scholarly journals Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy

2005 ◽  
Vol 385 (2) ◽  
pp. 339-345 ◽  
Author(s):  
Ricardo GOMES ◽  
Marta SOUSA SILVA ◽  
Alexandre QUINTAS ◽  
Carlos CORDEIRO ◽  
António FREIRE ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Single Point ◽  
Disease Onset ◽  
Point Mutations ◽  
Protein Glycation ◽  
Familial Amyloidotic Polyneuropathy ◽  
Soluble Form ◽  
Advanced Glycation ◽  
Advanced Glycation End Product ◽  
Amyloid Deposits

FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming β-fibrils in amyloid deposits. This theory does not explain the formation of β-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to β-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [Nδ-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4′-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40±9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.

scholarly journals Advanced Glycation End Product-Modified β2-Microglobulin is a Component of Amyloid Fibrils of Primary Localized Cutaneous Nodular Amyloidosis

2002 ◽  
Vol 118 (3) ◽  
pp. 479-484 ◽  
Author(s):  
Norihiro Fujimoto ◽  
Mayumi Yajima ◽  
Yoshihiro Ohnishi ◽  
Shingo Tajima ◽  
Akira Ishibashi ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Advanced Glycation ◽  
Advanced Glycation End Product ◽  
Β2 Microglobulin

Evidence against the formation of 2-amino-6-(2-formyl-5-hydroxymethyl-pyrrol-l-yl)-hexanoic acid ('pyrraline') as an early-stage product or advanced glycation end product in non-enzymic protein glycation

1993 ◽  
Vol 84 (1) ◽  
pp. 87-93 ◽  
Author(s):  
Patricia R. Smith ◽  
Hanif H. Somani ◽  
Paul J. Thornalley ◽  
Jonathan Benn ◽  
Peter H. Sonksen
Keyword(s):  
Maillard Reaction ◽  
Early Stage ◽  
Hexanoic Acid ◽  
Protein Glycation ◽  
Advanced Glycation ◽  
Keyhole Limpet Haemocyanin ◽  
Advanced Glycation End Product ◽  
Physiological Conditions

1. It has been suggested that 2-amino-6-(2-formyl-5-hydroxymethyl-pyrrol-l-yl)-hexanoic acid ('pyrraline') is formed as an advanced glycation end product in the Maillard reaction under physiological conditions. Antibodies were raised to caproyl-pyrraline linked to keyhole-limpet haemocyanin and were used to develop an e.l.i.s.a. and Western blotting system for the specific detection of pyrraline in samples in vivo and in vitro. 2. Human serum albumin was isolated from the serum samples of diabetic and non-diabetic subjects. Pyrraline was not detected (<1.2 pmol) in any of the samples, indicating that it was not a major advanced glycation end product in vivo. 3. BSA was incubated separately with D-glucose and a model fructosamine, N-(l-deoxy-D-fructos-l-yl)-hippuryl-lysine, under physiological conditions for 30 days. Aliquots removed from the incubations at 5 day intervals contained no detectable pyrraline, indicating that pyrraline was not an early-stage product of the Maillard reaction in vitro. 4. The model fructosamine, N>-(1-deoxy-D-fructos-l-yl)-hippuryl-lysine, was incubated at pH 7.4 and 37°C for 25 days during which it degraded to hippuryl-lysine and N>-carboxymethyl-hippuryl-lysine. Aliquots were removed at 5 day intervals and assayed for pyrraline. None was detected (<23 pmol/ml) in the course of the degradation of the fructosamine (400 nmol/ml degraded), indicating that pyrraline was not a major product of the degradation of fructosamine under physiological conditions in vitro. 5. We conclude that pyrraline is not a major intermediate or advanced glycation end product in the Maillard reaction under physiological conditions in vitro and in vivo. A previous report of immunoassay of pyrraline may have given positive results because of non-specific antibodies raised to impure hapten.

scholarly journals Tegsedi (Inotersen): An Antisense Oligonucleotide Approved for the Treatment of Adult Patients with Hereditary Transthyretin Amyloidosis

