Kurarinone, a flavonoid from Radix Sophorae Flavescentis, inhibits RANKL-induced osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages.

Inflammation-induced osteoclast proliferation is a crucial contributor to impaired bone metabolism. Kurarinone (KR), a flavonoid extracted from the Radix Sophorae Flavescentis, exhibits notable anti-inflammatory properties. Nevertheless, the precise influence of KR on osteoclast formation remains unclear. This study's objective was to assess the impact of KR on osteoclast activity in vitro and unravel its underlying mechanism. Initially, a target network for KR-osteoclastogenesis-osteoporosis was constructed using network pharmacology. Subsequently, the intersecting targets were identified through the Venny platform and a PPI network was created using Cytoscape 3.9.1. Key targets within the network were identified employing topological algorithms. GO enrichment and KEGG pathway analysis were then performed on these targets to explore their specific functions and pathways. Additionally, molecular docking of potential core targets of KR was conducted, and the results were validated through cell experiments. A total of 83 target genes overlapped between KR and osteoclastogenesis-osteoporosis targets. Enrichment analysis revealed their role in inflammatory response, protein tyrosine kinase activity, osteoclast differentiation, and MAPK and NF-κB signaling pathways. PPI analysis and molecular docking demonstrate that key targets MAPK14 and MAPK8 exhibit more stable binding with KR compared to other proteins. In vitro experiments demonstrate that KR effectively inhibits osteoclast differentiation and bone resorption without cellular toxicity. It suppresses key osteoclast genes (NFATc1, c-Fos, TRAP, MMP9, Ctsk, Atp6v2), hinders IκB-α degradation, and inhibits ERK and JNK phosphorylation, while not affecting p38 phosphorylation. The results indicate that KR may inhibit osteoclast maturation and bone resorption by blocking NF-κB and MAPK signaling pathways, suggesting its potential as a natural therapeutic agent for osteoporosis.

Network Pharmacology and Experimental Validation to Elucidate the Pharmacological Mechanisms of Luteolin Against Chondrocyte Senescence.

BACKGROUND: Luteolin, a flavonoid found in various medicinal plants, has shown promising antioxidant, anti-inflammatory, and anti-aging properties. The cartilaginous endplate (CEP) represents a crucial constituent of the intervertebral disc (IVD), assuming a pivotal responsibility in upholding both the structural and functional stability of the IVD. OBJECTIVE: Exploring the precise mechanism underlying the protective effects of luteolin against senescence and degeneration of endplate chondrocytes (EPCs). METHODS: Relevant targets associated with luteolin and aging were obtained from publicly available databases. To ascertain cellular functions and signaling pathways, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were employed. Core genes were identified through the construction of a protein-protein interaction (PPI) network. Molecular docking (MD) was utilized to assess the binding affinity of luteolin to these core genes. Finally, the impact of luteolin on the senescence and degeneration of EPCs was evaluated in an in vitro cellular senescence model induced by tert-butyl hydroperoxide (TBHP). RESULTS: There are 145 overlapping targets between luteolin and senescence. Analysis using GO revealed that these targets primarily participate in cellular response to oxidative stress and reactive oxygen species. KEGG analysis demonstrated that these markers mainly associate with signaling pathways such as p53 and PI3K-Akt. MD simulations exhibited luteolin's binding affinity to P53, Cyclin-dependent kinase (CDK)2, and CDK4. Cell cycle, cell proliferation, and ß- galactosidase assays confirmed that luteolin mitigated senescence in SW1353 cells. Western blot assays exhibited that luteolin significantly suppressed the expression of Matrix Metallopeptidase (MMP) 13, P53, and P21, while concurrently promoting CDK2, CDK4, and Collagen Type II Alpha 1 (COL2A1) expression. CONCLUSION: In summary, luteolin demonstrated beneficial properties against aging and degeneration in EPCs, offering novel insights to mitigate the progression of intervertebral disc degeneration (IVDD).

ATG9A as a potential diagnostic marker of intervertebral disc degeneration: Inferences from experiments and bioinformatics analysis incorporating sc-RNA-seq data.

