Maltol ameliorates intervertebral disc degeneration through inhibiting PI3K/AKT/NF-κB pathway and regulating NLRP3 inflammasome-mediated pyroptosis

Abstract

Objectives As one of the major causes of low back pain, intervertebral disc degeneration (IDD) has caused a huge problem for humans. Increasing evidence indicates that NLRP3 inflammasome-mediated pyroptosis of NP cells displays an important role in the progression of IDD. Maltol (MA) is a flavoring agent extracted from red ginseng. Due to its anti-inflammatory and antioxidant effects, MA has been widely considered by researchers. Therefore, we hypothesized that MA may be a potential IVD protective agent by regulating NP cells and their surrounding microenvironment. Methods In vitro, qRT-PCR, and Western blot were used to explore the effect of MA on the transcription and protein expression of the anabolic protein (ADAMTS5, MMP3, MMP9) catabolic protein (Aggrecan), and pro-inflammatory factor (iNOS COX-2). Next, the effects of MA on PI3K/AKT/NF-κB pathway and pyroptosis pathway were analyzed by Western blot and immunofluorescence. Molecular docking was used to investigate the relationship between PI3K and MA. Moreover, ELISA was also used to detect the effects of MA on inflammatory factors (TNF-α, PGE2, IL-1β, and IL-18). In vivo, the effects of MA on the vertebral structure of IDD mice were studied by HE and SO staining and the effects of MA on ECM and PI3K/AKT/NF-κB and pyroptosis pathway of IDD mice were studied by immunohistochemical staining. Results MA can ameliorate intervertebral disc degeneration in vivo and in vitro. Specifically, the molecular docking results showed that the binding degree of MA and PI3K was significant. Second, in vitro studies showed that MA inhibited the degradation of ECM and inflammatory response by inhibiting the PI3K/AKT/NF-κB pathway and the pyroptosis mediated by NLRP3 inflammasome, which increased the expression of anabolic proteins, decreased the expression of catabolic proteins, and decreased the secretion of inflammatory mediators such as IL-18 and IL-1β. In addition, according to the study results of the mouse lumbar instability model, MA also improved the tissue disorder and degradation of the intervertebral disc, reduced the loss of proteoglycan and glycosaminoglycan, and inhibited intervertebral disc inflammation, indicating that MA has a protective effect on the intervertebral disc to intervertebral disc in mice. Conclusions Our results suggest that MA slowed IDD development through the PI3K/AKT/NF-κB signaling pathway and NLRP3 inflammasome-mediated pyroptosis, indicating that MA appeared to be a viable medication for IDD treatment.

Apigetrin alleviates intervertebral disk degeneration by regulating nucleus pulposus cell autophagy

“…Previous studies have found that the mitogen‐activated protein kinase (MAPK), nuclear factor‐kappaB (NF‐κB), and PI3K/AKT/mTOR signaling pathways play a crucial role in the progression of IVDD. 20 , 38 , 39 , 40 Therefore, these three signaling pathways were studied to further explore the mechanisms of API against IVDD. P‐P38, P‐ERK, P‐JNK, and P‐P65 were significantly upregulated following IL‐1β stimulation (Figure 5A,B ).…”

Aucubin Alleviates Intervertebral Disc Degeneration by Repressing NF-κB-NLRP3 Inflammasome Activation in Endplate Chondrocytes

“…NLRP3/Caspase-1 axis activation plays an important role in neuroinflammation and neuronal injury in various neurological diseases. 52,53 Previous studies have identified the effect of pyroptosis in nucleus pulposus cells during IDD, 14,54,55 and recently, Caspase-1 and NLRP3 expression has been reported to be upregulated in CEP of patients with degenerative disease. 56 Consistently, as both in vivo and in vitro studies presented in the current study, Au inhibited the phosphorylation of P65 and reduced the activity of NF-κB signaling, thereby decreased the expression of NLRP3 and Caspase-1, suggested that Au reduced chondrocyte pyroptosis by decreasing the activation of NF-κB signaling.…”

“…Highly active NF-κB signaling contributes to programmed chondrocyte death such as apoptosis and pyroptosis, which exacerbates CEP calcification. 14 , 15 The NLR pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex composed of NLRP3 and the inflammatory protease Caspase-1, in addition, hyperactivation of NLRP3 inflammasome implicated in a wide of inflammatory disorders. 16 , 17 Besides, the NLRP3 is downstream of the NF-κB signaling pathway, and activation of the NLRP3 inflammasome leads to IDD by promoting pyroptosis in NP cell, and ECM degradation in IVD.…”

Ginsenoside Rg1 relieves rat intervertebral disc degeneration and inhibits IL-1β-induced nucleus pulposus cell apoptosis and inflammation via NF-κB signaling pathway

“…Gong et al showed that maltol, as a flavoring agent extracted from red ginseng, slowed IVDD development through the PI3K/AKT/NF-κB signaling pathway and NLRP3 inflammasome–mediated pyroptosis, which may be a viable medication for IVDD treatment (Gong et al . 2023 ). As an effective component of traditional Chinese medicine, ginsenoside Rg1 had been proved to promote ECM synthesis and cell proliferation, and inhibit apoptosis in degenerative NP cells via inhibiting the Wnt/β-catenin pathway, to alleviate the IVDD progress in the previous study (Yu et al .…”