the urine.[8] The resistance of extraceullar matrix proteins to proteolysis, renders AGEs of these proteins less conducive to elimination.[8] While the AGE free adducts are released directly into the urine, AGE-peptides have been shown to be endocytosed by the epithelial cells of the proximal tubule and subsequently degraded by the endolysosomal system to produce AGE-amino acids. The AGE-amino acids are hypothesised to then be exported back into the lumen of the nephron for subsequent excretion.[6] AGE free adducts are the major form through which AGEs are excreted in urine with AGE-peptides occurring to a lesser extent[6] but accumulate in the plasma patients with chronic renal failure.[8] Various organelles labeled. ...
Larger, extracellularly-derived, AGE proteins cannot pass through the basement membrane of the renal corpuscle and must first be degraded into AGE-petides and AGE free adducts. Peripheral macrophage[6] have been implicated in this process although the real-life involvement of the liver has been disputed.[9] A renal corpuscle is the initial filtering component of a nephron in the kidney. ...
A macrophage of a mouse stretching its arms to engulf two particles, possibly pathogens Macrophages (Greek: big eaters, from makros large + phagein eat) are cells within the tissues that originate from specific white blood cells called monocytes. ...
Clearance in diabetes and kidney dysfunction Large AGE proteins unable to enter the Bowman's capsule are capable of binding to receptors on endothelial and mesangial cells and to the mesangial matrix[6]. Activation of RAGE induces production of a variety of cytokines, including TNFβ which mediates an ihibition of metalloproteinase and increases production of mesangial matrix, leading to glomerulosclerosis[7] and decreasing kidney function in patients with unusually high AGE levels. The Bowmans capsule(other names: capsula glomeruli, glomerular capsule) is a cup like sac at the beginning of the tubular component of a nephron in the mammalian kidney. ...
The metalloendopeptidases (also called metalloproteinases or metalloproteases) are a class of enzymes from the group of endopeptidases. ...
Glomerulosclerosis refers to a hardening of the glomerulus in the kidney. ...
Although the only form suitable for urinary excretion, the breakdown products of AGE, AGE-peptides and AGE free adducts are more aggressive than their AGE-proteins from which they are derived, and can perpetuate related pathology in diabetic patients, even after hyperglycemia has been brought under control.[6] Since perpetuation may result through their oxidative effects (some AGE have innate catalytic oxidative capacity while activation of NAD(P)H oxidase through activation of RAGE and damage to mitochondrial proteins leading to mitochondrial dysfunction can also induce oxidative stress) concurrent treatment with antioxidants, may help to stem the vicious cycle.[7] Ultimately, effective clearance is necessary, and those suffering AGE increases due to kidney dysfunction (in the presence or absence of diabetes) will require a kidney transplant.[6]
In diabetics, suffering from increase AGE production, subsequent kidney damage (by AGE production in the glomerulus) reduces the subsequent urinary removal of AGEs, forming a positive feedback loop and further increasing the rate of damage.
Therapeutic intervention AGE's are the subject of ongoing research. AGE crosslink breaking drugs are currently being developed for the purpose breaking crosslinks between proteins. Alt-711, also called alagebrium developed by Synvista Therapeutics Inc. is the first of these to reach clinical trials. Molecular structure Alagebrium (formerly known as ALT-711; chemical name 4,5-dimethyl-3-(2-oxo-2-phenylethyl)-thiazolium chloride) is a drug produced by Synvista Therapeutics Inc. ...
Alagebrium is a chemical compound that was shown to break A.G.E. (Advanced Glycation End-product) crosslinks. ...
Glycation inhibitors include aminoguanidine[10] (sold as Pimagedine), carnosine[11] and aspirin[12]; it is also believed that alpha-lipoic acid and acetyl-l-carnitine can also reduce glycation damage[13] Carnosine (beta-alanyl-L-histidine) is a dipeptide of the amino acids beta-alanine and histidine. ...
This article is about the drug. ...
Lipoic acid or α-lipoic acid has formula C8H14S2O2 and systematic name 5-(1,2-dithiolan-3-yl)pentanoic acid. ...
Acetyl-L-carnitine is an acetylated form of L-carnitine, which is far superior to normal L-carnitine in terms of bioavailability. ...
See also Glycosylation is the process or result of addition of saccharides to proteins and lipids. ...
Glucosepane is a protein cross-linking product. ...
Methylglyoxal, also called pyruvaldehyde or 2-oxo-propanal (CH3-CO-CH=O or C3H4O2) is the aldehyde form of pyruvic acid. ...
The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism. ...
References - ^ Miyata T, Oda O, Inagi R, Iida Y, Araki N, Yamada N, Horiuchi S, Taniguchi N, Maeda K, Kinoshita T (1993). "beta 2-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyloidosis". The Journal of Clinical Investigation 92 (3): 1243-1252. PMID 8376584.
- ^ a b Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, Heitmann K, Vlassara H (1997). "Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy". Proceedings of the National Academy of Sciences (USA) 94 (12): 6474-6479. PMID 9177242.
- ^ Dominiczak MH (2003). "Obesity, glucose intolerance and diabetes and their links to cardiovascular disease. Implications for laboratory medicine". Clin. Chem. Lab. Med. 41 (9): 1266–78. PMID 14598880.
- ^ Brownlee M (2005). "The pathobiology of diabetic complications: a unifying mechanism". Diabetes 54 (6): 1615–25. PMID 15919781.
- ^ Wells-Knecht KJ, Zyzak DV, Litchfield JE, Thorpe SR, Baynes JW (1995). "Mechanism of autoxidative glycosylation: identification of glyoxal and arabinose as intermediates in the autoxidative modification of proteins by glucose". Biochemistry 34 (11): 3702-3709. PMID 7893666.
- ^ a b c d e f g h Gugliucci A, Bendayan M (1996). "Renal fate of circulating advanced glycated end products (AGE): evidence for reabsorption and catabolism of AGE-peptides by renal proximal tubular cells". Diabetologia 39 (2): 149–60. PMID 8635666.
- ^ a b c Yan HD, Li XZ, Xie JM, Li M (2007). "Effects of advanced glycation end products on renal fibrosis and oxidative stress in cultured NRK-49F cells". Chin. Med. J. 120 (9): 787–93. PMID 17531120.
- ^ a b c Gugliucci A, Mehlhaff K, Kinugasa E, et al (2007). "Paraoxonase-1 concentrations in end-stage renal disease patients increase after hemodialysis: correlation with low molecular AGE adduct clearance". Clin. Chim. Acta 377 (1-2): 213–20. doi:10.1016/j.cca.2006.09.028. PMID 17118352.
- ^ Svistounov D, Smedsrød B (2004). "Hepatic clearance of advanced glycation end products (AGEs)--myth or truth?". J. Hepatol. 41 (6): 1038–40. doi:10.1016/j.jhep.2004.10.004. PMID 15582139.
- ^ A. Gugliucci, "Sour Side of Sugar, A Glycagtion Web Page
- ^ A.R. Hipkiss, C. Brownson, M. J. Carrie, "Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups," Mech Ageing Dev. (2001) Sep 15;122(13) pp. 1431-45.
- ^ R. Bucala, A. Cerami, "Advanced Glycosylation: Chemistry, Biology, and Implications for Diabetes and Aging," Advances in Pharmacology, Volume 23. (1992) pp. 1 - 34
- ^ B. N. Ames; J. Liu, "Delaying the mitochondrial decay of aging with acetylcarnitine" (2005) Annals of the New York Academy of Sciences, 1033 (1) pp. 108-16.
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