imidazolone and Inflammation

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase, being involved in endothelial dysfunction. Furthermore, ADMA levels have been shown to predict future cardiovascular events in patients with coronary risk factors, such as diabetes and hypertension. We have previously found that glyceraldehyde-derived advanced glycation end products (glycer-AGEs) stimulate ADMA generation

Topics: Aged; Arginine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glycation End Products, Advanced; Humans; Hypoglycemic Agents; Imidazoles; Inflammation; Male; Middle Aged; Protein Binding; Pyruvaldehyde; Vascular Stiffness

The pathogenesis of coronavirus disease 2019 (COVID-19) is associated with a hyperinflammatory response. The mechanisms of SARS-CoV-2-induced inflammation are scantly known. Methylglyoxal (MG) is a glycolysis-derived byproduct endowed with a potent glycating action, leading to the formation of advanced glycation end products (AGEs), the main one being MG-H1. MG-H1 exerts strong pro-inflammatory effects, frequently mediated by the receptor for AGEs (RAGE). Here, we investigated the involvement of the MG-H1/RAGE axis as a potential novel mechanism in SARS-CoV-2-induced inflammation by resorting to human bronchial BEAS-2B and alveolar A549 epithelial cells, expressing different levels of the ACE2 receptor (R), exposed to SARS-CoV-2 spike protein 1 (S1). Interestingly, we found in BEAS-2B cells that do not express ACE2-R that S1 exerted a pro-inflammatory action through a novel MG-H1/RAGE-based pathway. MG-H1 levels, RAGE and IL-1β expression levels in nasopharyngeal swabs from SARS-CoV-2-positive and -negative individuals, as well as glyoxalase 1 expression, the major scavenging enzyme of MG, seem to support the results obtained in vitro. Altogether, our findings reveal a novel mechanism involved in the inflammation triggered by S1, paving the way for the study of the MG-H1/RAGE inflammatory axis in SARS-CoV-2 infection as a potential therapeutic target to mitigate COVID-19-associated pathogenic inflammation.

Topics: Angiotensin-Converting Enzyme 2; COVID-19; Glycation End Products, Advanced; Humans; Inflammation; Pyruvaldehyde; Receptor for Advanced Glycation End Products; SARS-CoV-2; Spike Glycoprotein, Coronavirus

Topics: Animals; Caco-2 Cells; Claudin-1; Fluoresceins; Humans; Imidazoles; Inflammation; Intestinal Mucosa; Isothiocyanates; Mice; Mice, Inbred ICR; Molecular Weight; NF-kappa B; Occludin; Permeability; Polysaccharides; Pyruvaldehyde; Reactive Oxygen Species; RNA, Messenger; Tight Junctions

Glyceraldehyde-derived advanced glycation end products contribute to vascular inflammation in diabetes. However, what advanced glycation end product structure could evoke inflammatory reactions remains unknown. We examined whether and how methylglyoxal-derived hydroimidazolone 1, one of the advanced glycation end products formed from glyceraldehyde, elicits inflammatory reactions in human umbilical vein endothelial cells.. Glyceraldehyde-advanced glycation end products-aptamer was prepared using a systemic evolution of ligands by exponential enrichment. The binding affinities of methylglyoxal-derived hydroimidazolone 1 to receptor for advanced glycation end products or advanced glycation end product-aptamer were measured with a quartz crystal microbalance. Intracellular reactive oxygen species generation and THP-1 cell adhesion were evaluated using fluorescent probes. Gene expression was analysed by reverse transcription polymerase chain reaction.. Our present results indicate that methylglyoxal-derived hydroimidazolone 1 evokes inflammatory reactions in human umbilical vein endothelial cells via receptor for advanced glycation end products, although apparently limited to supraphysiological levels of methylglyoxal-derived hydroimidazolone 1. Methylglyoxal-derived hydroimidazolone 1 is a distinct advanced glycation end product structure that could mediate harmful effects of methylglyoxal and glyceraldehyde-mediated glycation processes.

Topics: Cell Adhesion; Cell Line; Glycation End Products, Advanced; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles; Inflammation; Inflammation Mediators; Leukocytes; Protein Binding; Pyruvaldehyde; Reactive Oxygen Species; Receptor for Advanced Glycation End Products; Signal Transduction; Time Factors

This communication describes the synthesis and in vitro PDE4 inhibitory activity of a novel series of imidazol-2-one and 2-cyanoiminoimidazole derivatives. The compounds described were also tested in in vivo models to evaluate their anti-inflammatory activity after topical administration as well as their gastro-intestinal side effects. Several compounds proved to be potent PDE4 inhibitors and some 2-cyanoiminoimidazoles showed less pronounced gastro-intestinal side effects than reference compounds but maintained anti-inflammatory activity after topical administration.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Topical; Animals; Anti-Inflammatory Agents; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Dose-Response Relationship, Drug; Ear Diseases; Enzyme Inhibitors; Humans; Imidazoles; Inflammation; Inhibitory Concentration 50; Rats; Structure-Activity Relationship