Exploration of the mode of death and potential death mechanisms of nucleus pulposus cells.

Intervertebral disc degeneration (IVDD) is a common chronic orthopaedic disease in orthopaedics that imposes a heavy economic burden on people and society. Although it is well established that IVDD is associated with genetic susceptibility, ageing and obesity, its pathogenesis remains incompletely understood. Previously, IVDD was thought to occur because of excessive mechanical loading leading to destruction of nucleus pulposus cells (NPCs), but studies have shown that IVDD is a much more complex process associated with inflammation, metabolic factors and NPCs death and can involve all parts of the disc, characterized by causing NPCs death and extracellular matrix (ECM) degradation. The damage pattern of NPCs in IVDD is like that of some programmed cell death, suggesting that IVDD is associated with programmed cell death. Although apoptosis and pyroptosis of NPCs have been studied in IVDD, the pathogenesis of intervertebral disc degeneration can still not be fully elucidated by using only traditional cell death modalities. With increasing research, some new modes of cell death, PANoptosis, ferroptosis and senescence have been found to be closely related to intervertebral disc degeneration. Among these, PANoptosis combines essential elements of pyroptosis, apoptosis and necroptosis to form a highly coordinated and dynamically balanced programmed inflammatory cell death process. Furthermore, we believe that PANoptosis may also crosstalk with pyroptosis and senescence. Therefore, we review the progress of research on multiple deaths of NPCs in IVDD to provide guidance for clinical treatment.

Bioinformatics-based discovery of intervertebral disc degeneration biomarkers and immune-inflammatory infiltrates.

Background: Intervertebral disc degeneration (IVDD) is a common chronic disease in orthopedics, and its molecular mechanisms are still not well explained. Aim: This study's objective was to bioinformatics-based discovery of IVDD biomarkers and immune-inflammatory infiltrates. Materials and Methods: The IVDD illness gene collection was gathered from GeneCards, DisGeNet, and gene expression profiles were chosen from the extensive Gene Expression Omnibus database (GSE124272, GSE150408, and GSE153761). The STRING database was used to create a network of protein-protein interactions, while the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases were used for functional enrichment analysis. Using hub genes, the immune cell infiltration between IVDD patient samples and control tissues was examined. Finally, quantitative polymerase chain reaction and Western blot experiments were used to verify the expression of hub genes. Results: A total of 27 differentially expressed hub genes were identified by bioinformatics. According to GO and KEGG analyses, hub genes were prominent in immunological responses, chemokine-mediated signaling pathways, and inflammatory responses, with the key signaling pathways engaged in cellular senescence, apoptosis, Th1 and Th2 cell differentiation, and Th17 cell differentiation. Immune cell infiltration research revealed that T cells, lymphocytes, B cells, and NK cells were decreased in IVDD patients while monocytes, neutrophils, and CD8 T cells were increased. The expression levels of the senescence hub genes SP1, VEGFA, IL-6, and the apoptosis key gene CASP3 were considerably greater in the IVDD model group than in the control group, according to in vitro validation. Conclusion: In conclusion, the cellular senescence signaling pathway, the apoptosis signaling pathway, and associated hub genes play significant roles in the development and progression of IVDD, this finding may help direct future research on the senescence signaling route in IVDD.

Mechanisms of inhibition of nucleus pulposus cells pyroptosis through SDF1/CXCR4-NFkB-NLRP3 axis in the treatment of intervertebral disc degeneration by Duhuo Jisheng Decoction.

Intervertebral disc degeneration (IVDD) is one of the leading causes of lower back pain and the most common health problem in the world. Inflammasomes, which is mainly caused by NLRP3, mediated nucleus pulposus pyroptosis has been discovered to be strongly related to IVDD. In addition, Duhuo Jisheng Decoction (DHJSD) has anti-inflammatory and regulatory effects on NLRP3 inflammasome, but the molecular mechanism of whether DHJSD can regulate pyroptosis through NLRP3 to treat IVDD is unclear. In this study, we used a bioinformatics way to discover the molecular mechanism of DHJSD regulation of pyroptosis in IVDD, and validated our predictions through vitro and vivo experiments. Through bioinformatics, we found that NLRP3, GSDMD, IL-1ßand other hub proteins of pyroptosis were highly expressed in IVDD SD rats, and network pharmacology discovered that DHJSD may control cellular senescence, apoptosis, and pyroptosis in order to treat IVDD. Additional findings demonstrated that DHJSD could successfully treat IVDD brought on by imaging and histomorphological analysis. Western blot showed that NLRP3, a key protein of pyroptosis, was elevated in rat degenerated nucleus pulposus tissue and lipopolysaccharide-treated Nucleus pulposus Cells (NPCs), and that DHJSD intervention was effective in reducing LPS-induced inflammatory responses and further suppressing the expression of pyroptosis related proteins to improve IVDD. The specific mechanism is that DHJSD inhibits NPCs pyroptosis via the SDF-1/CXCR4-NF-kB-NLRP3 axis. In conclusion, we revealed the intrinsic mechanism of DHJSD regulation of NPCs pyroptosis to improve IVDD and its intrinsic value for IVDD treatment.

