Nitrovanillin derivative ameliorates AGE-RAGE nexus associated inflammation: A step towards the amelioration of vascular complications under diabetic environment

Abstract

Introduction

Advanced glycation endproducts (AGEs) are implicated in various pathological conditions, including diabetes, inflammation, and cardiovascular diseases. Methylglyoxal (MGO), a potent glycation agent, leads to the formation of MGO-derived AGEs, which promote structural and functional anomalies in various cellular and tissues proteins. AGEs stimulate the proliferation of monocytes, and induce a pro-inflammatory state through AGE-RAGE interactions, triggering oxidative stress, and inflammatory condition that contribute to the progression of atherosclerosis, and other diabetic complications.

Objective

The current study was aimed to explore the antioxidant and anti-inflammatory properties of a series of novel antiglycation compounds, nitrovanillin derivatives, by modulating the AGEs-stimulated intracellular signaling pathways involved in inflammation.

Methods

The preliminary safety profile of nitrovanillin derivatives was assessed by using human hepatocytes (HepG2), and monocytes (THP-1) cell lines via MTT, and WST-1 assays, respectively. Antioxidant activity of the compounds was determined by using DCFH-DA technique. Western blotting, immunocytochemistry, and ELISA methods were employed to assess the levels of pro-inflammatory markers (RAGE, COX-1, COX-2, NF-κB, and PGE₂) in MGO-AGEs stimulated THP-1 monocytes.

Result

Among the nitrovanillin derivatives 1–11, only compound 2, ((E)-2-methoxy-6-nitro-4-(((2-(trifluoromethyl)phenyl)imino)methyl)phenol), was found non-toxic to HepG2, and THP-1 cells. Compound 2 lowered the MGO-AGEs-induced reactive oxygen species (ROS) production by inhibiting the upstream signaling of NADPH oxidase and MAPK-p38, which subsequently inhibited the NF-κB activation in THP-1 monocytes. Compound 2 also reversed the AGEs-mediated COX-1 suppression, COX-2 upregulation, and PGE₂ production by blocking the AGE-RAGE ligation in THP-1 monocytes.

Conclusion

In conclusion, nitrovanillin 2 ((E)-2-methoxy-6-nitro-4-(((2-(trifluoromethyl)phenyl)imino)methyl)phenol) is a potential candidate for mitigating MGO-AGEs mediated vasculopathy by the inhibition of AGE-RAGE-p38/NF-κB nexus in THP-1 monocytes. It may offer a therapeutic option for the patients with diabetes and chronic inflammatory vascular complications, and thus offering new avenues for treatment development.