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Molecular Strategies to Prevent, Inhibit, and Degrade Advanced Glycoxidation and Advanced Lipoxidation End Products

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Molecular Strategies to Prevent, Inhibit, and Degrade Advanced Glycoxidation and Advanced Lipoxidation End Products Free Radical Research, August 2013; 47(Suppl. 1): 93–137 © 2013 Informa UK, Ltd. ISSN 1071-5762 print/ISSN 1029-2470 online DOI: 10.3109/10715762.2013.792926 REVIEW ARTICLE Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products Giancarlo Aldini 1 , Giulio Vistoli 1 , Milan Stefek 2 , N. Chondrogianni 3 , Tilman Grune 4 , Jolanta Sereikaite5 , Izabela Sadowska-Bartosz6 & Grzegorz Bartosz 6,7 1 Department of Pharmaceutical Sciences, University of Milan, Milan, Italy, 2 Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia, 3 National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Greece, 4 Friedrich Schiller University, Jena, Germany, 5 Vilnius Gediminas Technical University, Lithuania, 6 Department of Biochemistry and Cell Biology, University of Rzesz ó w, Rzesz ó w, Poland, and 7 Department of Molecular Biophysics, University of Ł ó d ź , Ł ó d ź , Poland Abstract The advanced glycoxidation end products (AGEs) and lipoxidation end products (ALEs) contribute to the development of diabetic complications and of other pathologies. The review discusses the possibilities of counteracting the formation and stimulating the degradation of these species by pharmaceuticals and natural compounds. The review discusses inhibitors of ALE and AGE formation, cross-link breakers, ALE/AGE elimination by enzymes and proteolytic systems, receptors for advanced glycation end products (RAGEs) and blockade of the ligand – RAGE axis. Keywords: Glycoxidation , lipoxidation , antioxidants , cross-link breakers , proteasomes Abbreviations: A β , amyloid β -peptide; AD, Alzheimer ’ s disease; AGEs, advanced glycoxidation end products; ALEs, advanced lipoxidation end products; CEL, N- ε-(carboxyethyl)lysine; CML, N- ε-(carboxymethyl)lysine; DAP, diaminopropionic acid; 3-DG, 3-deoxyglucosone; FN3K, fructosamine-3-kinase; GO, glyoxal; GOLD, glyoxal–lysine dimer; GSH, glutathione; HMGB1, high-mobility group box 1proteins; HNE, 4-hydroxynonenal; LDL, low-density lipoprotein; oxLDL, oxidized LDL; LPA, lysophosphatidic acid; MDA, malondialdehyde; MG, methylglyoxal; MMP, metalloproteinase; MOLD, methylglyoxal–lysine dimer; ONE, 4-oxo-2-nonenal; PM, pyridoxamine; PTB, N-phenacylthiazolium; PMT, pyridinium (3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]); RAGE, receptor for advanced glycation end products; fRAGE, full-length RAGE; sRAGE, shortened RAGE; esRAGE, endogenous secretory RAGE; RCS, reactive carbonyl species; ROS, reactive oxygen species; STZ, streptozotocin; UPS, ubiquitin-proteasome system; VEGF, vascular endothelial growth factor. For personal use only. AGEs, ALEs, and RAGE as drug target (GA) and cerebral vessels was related to the severity of cogni- Advanced glycoxidation [1 – 3] end products (AGEs) and tive impairment in patients with cerebrovascular disease advanced lipoxidation end-products (ALEs) are widely [13]. Also, ALEs have been reported as useful biomarkers studied as reporters of oxidative and glycoxidative of oxidative damage. The Michael adduct of HNE to pro- damage [4 – 8]. The most common analytical methods teins was found to be signifi cantly elevated in patients with for their quantitative determination are based on a variety of oxidative stress-based diseases, such as Alzheim- ELISA or Western blot assays, using a variety of com- er ’ s disease [14], chronic pancreatitis [15], obesity and insu- mercially available antibodies against AGEs, such as lin resistance [16], and systemic lupus erythematosus [17]. N- ε -(carboxymethyl)lysine (CML), N- ε -(carboxyethyl) Besides being considered as reliable biomarkers of Free Radic Res Downloaded from informahealthcare.com by Universita Statale Milano on 01/27/14 lysine (CEL), and ALEs, the most popular being 4- oxidative damage, as well as as predictors and prognos- hydroxynonenal (HNE)- and malondialdehyde (MDA)- tic factors, more recently, AGEs and ALEs have also adducted proteins. The content of AGEs and ALEs in been recognized as important pathogenetic factors of tissue and body fl uids has been correlated with diff erent some oxidative-based diseases, as supported by the fol- oxidative-stress based diseases. For instance, the serum lowing facts: (1) as pointed out above, a strict correlation levels of CML, one of the most studied AGEs, are asso- between the amount of AGEs/ALEs in tissues and fl uids ciated with the severity of diabetes-related disease, and disease states has been found, in both animal and including retinopathy [9] and microangiopathy [10], human subjects; (2) a substantial amount of literature is chronic kidney disease, as well as with