Reactivity, Selectivity, and Reaction Mechanisms of Aminoguanidine, Hydralazine, Pyridoxamine, and Carnosine as Sequestering Agents of Reactive Carbonyl Species: A Comparative Study

Colzani, Mara; Maddis, Danilo De; Casali, G; Carini, Marina; Vistoli, Giulio; Aldini, Giancarlo

doi:10.1002/cmdc.201500552

Cited by 63 publications

(70 citation statements)

References 47 publications

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“…These findings are in line with recent studies demonstrating poor quenching activity of carnosine derivatives towards MG [14, 42]. Quenching capacity of carnosine is higher against other reactive metabolites such as acrolein and HNE [14, 40, 41, 43]. Although both, HNE and MG, belong to the group of reactive carbonyl species reacting with the nucleophilic groups in proteins, the two compounds are chemically distinct with both very different reaction kinetics leading to different stable end products.…”

Section: Discussionsupporting

confidence: 82%

“…Carnosine acts through two reactive moieties, one of the nitrogen atoms of the imidazole ring or the amino group nitrogen of the β-alanine residue. These nucleophilic nitrogens target the two reactive sites of α, β-unsaturated aldehydes, the aldehyde function or the electrophilic C3 atom [14]. Cellular uptake of carnosine occurs by proton-coupled oligopeptide transporters (POTs), membrane proteins that translocate various small peptides and peptide-like drugs across the biological membrane via an inwardly-directed proton gradient and negative membrane potential [15].…”

Section: Introductionmentioning

confidence: 99%

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Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Weigand

Singler

Fleming

et al. 2018

Cell Physiol Biochem

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Background/Aims: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. Methods: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. Results: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143±13%, p<0.001) and tubular cells (129±3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. Conclusion: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Weigand

Singler

Fleming

et al. 2018

Cell Physiol Biochem

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“…Hydralazine contains a nucleophilic hydrazine moiety which binds with free and protein-bound aldehydes to form stable hydrazones [23,24 •• ]. In animal models of atherosclerosis, hydralazine administration was found to reduce athero- sclerotic lesion size and decrease carbonyl protein adducts within aortic sinuses, suggesting hydralazine possesses anti-atherogenic properties.…”

Section: Clinically Approved Agents With Aldehyde Scavenging Capacitiesmentioning

confidence: 99%

Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

Nelson

Baba

Anderson

2017

Current Opinion in Pharmacology

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Aldehydes are continuously formed in biological systems through enzyme-dependent and spontaneous oxidation of lipids, glucose, and primary amines. These highly reactive, biogenic electrophiles can become toxic via covalent modification of proteins, lipids and DNA. Thus, agents that scavenge aldehydes through conjugation have therapeutic value for a number of major cardiovascular diseases. Several commonly-prescribed drugs (e.g., hydralazine) have been shown to have potent aldehyde-conjugating properties which may contribute to their beneficial effects. Herein, we briefly describe the major sources and toxicities of biogenic aldehydes in cardiovascular system, and provide an overview of drugs that are known to have aldehyde-conjugating effects. Some compounds of phytochemical origin, and histidyl-dipeptides with emerging therapeutic value in this area are also discussed.

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“…Comparison of carnosine scavenging of HNE, methylglyoxal, glyoxal, and MDA in vitro showed that carnosine was most effective at scavenging HNE [93]. In vivo evidence for the ability of carnosine to scavenge RCS include detection of HNE modified carnosine in the urine of Zucker fatty rats [94] and detection of acrolein-carnosine adducts in human urine [95].…”

Section: Reactive Carbonyl Species Scavengers Ameliorate Diseasementioning

confidence: 99%

Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases

Davies

Zhang

2017

Curr Pharmacol Rep

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Purpose of the review To summarize recent evidence supporting the use of reactive carbonyl species scavengers in the prevention and treatment of disease. Recent findings The newly developed 2-aminomethylphenol class of scavengers shows great promise in preclinical trials for a number of diverse conditions including neurodegenerative diseases and cardiovascular disease. In addition, new studies with the thiol-based and imidazole-based scavengers have found new applications outside of adjunctive therapy for chemotherapeutics. Summary Reactive oxygen species (ROS) generated by cells and tissues act as signaling molecules and as cytotoxic agents to defend against pathogens, but ROS also cause collateral damage to vital cellular components. The polyunsaturated fatty acyl chains of phospholipids in the cell membranes are particularly vulnerable to damaging peroxidation by ROS. Evidence suggests that the breakdown of these peroxidized lipids to reactive carbonyls species plays a critical role in many chronic diseases. Antioxidants that abrogate ROS-induced formation of reactive carbonyl species also abrogate normal ROS signaling and thus exert both beneficial and adverse functional effects. The use of scavengers of reactive dicarbonyl species represent an alternative therapeutic strategy to potentially mitigate the adverse effects of ROS without abrogating normal signaling by ROS. In this review, we focus on three classes of reactive carbonyl species scavengers: thiol-based scavengers (2-mercaptoethanesulfonate and amifostine), imidazole-based scavengers (carnosine and its analogs), and 2-aminomethylphenols-based scavengers (pyridoxamine, 2-hydroxybenzylamine, and 5’-O-pentyl-pyridoxamine) that are either undergoing pre-clinical studies, advancing to clinical trials, or are already in clinical use.

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Reactivity, Selectivity, and Reaction Mechanisms of Aminoguanidine, Hydralazine, Pyridoxamine, and Carnosine as Sequestering Agents of Reactive Carbonyl Species: A Comparative Study

Cited by 63 publications

References 47 publications

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal

Biogenic Aldehydes as Therapeutic Targets for Cardiovascular Disease

Reactive Carbonyl Species Scavengers—Novel Therapeutic Approaches for Chronic Diseases

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