BACKGROUND: Disfunctional autophagy plays a pivotal role in Intervertebral Disc Degeneration (IDD) progression. however, the connection between Autophagy-related gene 9A (ATG9A) and IDD has not been reported. METHODS: Firstly, transcriptome datasets from the GEO and Autophagy-related genes (ARGs) from GeneCards were carried out using R. Following this, IDD-specific signature genes were identified through methods such as least absolute shrinkage and selection operator (LASSO), random forest (RF), and support vector machine (SVM) analyses. Validation of these findings proceeded through in vitro experiments, evaluation of independent datasets, and analysis of receiver operating characteristic (ROC) curves. Subsequent steps incorporated co-expression analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA), and construction of competing endogenous RNA (ceRNA) network. The final section established the correlation between immune cell infiltration, ATG9A, and IDD utilizing the CIBERSORT algorithm and single-cell RNA (scRNA) sequencing data. RESULTS: Research identified 87 differentially expressed genes, with only ATG9A noted as an IDD signature gene. Analysis of in vitro experiments and independent datasets uncovered a decrease in ATG9A expression within the degeneration group. The area under the curve (AUC) of ATG9A exceeded 0.8 following ROC analysis. Furthermore, immune cell infiltration and scRNA sequencing data analysis elucidated the substantial role of immune cells in IDD progression. A ceRNA network was constructed, centered around ATG9A, included 4 miRNAs and 22 lncRNAs. CONCLUSION: ATG9A was identified as a diagnostic gene for IDD, indicating its viability as a effective target for therapy disease.

Neurocomputations on dual-brain signals underlie interpersonal prediction during a natural conversation.

Prediction on the partner's speech plays a key role in a smooth conversation. However, previous studies on this issue have been majorly conducted at the single-brain rather than dual-brain level, leaving the interpersonal prediction hypothesis untested. To fill this gap, this study combined a neurocomputational modeling approach with a natural conversation paradigm in which two salespersons persuaded a customer to buy their product with their haemodynamic signals being collected using functional near-infrared spectroscopy hyperscanning. First, the results showed a cognitive hierarchy in a natural conversation, with the lower-level process (i.e., pragmatic representation of the persuasion) in the salesperson interacting with the higher-level process (i.e., value representation of the product) in the customer. Next, we found that the right dorsal lateral prefrontal cortex (rdlPFC) and temporoparietal junction (rTPJ) were associated with the representation of the product's value in the customer, while the right inferior frontal cortex (rIFC) was associated with the representation of the pragmatic processes in the salesperson. Finally, neurocomputational modeling results supported the prediction of the salesperson's lower-level brain activity based on the customer's higher-level brain activity. Moreover, the updating weight of the prediction model based on the neural computation between the rIFC of the salesperson and the rTPJ of the customer was closely associated with the interaction context, whereas that based on the rIFC-rdlPFC was not. In summary, these findings provide initial support for the interpersonal prediction hypothesis at the dual-brain level and reveal a hierarchy for the interpersonal prediction process.

Biasing the neurocognitive processing of videos with the presence of a real cultural other.

In the digital age, while short videos present vital events with powerful information, the presence of cultural cues may bias our processing of videos of foreign cultures. However, the underlying neurocognitive processes remain unclear. In this study, we hypothesized that cultural cues might bias video processing by either enhancing cultural perspective-taking or shifting cultural self-schema. To test these hypotheses, we used a novel paradigm in which the cultural cue was a real cultural other (the priming participants) who watched American/Chinese videos together with the primed participants. The results showed that when the cue was present, the right temporoparietal junction (rTPJ) response to videos with other cultural content was shifted, showing a priming effect. Moreover, the activity pattern in the rTPJ was more congruent with the primed culture than with the original culture, reflecting a neural biasing effect. Finally, intersubject representational similarity analysis indicated that the neural biasing effect in the rTPJ was more closely associated with cultural perspective-taking than with cultural self-schema. In summary, these findings support the perspective-taking hypothesis, suggesting that cultural cues can significantly bias our cultural mindset by altering cultural perspective-taking when we are exposed to culture-relevant naturalistic stimuli.

Interpersonal conflict increases interpersonal neural synchronization in romantic couples.

Previous studies on dual-brain social interaction have shown different patterns of interpersonal neural synchronization (INS) between conflictual and supportive interactions, but the role of emotion in the dual-brain mechanisms of such interactions is not well understood. Furthermore, little is known about how the dual-brain mechanisms are affected by relationship type (e.g., romantic relationship vs. friendship) and interaction mode (e.g., verbal vs. nonverbal). To elaborate on these issues, this study used functional near-infrared spectroscopy to collect hemodynamic signals from romantic couples and cross-sex friends while they were discussing conflictual, neutral, or supportive topics. For the couples but not the friends, INS between the sensorimotor cortex of both participants was greater when discussing the conflictual topic than when discussing the supportive topic. INS was positively correlated with the arousal level but not the valence level of communication contents. INS was also positively correlated with interpersonal physiological synchronization based on galvanic skin response, a physiological measure of arousal. Furthermore, the differences in INS between the conflictual and supportive topics were closely associated with verbal rather than nonverbal behaviors. Together, these findings suggest that it is the arousal level induced by verbal interactions during interpersonal conflicts that increases romantic couples' INS.