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Advanced Glycation Endproducts (AGEs) are the result of a chain of chemical reactions after an initial glycation reaction. Glycation (sometimes called non-enzymatic Glycosylation) is the result of a sugar molecule such as Fructose or Glucose, bonding to a Protein The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. The Amadori rearrangement is an Organic reaction describing the acid or base catalyzed Isomerization or Rearrangement reaction of the N- Schiff base (or azomethine) named after Hugo Schiff, is a Functional group that contains a Carbon - Nitrogen Double bond The Maillard reaction is a Chemical reaction between an Amino acid and a Reducing sugar, usually requiring Heat. (The literature is inconsistent in applying these terms. For example, Maillard reaction products are sometimes considered intermediates and sometimes end products. ) Side products generated in intermediate steps may be oxidizing agents (such as hydrogen peroxide), or not (such as beta amyloid proteins). [1] "Glycosylation" is sometimes used for "glycation" in the literature, usually as 'non-enzymatic glycosylation. Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic Glycation (sometimes called non-enzymatic Glycosylation) is the result of a sugar molecule such as Fructose or Glucose, bonding to a Protein '

Contents

AGE formation

AGEs may be formed external to the body (exogenously) by heating (e. Exogenous (or exogeneous) (from the Greek words "exo" and "gen" meaning "outside" and "production" refers to an action or g. cooking) sugars with fats or proteins[2]; or, inside the body (endogenously) through normal metabolism and aging. The word endogenous means "arising from within" the opposite of Exogenous. Under certain pathologic conditions (e. g. oxidative stress due to hyperglycemia in patients with diabetes), AGE formation can be increased beyond normal levels. Hyperglycemia, hyperglycaemia, or high blood sugar is a condition in which an excessive amount of Glucose circulates in the Blood plasma Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc

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. Nicotinamide adenine dinucleotide, abbreviated NAD+, is a Coenzyme found in all living cells The compound is a dinucleotide since it consists For the town in France see Flavin Aveyron. Flavin (from Latin flavus, "yellow" is the common name for a group of Organic In Cellular biology, an electrochemical gradient is a spatial variation of both Electrical potential and chemical Concentration across a membrane The coenzyme Q: cytochrome c — oxidoreductase, sometimes called the cytochrome bc 1 complex, and at other times complex III An electron transport chain couples a chemical reaction between an electron donor (such as NADH) and an electron acceptor (such as O2) to the transfer [5] This results in mitochondrial production of reactive oxygen species, activating PARP1 by damaging DNA. Reactive oxygen species (ROS are ions or very small molecules that include Oxygen Ions free radicals, and Peroxides both inorganic and Poly (ADP-ribose polymerase family member 1, also known as 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. Glyceraldehyde 3-phosphate dehydrogenase (abbreviated as GAPDH or less commonly as G3PDH ( is an Enzyme that catalyzes the sixth step of These metabolites activate multiple pathogenic mechanisms, one of which includes increased production of AGEs.

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. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the Smooth muscle is a type of non- Striated muscle, found within the Tunica media layer of large and small Arteries and Veins, the bladder An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor In Biochemistry, a receptor is a Protein molecule embedded in either the Plasma membrane or Cytoplasm of a cell to which a mobile signaling RAGE, the receptor for advanced glycation endproducts is a 35kD transmembrane receptor of the Immunoglobulin super family which was first characterized Inflammation ( Latin, inflamatio, to set on fire is the complex biological response of vascular tissues to harmful stimuli such as Pathogens Atherosclerosis is a Disease affecting arterial Blood vessels It is a chronic inflammatory response in the walls of arteries in large part due to the accumulation Asthma is a chronic Condition involving the Respiratory system in which the airways occasionally constrict become inflamed, and are Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs. [6]

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. Diabetes mellitus (ˌdaɪəˈbiːtiːz or /ˌdaɪəˈbiːtəs/ /məˈlaɪtəs/ or /ˈmɛlətəs/ often referred to simply as diabetes ( Ancient Greek: grc

They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide, oxdising LDL,[7] binding cells including macrophage, endothelial and mesangial cells to induce the secretion of a variety of cytokines and enhancing oxidative stress[8][7]