2019 ◽  
Vol 12 (2) ◽  
pp. 78 ◽  
Author(s):  
Luís Gales
Keyword(s):  
Antisense Oligonucleotide ◽  
Single Point ◽  
Point Mutations ◽  
Transthyretin Amyloidosis ◽  
Global Marketing ◽  
Chemically Modified ◽  
Amyloid Deposits ◽  
Single Point Mutations ◽  
Health Canada ◽  
Hereditary Transthyretin Amyloidosis

Tegsedi (Inotersen) is a chemically modified antisense oligonucleotide that inhibits the hepatic production of transthyretin (TTR). Several single-point mutations in TTR destabilize its structure, leading to the aggregation and accumulation of amyloid deposits in the nervous system, heart, kidneys and eyes. In July 2018, Tegsedi was approved by the European Commission for use in adults with stage one and two polyneuropathies. Later on, in October 2018, the FDA and Health Canada also approved its use for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults in the U.S. and Canada. Tegsedi was developed by Ionis Pharmaceuticals, the company that holds the global marketing license, together with its subsidiary Akcea Therapeutics.

scholarly journals Modulation of the Mechanisms Driving Transthyretin Amyloidosis

2020 ◽  
Vol 13 ◽  
Author(s):  
Filipa Bezerra ◽  
Maria João Saraiva ◽  
Maria Rosário Almeida
Keyword(s):  
Amyloid Fibrils ◽  
Single Point ◽  
Point Mutations ◽  
Disease Process ◽  
Wild Type ◽  
Transthyretin Amyloidosis ◽  
Natural Ligand ◽  
Single Point Mutations ◽  
Pharmacologic Agents ◽  
Plasma Stabilization

Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.

scholarly journals Receptor for Advanced Glycation End Products on Human Synovial Fibroblasts: Role in the Pathogenesis of Dialysis-Related Amyloidosis

2002 ◽  
Vol 13 (5) ◽  
pp. 1296-1306
Author(s):  
Fan Fan Hou ◽  
Jian Ping Jiang ◽  
Jun Qi Guo ◽  
Guo Bao Wang ◽  
Xun Zhang ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Amyloid Fibrils ◽  
Synovial Fibroblasts ◽  
Dependent Manner ◽  
Advanced Glycation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Amyloid Deposits ◽  
Glycation End Products ◽  
End Products ◽  
Inflammatory Processes

ABSTRACT. An important component of amyloid fibrils in dialysis-related amyloidosis (DRA) is β2-microglobulin (β2m) modified with advanced glycation end products (AGE). The amyloid deposits are located principally in joint structures, with adjacent chronic inflammatory reaction characterized by monocyte infiltration. This study examined the interaction of AGE-β2m with human synovial fibroblasts and investigated the proinflammatory effects of that interaction. It was demonstrated that human synovial fibroblasts constitutively expressed the receptor for AGE (RAGE). RAGE expression was detected mainly in synovial intima and was upregulated in DRA synovium. 125I-AGE-β2m bound to immobilized human synovial fibroblasts in a specific, dose-dependent manner (Kd of approximately 138.0 nM), and binding was inhibited by anti-RAGE IgG. Incubation of human synovial fibroblasts with AGE-β2m induced degradation of this AGE-modified protein, as well as increased monocyte chemoattractant protein-1 (MCP-1) mRNA and protein expression. The amount of MCP-1 produced by AGE-β2m-stimulated human synovial fibroblasts was sufficient to induce the chemotaxis of monocytes. MCP-1 synthesis resulted from engagement of RAGE, because the increase in MCP-1 synthesis was attenuated by preincubation of human synovial fibroblasts with anti-RAGE IgG. These data provide evidence of RAGE-mediated perturbation of human synoviocytes, which may be involved in the pathogenesis of inflammatory processes associated with DRA.

scholarly journals Advanced glycation end product in familial amyloidotic polyneuropathy (FAP)

2000 ◽  
Vol 247 (4) ◽  
pp. 485-492 ◽  
Author(s):  
N. Nyhlin ◽  
Y. Ando ◽  
R. Nagai ◽  
O. Suhr ◽  
M. El Sahly ◽  
...  
Keyword(s):  
Familial Amyloidotic Polyneuropathy ◽  
Advanced Glycation ◽  
Advanced Glycation End Product
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