4′-Methoxyresveratrol Alleviated AGE-Induced Inflammation via RAGE-Mediated NF-κB and NLRP3 Inflammasome Pathway

Abstract

Advanced glycation end products (AGEs) could interact with the receptor for AGE (RAGE) as a sterile danger signal to induce inflammation. 4′-methoxyresveratrol (4′MR), a polyphenol derived from Dipterocarpaceae, has not been studied for its anti-inflammation effects. In the present study, we sought to explore the protective role of 4′MR in AGEs-induced inflammatory model using RAW264.7 macrophages. 4′MR significantly inhibited gene expression of pro-inflammatory cytokines and chemokines, such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1), as well as two typical pro-inflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2). Besides, 4′MR significantly decreased oxidative stress, demonstrated by levels of ROS production, protein carbonyl and advanced oxidation protein product via down-regulation of NADPH oxidase. Further analysis showed that 4′MR attenuated the RAGE overexpression induced by MGO-BSA. It also blocked the downstream signal of AGE-RAGE, particularly, MAPKs including p38 and JNK, and subsequently reduced NF-κB activation. Additionally, 4′MR significantly abated the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome including NLRP3 and cleaved caspase-1 and reduced the secretion of mature IL-1β. Taken together, our results suggest that the anti-inflammatory effect of 4′MR is mainly through suppressing RAGE-mediated MAPK/NF-κB signaling pathway and NLRP3 inflammasome activation. 4′MR could be a novel therapeutic agent for inflammation-related diseases.

The effect of NLRP inflammasome on the regulation of AGEs‐induced inflammatory response in human periodontal ligament cells

“…The latest studies have shown that aberrant activation of NLRP3‐inflammasomes was closely related to the development and prognosis of diabetes and its complications . It is confirmed that under AGEs stimulation, NLRP3 inflammasome is essential to IL‐1β production since inhibiting the activation of NLRP3 inflammasome could significantly abate the AGEs‐induced production of IL‐1β . In addition, as the first NLR shown to form inflammasome, NLRP1 functions to activate caspase‐1 and subsequently cleaves IL‐1β and IL‐18 .…”

“…[28][29][30] It is confirmed that under AGEs stimulation, NLRP3 inflammasome is essential to IL-1β production since inhibiting the activation of NLRP3 inflammasome could significantly abate the AGEs-induced production of IL-1β. 31 In addition, as the first NLR shown to form inflammasome, NLRP1…”

Redox Signaling and Advanced Glycation Endproducts (AGEs) in Diet-Related Diseases

“…Recent studies have shown that Ne(carboxymethyl)lysine (CML) adducts of proteins, the most frequent type of AGEs found in vivo, interact with RAGE to activate signal transduction pathways [19,20], ultimately leading to the expression of proinflammatory genes [21]. Thus, it has been shown that treating cells with AGEs produces a rapid increase in both mRNA and protein levels of RAGE [22] which is suppressed after pretreatment with the anti-RAGE antibody [23].…”

“…This initiates several signal transduction cascades that involve p21RAS, p44/p42 mitogen-activated protein kinases (MAPK), PI3K-AKT, ERK1/2, JNK, p38, protein kinase C (PKC), and NF-κB activation [14,25,[28][29][30][31][32][33][34][35][36], finally resulting in the production of cytokines, chemokines, and other proinflammatory molecules that induce inflammation [37][38][39][40][41][42], apoptosis, and proliferation [43][44][45][46][47][48]. Among these molecules, IL-6, TNF-α, IL-1β, MCP-1, tissue factor (TF), and VCAM-1 are upregulated by AGEs [22,27] (Figure 2). Antioxidants 2020, 9, x FOR PEER REVIEW 4 of 20 Figure 2.…”

Use of agro‐industrial residues as potent antioxidant, antiglycation agents, and α‐amylase and pancreatic lipase inhibitory activity

“…Advanced glycation end products (AGEs) are the final components of a series of nonenzymatic reactions—jointly called Maillard Reaction—that have deleterious effects on health when accumulated in the body. These effects arise from interactions of AGEs with proteins and/or cellular receptors that lead to increased expression of inflammatory mediators (ciclooxigenase‐2, tumor necrosis factor‐alpha [TNF‐α] e interleukin 6 [IL‐6]), morphofunctional alterations, and oxidative stress (Ahmed, ; Jakus & Rietbrock, ; Jin et al, ; Yu, Tao, Zhao, Hu, & Wang, ).…”