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. Nitric oxide or nitrogen monoxide is a Chemical compound with Chemical formula N[[Oxygen O]] [9] The resistance of extraceullar matrix proteins to proteolysis, renders AGEs of these proteins less conducive to elimination. [9] 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. Lysosomes are Organelles that contain Digestive enzymes (acid Hydrolases. The AGE-amino acids are hypothesised to then be exported back into the lumen of the nephron for subsequent excretion. [7] AGE free adducts are the major form through which AGEs are excreted in urine with AGE-peptides occurring to a lesser extent[7] but accumulate in the plasma patients with chronic renal failure. [9]

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. In the Kidney, a renal corpuscle is the initial blood-filtering component of a Nephron. Peripheral macrophage[7] have been implicated in this process although the real-life involvement of the liver has been disputed. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that [10]

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[7]. The Bowman's 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 Activation of RAGE induces production of a variety of cytokines, including TNFβ which mediates an inhibition of metalloproteinase and increases production of mesangial matrix, leading to glomerulosclerosis[8] and decreasing kidney function in patients with unusually high AGE levels. Metalloproteinases (or metalloproteases constitute a family of Enzymes from the group of Proteinases classified by the nature of the most prominent Functional 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. [7] 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. [8] 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. [7]

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. Alagebrium (formerly known as ALT-711) is a drug produced by Alteon Corporation which is currently being evaluated in clinical trials Alagebrium (formerly known as ALT-711) is a drug produced by Alteon Corporation which is currently being evaluated in clinical trials

Glycation inhibitors include aminoguanidine[11] (sold as Pimagedine), carnosine[12] and aspirin;[13] it is also believed that alpha-lipoic acid and acetyl-l-carnitine can also reduce glycation damage[14]

See also

References

  1. ^ Miyata T, Oda O, Inagi R, Iida Y, Araki N, Yamada N, Horiuchi S, Taniguchi N, Maeda K, Kinoshita T (1993). Carnosine ( beta -alanyl-L-histidine is a Dipeptide of the Amino acids Beta-alanine and Histidine. Aspirin, or acetylsalicylic acid (ASA (əˌsɛtɨlsælɨˌsɪlɨk ˈæsɨd is a Salicylate drug, often used as an Analgesic to relieve Lipoic acid is an Organic compound, one Enantiomer of which is an essential cofactor for many enzyme complexes Acetyl -L-carnitine or ALCAR, is an Acetylated form of L- Carnitine. Glycosylation is the enzymatic process that links Saccharides to produce glycans, either free or attached to Proteins and Lipids This enzymatic Glucosepane is a Protein Cross-linking product It is the most common protein cross-link found in senescent Skin. Methylglyoxal, also called pyruvaldehyde or 2-oxo-propanal (CH3-CO-CH=O or C3H4O2 is the Aldehyde form of 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 "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. The Journal of Clinical Investigation (JCI or J Clin Invest) is a leading biomedical journal, with a 2007 Impact factor of 16 doi:10.1172/JCI116696. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 8376584.  
  2. ^ 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. doi:10.1073/pnas.94.12.6474. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 9177242.  
  3. ^ 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. doi:10.1515/CCLM.2003.194. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14598880.  
  4. ^ Brownlee M (2005). "The pathobiology of diabetic complications: a unifying mechanism". Diabetes 54 (6): 1615–25. doi:10.2337/diabetes.54.6.1615. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15919781.  
  5. ^ Topol, Eric J. ; Robert M. Califf (2006). Textbook of Cardiovascular Medicine. Lippincott Williams & Wilkins, 42. ISBN 0781770122.  
  6. ^ 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.  
  7. ^ 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. doi:10.1007/BF00403957. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 8635666.  
  8. ^ 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.  
  9. ^ 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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 17118352.  
  10. ^ 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. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 15582139.  
  11. ^ A. Gugliucci, "Sour Side of Sugar, A Glycagtion Web Page
  12. ^ 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.
  13. ^ R. Bucala, A. Cerami, "Advanced Glycosylation: Chemistry, Biology, and Implications for Diabetes and Aging," Advances in Pharmacology, Volume 23. (1992) pp. 1 - 34
  14. ^ 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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