Knockdown of DAPK1 attenuates IL-1β-induced extracellular  matrix degradation and inflammatory response in osteoarthritis chondrocytes via regulating the p38 MAPK-signaling pathway

Wei, Jie; Chen, Gao; Hu, Ke; Li, Mingyue; Li, Jingshi; Shen, Mengman; Zhang, Shuyu

doi:10.15586/aei.v50i6.744

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…16 These observations shed light on novel therapeutic strategies for management of vascular disease. Importantly, the inhibitory effects of curcumol on HASMCs were dose-dependent, and it aso downregulated the protein levels of matrix metalloproteinase-9 (MMP-9) 17 and matrix metalloproteinase-2 (MMP-2), 18 both of which are essential for cell migration. 19 In addition, Western Blot analyses disclosed that curcumol effectively decreased the LC3-II to LC3-I ratio while enhanced the P62 expression in a dose-dependent manner, and they serve as autophagy indicators.…”

Section: Discussionmentioning

confidence: 99%

Curcumol reduces lower limb arteriosclerosis in rats by inhibiting human arterial smooth muscle cell activity

Yang,

Huang,

Liang

et al. 2024

Clin Exp Pharma Physio

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Cardiovascular diseases, particularly those involving arterial stenosis and smooth muscle cell proliferation, pose significant health risks. This study aimed to investigate the therapeutic potential of curcumol in inhibiting platelet‐derived growth factor‐BB (PDGF‐BB)‐induced human aortic smooth muscle cell (HASMC) proliferation, migration and autophagy. Using cell viability assays, 5‐ethynyl‐2′‐deoxyuridine (EdU) incorporation assays and Western Blot analyses, we observed that curcumol effectively attenuated PDGF‐BB‐induced HASMC proliferation and migration in a concentration‐dependent manner. Furthermore, curcumol mitigated PDGF‐BB‐induced autophagy, as evidenced by the downregulation of LC3‐II/LC3‐I ratio and upregulation of P62. In vivo experiments using an arteriosclerosis obliterans model demonstrated that curcumol treatment significantly ameliorated arterial morphology and reduced stenosis. Additionally, curcumol inhibited the activity of the KLF5/COX2 axis, a key pathway in vascular diseases. These findings suggest that curcumol has the potential to serve as a multi‐target therapeutic agent for vascular diseases.

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Section: Discussionmentioning

confidence: 99%

Curcumol reduces lower limb arteriosclerosis in rats by inhibiting human arterial smooth muscle cell activity

Yang,

Huang,

Liang

et al. 2024

Clin Exp Pharma Physio

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“…The inflammatory cytokine IL-1β promotes the synthesis and release of numerous inflammatory mediators, including COX-2, all of which play a role in chondrocyte dysfunction in progressive OA [26][27][28]. Evidence suggests that blocking the ability of IL-1β to stimulate the production of inflammatory mediators may be beneficial for OA patients [29,30]. In our study, treatment of chondrocytes with IL-1β resulted in a decrease in cell viability and an increase in the expression of COX-2, PG545 was able to attenuate these effects, whereas 3-MA was able to counteract them.…”