Research Progress on the Pathogenesis of Knee Osteoarthritis.

Knee osteoarthritis (KOA) is a chronic joint bone disease characterized by inflammatory destruction and hyperplasia of bone. Its main clinical symptoms are joint mobility difficulties and pain, severe cases can lead to limb paralysis, which poses major pressure to the quality of life and mental health of patients, but also brings serious economic burden to society. The occurrence and development of KOA is influenced by many factors, including systemic factors and local factors. The joint biomechanical changes caused by aging, trauma and obesity, abnormal bone metabolism caused by metabolic syndrome, the effects of cytokines and related enzymes, genetic and biochemical abnormalities caused by plasma adiponectin, etc. all directly or indirectly lead to the occurrence of KOA. However, there is little literature that systematically and comprehensively integrates macro- and microscopic KOA pathogenesis. Therefore, it is necessary to comprehensively and systematically summarize the pathogenesis of KOA in order to provide a better theoretical basis for clinical treatment.

Exploring the pharmacological mechanism of Duhuo Jisheng Decoction in treating intervertebral disc degeneration based on network pharmacology.

BACKGROUND: The purpose of this study was to examine the mechanism of Duhuo Jisheng Decoction (DHJSD) in the treatment of intervertebral disc degeneration (IVDD). METHODS: The active compounds of DHJSD and their corresponding targets were obtained from the TCMSP database. "Intervertebral disc degeneration" was used as a search term in the DisGeNET, GeneCards, Comparative Toxicogenomics Database, and MalaCards database to obtain disease-related targets. Following the discovery of overlapping DHJSD and IVDD targets, enrichment analyses for Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome, and WikiPathways were performed. Cytoscape 3.9.1 was used to build the "DHJSD-Active Ingredients-Target Genes-IVDD" network and protein-protein interaction network, and CytoHubba was used to screen the pivotal genes. Molecular docking confirmed the binding activity of hub genes and key components. RESULTS: The bioinformatic analysis of DHJSD in the treatment of IVDD revealed 209 potential therapeutic gene targets, including 36 important gene targets and 10 of these crucial gene targets. Enrichment analysis of 36 key therapeutic targets showed that the biological processes involved in the Gene Ontology analysis of DHJSD in treating IVDD were mainly cytokine-mediated signaling pathway, inflammatory response, negative regulation of apoptotic process, and vascular endothelial growth factor production. The Kyoto Encyclopedia of Genes and Genomes signaling pathway is mainly involved in TNF signaling pathway, Th17 cell differentiation, IL-17 signaling pathway, and HIF-1 signaling pathway. The Recactome signaling pathway is mainly involved in cytokine signaling in immune system, cellular responses to stress, immune system, cytokines, and inflammatory response. HIF1A and PPARG regulation of glycolysis are mostly involved in the WikiPathways signaling system. The findings demonstrated that to cure IVDD, DHJSD affects the pathogenic processes of inflammation, extracellular matrix, cellular senescence, autophagy, apoptosis, focal death, and proliferation through the aforementioned targets and signaling pathways. The results of molecular docking demonstrated that the protein can be effectively bound by the DHJSD active component. Further evidence was provided for the molecular mechanism through which DHJSD works to treat IVDD. CONCLUSION: This study uncovers the multi-component, multi-target, and multi-pathway characteristics of DHJSD for the treatment of IVDD, offering fresh perspectives to further investigate the mechanism of DHJSD for the treatment of IVDD.

A review of Duhuo Jisheng decoction mechanisms in intervertebral disc degeneration in vitro and animal studies.

Intervertebral disc degeneration (IVDD) has become a serious public health problem, placing a heavy burden on society and the healthcare system. Its pathogenesis is not completely clear and may be closely related to mechanical damage, inflammatory factors, oxidative stress and death of nucleus pulposus cells (NPCs). The treatment of IVDD mainly includes conservative treatment and surgery. Conservative treatment is based on hormonal and anti-inflammatory drugs and massage techniques, which can relieve the pain symptoms to a certain extent, but cannot solve the problem from the root cause. Surgical treatment is mainly by removing the herniated nucleus pulposus, but it is more traumatic for IVDD patients, expensive and not suitable for all patients. Therefore, it is extremely important to clarify the pathogenesis of IVDD, to find an effective and convenient treatment and to further elaborate its mechanism of action. The effectiveness of traditional Chinese medicine in the treatment of IVDD has been well demonstrated in clinical medical research. We have been working on the Chinese herbal formula Duhuo Jisheng Decoction, which is a common formula for the treatment of degenerative disc disease. Not only does it have significant clinical effects, but it also has few adverse effects. At present, we found that its mechanism of action mainly involves regulation of inflammatory factors, reduction of apoptosis and pyroptosis of NPCs, inhibition of extracellular matrix degradation, improvement of intestinal flora, etc. However, a few relevant articles have yet comprehensively and systematically summarized the mechanisms by which they exert their effect. Therefore, this paper will comprehensively and systematically explain on it. This is of great clinical significance and social value for elucidating the pathogenesis of IVDD and improving the symptoms of patients, and will provide a theoretical basis and scientific basis for the treatment of IVDD with traditional Chinese medicine.