Ganoderic Acid A alleviates the degeneration of intervertebral disc via suppressing the activation of TLR4/NLRP3 signaling pathway

Wang, Dan; Cai, Xianhua; Xu, Feng; Kang, Hui; Li, Yanjin; Feng, Ruibing

doi:10.1080/21655979.2022.2070996

Cited by 11 publications

(6 citation statements)

References 27 publications

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“…The activation of the TLR4/NLRP3 signaling axis could cause apoptosis, oxidative stress, and inflammatory responses in NP cells. It has been reported that the activation of the NF-κB/NLRP3 signaling pathway could decrease cellular functions of NP cells and promoted cell pyroptosis ( 27 ). NF-κB signaling activation improved NLRP3 inflammasome activity, and NLRP3 activation increased NF-κB signaling activation induced by TNF-α.…”

Section: Discussionmentioning

confidence: 99%

Identification of a potential novel biomarker in intervertebral disk degeneration by bioinformatics analysis and experimental validation

Yang

Yuan

2023

Front. Immunol.

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BackgroundIntervertebral disk degeneration (IVDD) is a major cause of low back pain and one of the most common health problems all over the world. However, the early diagnosis of IVDD is still restricted. The purpose of this study is to identify and validate the key characteristic gene of IVDD and analyze its correlation with immune cell infiltration.Methods3 IVDD-related gene expression profiles were downloaded from the Gene Expression Omnibus database to screen for differentially expressed genes (DEGs). Gene Ontology (GO) and gene set enrichment analysis (GSEA) were conducted to explore the biological functions. Two machine learning algorithms were used to identify characteristic genes, which were tested to further find the key characteristic gene. The receiver operating characteristic curve was performed to estimate the clinical diagnostic value of the key characteristic gene. The excised human intervertebral disks were obtained, and the normal nucleus pulposus (NP) and degenerative NP were carefully separated and cultured in vitro. The expression of the key characteristic gene was validated by real-time quantitative PCR (qRT-PCR). The related protein expression in NP cells was detected by Western blot. Finally, the correlation was investigated between the key characteristic gene and immune cell infiltration.ResultsA total of 5 DEGs, including 3 upregulated genes and 2 downregulated genes, were screened between IVDD and control samples. GO enrichment analysis showed that DEGs were enriched to 4 items in BP, 6 items in CC, and 13 items in MF. They mainly included the regulation of ion transmembrane transport, transporter complex, and channel activity. GSEA suggested that the cell cycle, DNA replication, graft versus host disease, and nucleotide excision repair were enriched in control samples, while complement and coagulation cascades, Fc γ R–mediated phagocytosis, neuroactive ligand–receptor interaction, the NOD-like receptor signaling pathway, gap junctions, etc., were enriched in IVDD samples. Furthermore, ZNF542P was identified and tested as key characteristic gene in IVDD samples through machine learning algorithms and showed a good diagnostic value. The results of qRT-PCR showed that compared with normal NP cells, the expression of ZNF542P gene was decreased in degenerated NP cells. The results of Western blot suggested that compared with normal NP cells, the expression of NLRP3 and pro Caspase-1 was increased in degenerated NP cells. Finally, we found that the expression of ZNF542P was positively related to the proportions of T cells gamma delta (γδT cells).ConclusionZNF542P is a potential biomarker in the early diagnosis of IVDD and may be associated with the NOD-like receptor signaling pathway and the infiltration of γδT cells.

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Section: Discussionmentioning

confidence: 99%

Identification of a potential novel biomarker in intervertebral disk degeneration by bioinformatics analysis and experimental validation

Yang

Yuan

2023

Front. Immunol.

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“…Studies have confirmed that activation of the TLR4/NLRP3 signaling pathway upregulates the expression of oxidative stress-related genes. Treatment with Ganoderic Acid A significantly upregulated ECM anabolic factors and inhibited the secretion of inflammatory factors and oxidative stress, thus protecting NPCs ( 57 ). Notably, Jacobsen et al recently altered the biomechanical properties of NPCs by attenuating actin alterations with the TLR4 inhibitor TAK-242, thereby attenuating inflammatory injury ( 58 ).…”

Section: Immunomodulation Associated With Ivddmentioning

confidence: 99%

Current status and development direction of immunomodulatory therapy for intervertebral disk degeneration

Gao,

Chen,

Zheng

et al. 2023

Front. Med.

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Intervertebral disk (IVD) degeneration (IVDD) is a main factor in lower back pain, and immunomodulation plays a vital role in disease progression. The IVD is an immune privileged organ, and immunosuppressive molecules in tissues reduce immune cell (mainly monocytes/macrophages and mast cells) infiltration, and these cells can release proinflammatory cytokines and chemokines, disrupting the IVD microenvironment and leading to disease progression. Improving the inflammatory microenvironment in the IVD through immunomodulation during IVDD may be a promising therapeutic strategy. This article reviews the normal physiology of the IVD and its degenerative mechanisms, focusing on IVDD-related immunomodulation, including innate immune responses involving Toll-like receptors, NOD-like receptors and the complement system and adaptive immune responses that regulate cellular and humoral immunity, as well as IVDD-associated immunomodulatory therapies, which mainly include mesenchymal stem cell therapies, small molecule therapies, growth factor therapies, scaffolds, and gene therapy, to provide new strategies for the treatment of IVDD.

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“…In the H 2 O 2 -mediated-degeneration model, ganoderic acid significantly inhibited the expression of TLR4 and NLRP3. However, it still remains uncertain whether ganoderic acid directly acts on TLR4 or triggers the secondary reduction in TLR4 by scavenging H 2 O 2 [ 96 ]. In addition to H 2 O 2 , high-mobility group box-1 protein (HMGB1) and DAMPs also act on TLR4 receptors [ 97 ].…”

Section: Therapeutic Strategies Targeting Pyroptosis and Nlrp3 Inflam...mentioning

confidence: 99%

Role of Pyroptosis in Intervertebral Disc Degeneration and Its Therapeutic Implications

et al. 2022

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Intervertebral disc degeneration (IDD), a progressive and multifactorial pathological process, is predominantly associated with low back pain and permanent disability. Pyroptosis is a type of lytic programmed cell death triggered by the activation of inflammasomes and caspases. Unlike apoptosis, pyroptosis is characterized by the rupture of the plasma membrane and the release of inflammatory mediators, accelerating the destruction of the extracellular matrix (ECM). Recent studies have shown that pyrin domain-containing 3 (NLRP3) inflammasome-mediated pyroptosis in nucleus pulposus (NP) cells is activated in the progression of IDD. Furthermore, targeting pyroptosis in IDD demonstrates the excellent capacity of ECM remodeling and its anti-inflammatory properties, suggesting that pyroptosis is involved in the IDD process. In this review, we briefly summarize the molecular mechanism of pyroptosis and the pathogenesis of IDD. We also focus on the role of pyroptosis in the pathological progress of IDD and its targeted therapeutic application.

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Ganoderic Acid A alleviates the degeneration of intervertebral disc via suppressing the activation of TLR4/NLRP3 signaling pathway

Cited by 11 publications

References 27 publications

Identification of a potential novel biomarker in intervertebral disk degeneration by bioinformatics analysis and experimental validation

Identification of a potential novel biomarker in intervertebral disk degeneration by bioinformatics analysis and experimental validation

Current status and development direction of immunomodulatory therapy for intervertebral disk degeneration

Role of Pyroptosis in Intervertebral Disc Degeneration and Its Therapeutic Implications

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