Exploring the Causal Relationship between Ibuprofen Use and Osteoarthritis Risk: A Mendelian Randomization Study.

This study explored the potential causal relationship between ibuprofen (IBU) use and the risk of developing osteoarthritis, a prevalent joint disorder characterized by pain and stiffness. We conducted a two-sample MR analysis using four distinct OA GWAS datasets as outcomes and single-nucleotide polymorphisms (SNPs) associated with IBU metabolism as exposures. The inverse variance weighted (IVW) and weighted median methods were utilized to assess the causal association by meta-analysis, while pleiotropy and heterogeneity were evaluated using MR-Egger regression and Cochran's Q statistics. The MR analysis provided strong evidence for a causal association between IBU use and an increased risk of OA. A meta-analysis of the IVW and weighted median results across all datasets demonstrated an OR = 1.116 (95% CI = 1.063-1.170) and an OR = 1.110 (95% CI = 1.041-1.184). The consistency of the results obtained from different methods enhanced the reliability of the findings. Low pleiotropy and minimal heterogeneity were observed, further validating the results. The study supports a causal link between IBU use and an increased risk of OA, suggesting that IBU may accelerate the progression of OA while relieving symptoms. These findings highlight the importance of cautious use of IBU in clinical practice, especially considering its potential impact on long-term joint health.

Mitochondrial Damage-Associated Molecular Patterns and Metabolism in the Regulation of Innate Immunity.

The innate immune system, as the host's first line of defense against intruders, plays a critical role in recognizing, identifying, and reacting to a wide range of microbial intruders. There is increasing evidence that mitochondrial stress is a major initiator of innate immune responses. When mitochondria's integrity is disrupted or dysfunction occurs, the mitochondria's contents are released into the cytosol. These contents, like reactive oxygen species, mitochondrial DNA, and double-stranded RNA, among others, act as damage-related molecular patterns (DAMPs) that can bind to multiple innate immune sensors, particularly pattern recognition receptors, thereby leading to inflammation. To avoid the production of DAMPs, in addition to safeguarding organelles integrity and functionality, mitochondria may activate mitophagy or apoptosis. Moreover, mitochondrial components and specific metabolic regulations modify properties of innate immune cells. These include macrophages, dendritic cells, innate lymphoid cells, and so on, in steady state or in stimulation that are involved in processes ranging from the tricarboxylic acid cycle to oxidative phosphorylation and fatty acid metabolism. Here we provide a brief summary of mitochondrial DAMPs' initiated and potentiated inflammatory response in the innate immune system. We also provide insights into how the state of activation, differentiation, and functional polarization of innate immune cells can be influenced by alteration to the metabolic pathways in mitochondria.

Network Pharmacology-Based Study on the Mechanism of Pinellia ternata in Asthma Treatment.

BACKGROUND: Pinellia ternata (PT), a medicinal plant, has had an extensive application in the treatment of asthma in China, whereas its underlying pharmacological mechanisms remain unclear. METHODS: Firstly, a network pharmacology method was adopted to collect activated components of PT from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Targets of PT were assessed by exploiting the PharmMapper website; asthma-related targets were collected from the OMIM website, and target-target interaction networks were built. Secondly, critical nodes exhibiting high possibility were identified as the hub nodes in the network, which were employed to conduct Gene Ontology (GO) comment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis. Finally, the tissue expression profiles of key candidate genes were identified by the Gene Expression Omnibus (GEO) database, and the therapeutic effect of PT was verified by an animal experiment. RESULTS: 57 achievable targets of PT on asthma were confirmed as hub nodes through using the network pharmacology method. As revealed from the KEGG enrichment analysis, the signaling pathways were notably enriched in pathways of the T-cell receptor signaling pathway, JAK-STAT signaling pathway, and cytokine-cytokine receptor interaction. The expression profiles of candidate genes including Mmp2, Nr3c1, il-10, il-4, il-13, il-17a, il-2, tlr4, tlr9, ccl2, csf2, and vefgα were identified. Moreover, according to transcriptome RNA sequencing data from lung tissues of allergic mice compared to normal mice, the mRNA level of Mmp2 and il-4 was upregulated (P < 0.001). In animal experiments, PT could alleviate the allergic response of mice by inhibiting the activation of T-helper type 2 (TH2) cells and the expression of Mmp2 and il-4. CONCLUSIONS: Our study provides candidate genes that may be either used for future studies related to diagnosis/prognosis or as targets for asthma management. Besides, animal experiments showed that PT could treat asthma by regulating the expression of Mmp2 and il-4.