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.

Mapping Knowledge Landscapes and Emerging Trends of the Links Between Bone Metabolism and Diabetes Mellitus: A Bibliometric Analysis From 2000 to 2021

“…Accordingly, small-molecular inhibitors such as TTP488, FPS-ZM1, etc. targeting RAGE and its intracellular signaling pathway have been developed (66,67). These small molecule inhibitors hold great promise for the treatment of multiple metabolic bone diseases and merit further investigation.…”

STS Protects Diabetic Glomerular Vascular Endothelial Barrier by Ameliorating EPC Dysfunction: Targeting RAGE-TXNIP-NLRP3 Inflammasome Pathway

“…HG-induced EPC dysfunction by activating TXNIP-NLRP3 in ammasome pathway through sthe formation of AGEs [71,72], and the RAGE-TXNIP pathway has also been shown to play a crucial role in a variety of cellular functional impairments [73][74][75]. Therefore, our results concluded that HG activated the RAGE-TXNIP-NLRP3 in ammasome pathway through the formation of AGEs.…”

Oxidized high mobility group B‐1 enhances metastability of colorectal cancer via modification of mesenchymal stem/stromal cells

“…In contrast, in MSCs, RAGE is induced and activated by HMGB1 to promote the expression of CXCR4, 57 TGFβ, and proinflammatory cytokines. 58 , 59 However, reports analyzing the modification of HMGB1 and its function in MSCs are scarce. The differential action of the oxidized and reduced forms in this study may be important for future targeting of MSCs.…”

“…Therefore, oxidized HMGB1 was considered to be a highly functional ligand for RAGE in cancer. In contrast, in MSCs, RAGE is induced and activated by HMGB1 to promote the expression of CXCR4, 57 TGFβ, and proinflammatory cytokines 58,59 . However, reports analyzing the modification of HMGB1 and its function in MSCs are scarce.…”