the formation and now available reporting the molecular and cellular patho- acceleration of diabetic and non-diabetic atherosclerotic genic mechanisms for the AGEs/ALEs involvement in lesions [11]. CML was also found to be elevated in cere- the onset and progression of diff erent diseases, including brospinal fl uid of patients with amyotrophic lateral scle- atherosclerosis, diabetes, and neurological disorders. rosis [12], and the tissue level of CML in cortical neurons The AGE/ALE damaging eff ect is mediated by diff erent Correspondence: Prof. Grzegorz Bartosz, Department of Molecular Biophysics, University of Ł ó d ź , Pomorska 141/143, 90-236 Ł ó d ź , Poland. Tel: ϩ 48 42 635-44076. Fax: ϩ 48 42 635-44-73. E-mail: [email protected] (Received date: 21 February 2013 ; Accepted date: 2 April 2013; Published online: 2 May 2013 ) 94 G. Aldini et al. mechanisms, including the dysfunction of the proteins In summary, AGEs/ALEs are involved as pathogenetic undergoing the oxidative modifi cation, protein polymer- factors in some oxidative-based diseases including athero- ization, signal transduction, immunoresponse, and RAGE sclerosis, diabetes, and Alzheimer ’ s disease (AD), and are activation; (3) compounds eff ective as inhibitors of now recognized as promising drug targets. On these AGEs/ALEs formation or able to block their biological grounds, several molecular approaches have been described eff ects have been found to signifi cantly ameliorate diff er- with the aim of inhibiting the damaging response induced ent oxidative-based diseases. by AGE/ALE formation. The aim of the present review is Hence, AGEs/ALEs are now considered as promising to systemically describe the molecular approaches thus far drug targets, and a substantial eff ort is dedicated to delve reported with a particular view of the rational drug design into the molecular strategies aimed at preventing, reduc- approach used. Compounds and strategies will also be ing, or removing these protein oxidation products [18,19]. critically commented on and their limits highlighted. The diff erent molecular approaches thus far reported can be grouped by considering at which level of the damaging AGE/ALE cascade they are eff ective and in particular if Inhibitors of ALE/AGE formation (GA) they act by inhibiting the AGE/ALE formation, accelerat- ing their catabolism or blocking their biological eff ects. Several molecular approaches have been considered for The fi rst level of action, the inhibition of AGE/ALE inhibiting AGE/ALE formation, and such diversity is due formation, also consists of diff erent approaches, which to the complex reactions leading to the AGE/ALE forma- target the diff erent inducers (ROS, metal ions) and inter- tion, which involves diff erent inducers, precursors, and mediate products (mainly reactive carbonyl species (RCS)) intermediates. In particular, as better described in the involved in the AGE/ALE formation. Antioxidants, metal paper entitled “ Advanced glycoxidation and lipoxidation ion chelators, and reactive carbonyl compound quenchers end products (AGEs and ALEs): an overview of their represent the most promising approaches so far reported mechanisms of formation ” and published in this series, for inhibiting AGE/ALE formation, in both in vitro and two main pathways are involved in the AGE formation. in vivo conditions. In some cases, as found for both natu- The former is based on the reaction of reducing sugars ral and synthetic compounds, the inhibition of AGEs/ (any sugar that either has an aldehyde group (aldoses) or ALEs formation does not proceed through a single specifi c is capable of forming one in solution through keto-enol mechanism but implicates multiple mechanisms, involv- isomerism (ketoses)) with the protein primary amino ing at least two of the following ones: antioxidant, metal groups (the amino terminus and the ε -amino group of ion chelation, and RCS quenching (reactions with RCS Lys), followed by metal ion catalyzed rearrangements. preventing their binding to vital macromolecules). Belong- The latter involves the reaction of RCS such as glyoxal For personal use only. ing to this fi rst group of approaches, also the xenobiotics (GO), methylglyoxal (MG), and 3-deoxyglucosone that act by potentiating the endogenous detoxifi cation sys- (3-DG; Figure 1) with the nucleophilic protein sites, and tem devoted to the metabolization/detoxifi cation of all the in particular Arg, Lys, and Cys. The RCS acting as AGE endogenous compounds involved in the AGE/ALE forma- precursors are generated by either sugar or AGEs decom- tion. Such a protective system consists of non-enzymatic position/autoxidation, a series of reactions which are and enzymatic antioxidants (compounds that prevent catalyzed by metal ions. ALEs are generated by only one undesired oxidation by reacting with oxidants or oxidation
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