Inhibitor of RAGE and glucose‑induced inflammation in bone marrow mesenchymal stem cells: Effect and mechanism of action.

Abstract

The occurrence and development of hyperglycemia-induced inflammation is associated with increased expression of receptor for advanced glycation end products (RAGE) and inflammatory factors, including IL-1β, TNF-α and IL-6. Previous studies have reported that the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome interacts with thioredoxin-interacting protein (TXNIP) and serves a crucial role in inflammation. FPS-ZM1 has been identified as target inhibitor of RAGE and has been shown to exert an anti-inflammatory effect in vitro. However, the underlying mechanism by which FPS-ZM1 impacts high glucose (HG)-induced inflammation in bone marrow mesenchymal stem cells (BMSCs) remains unclear. The present study explored the regulatory effect of FPS-ZM1 on HG-induced inflammation in BMSCs. Furthermore, the role of the TXNIP/NLRP3 inflammasome signaling pathway in the regulatory effects of FPS-ZM1 on HG-induced inflammation was studied. Cell viability was determined using Cell Counting Kit-8 and western blotting was used to assess the protein expression levels of RAGE. ELISA was used to determine the levels of inflammatory markers. Reverse transcription-quantitative PCR and western blotting were used to measure the mRNA and protein expression levels of TXNIP, caspase-1, thioredoxin (TRX), NLRP3 and apoptosis-related speck-like protein containing CARD (ASC). The results revealed that in BMSCs, RAGE expression was stimulated by HG, an effect which was reversed by treatment with FPS-ZM1. In addition, HG activated inflammatory factors, such as TNF-α, IL-1β and IL-6; however, their levels were suppressed when cells were treated with FPS-ZM1 or the TXNIP/NLRP3 pathway inhibitor, resveratrol (Res). Furthermore, FPS-ZM1 inhibited the mRNA and protein expression levels of TXNIP, caspase-1, NLRP3 and ASC, and promoted TRX expression, which was consistent with the effects of Res. These findings indicated that FPS-ZM1 may attenuate HG-induced inflammation in BMSCs. Furthermore, the TXNIP/NLRP3 inflammasome signaling pathway mediated the molecular mechanism underlying this effect.