Section: Discussionmentioning

confidence: 99%

PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy

Guo,

Li,

Wang

et al. 2023

Pharmacology

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Introduction: Osteoarthritis (OA) is a degenerative disease common in the elderly and is characterized by joint pain, swelling, and restricted movement. In recent years, heparanase has been reported to play an important role in the development of osteoarthritic cartilage. PG545 is a heparan sulfate mimetic with heparanase inhibitory activity. In this study, the therapeutic effects and possible mechanisms of PG545 were investigated in a chondrocyte injury model induced by interleukin-1β (IL -1β). Methods: Following treatment with PG545 or the autophagy inhibitor 3-methyladenine (3-MA), chondrocyte viability was detected using Cell Counting Kit-8 and fluorescein diacetate/propidium iodide double staining. The apoptosis rate of chondrocytes was determined by flow cytometry. Expression of light chain 3 and P62 was monitored by immunofluorescence labeling. Western blot, lentivirus infection with red fluorescent protein and green fluorescent protein, and quantitative real-time polymerase chain reaction were used to determine the expression levels of chondrocyte markers, apoptosis-related factors, autophagy proteins, and key proteins of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway. The expression and activity of stress-specific enzymes such as malondialdehyde, superoxide dismutase, and catalase (CAT) were investigated. Chondrocytes with ATG5 knockdown were used to investigate the relationship between the therapeutic effect of PG545 and autophagy. The therapeutic effect of PG545 was verified in vivo. Results: PG545 had a significant protective effect on chondrocytes by reducing oxidative stress, apoptosis, and degradation of chondrocytes and increasing chondrocyte proliferation. PG545 was effective in inducing autophagy in IL-1β-treated cells, while 3-MA attenuated the effect. The PI3K/Akt/mTOR pathway may be involved in the promotion of autophagy and OA treatment by PG545. Conclusion: PG545 was able to restore impaired autophagy and autophagic flux via the PI3K/Akt/mTOR pathway, thereby delaying the progression of OA, suggesting that PG545 may be a novel therapeutic approach for OA.

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“… 37 Additionally, the MAPK signaling pathway plays a role in regulating cytokine-mediated signaling pathways, including those that drive inflammation by producing cytokines. 38 Because both SVM-RFE, and RF analyses showed that TLR7 was the top ranked DE-NRGs, we performed a single gene GSEA on TLR7. In GSE55235 and GSE554757, TLR7 was significantly enriched in the Neutrophil extracellular trap formation.…”

Section: Discussionmentioning

confidence: 99%

Identification and Analysis of Neutrophil Extracellular Trap-Related Genes in Osteoarthritis by Bioinformatics and Experimental Verification

Luan,

Yang,

Kuang

et al. 2023

JIR

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Background Osteoarthritis (OA) is a common joint disease with long-term pain and dysfunction that negatively affects the quality of life of patients. Neutrophil extracellular traps (NETs), consisting of DNA, proteins and cytoplasm, are released by neutrophils and play an important role in a variety of diseases. However, the relationship between OA and NETs is unclear. Methods In our study, we used bioinformatics to explore the relationship between OA and NETs and the potential biological markers. GSE55235, GSE55457, GSE117999 and GSE98918 were downloaded from the Gene Expression Omnibus (GEO) database for subsequent analysis.After differential analysis of OA expression matrices, intersection with NET-related genes (NRGs) was taken to identify Differentially expressed NRGs (DE-NRGs) in OA processes. Evaluation of immune cell infiltration by ssGSEA and CIBERSORT algorithm. The GSVA method was used to analyze the activity changes of Neutrophils pathway, Neutrophil degranulation and Neutrophil granule constituents pathway. Results Based on RandomForest (RF), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) learning algorithms, five core genes (CRISPLD2, IL1B, SLC25A37, MMP9, and TLR7) were identified to construct an OA-related nomogram model for predicting OA progression. ROC curve results for these genes validated the nomogram’s reliability. Correlation analysis, functional enrichment, and drug predictions were performed for the core genes. TLR7 emerged as a key focus due to its high importance ranking in RF and SVM-RFE analyses. Gene Set Enrichment Analysis (GSEA) revealed a strong association between TLR7 and the Neutrophil extracellular trap pathway. Expression of core genes was demonstrated in mice OA models and human OA samples. TLR7 expression in ATDC5 cell line was significantly higher than control after TNFα induction, along with increased IL6 and MMP13. Conclusion TLR7 may be related to NETs and affects OA.

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Knockdown of DAPK1 attenuates IL-1β-induced extracellular matrix degradation and inflammatory response in osteoarthritis chondrocytes via regulating the p38 MAPK-signaling pathway

Cited by 7 publications

References 17 publications

Curcumol reduces lower limb arteriosclerosis in rats by inhibiting human arterial smooth muscle cell activity

Curcumol reduces lower limb arteriosclerosis in rats by inhibiting human arterial smooth muscle cell activity

PG545 Prevents Osteoarthritis Development by Regulating PI3K/AKT/mTOR Signaling and Activating Chondrocyte Autophagy

Identification and Analysis of Neutrophil Extracellular Trap-Related Genes in Osteoarthritis by Bioinformatics and Experimental Verification

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