Ion Currents Mediated by TRPA1 Channels in Freshly Dissociated Rat Articular Chondrocytes: Biophysical Properties and Regulation by Inflammatory ProcessesPonce, Jimenez, Roldan
et alPharmaceuticals (Basel) (2025) 18 (3)
Abstract: Background: Articular chondrocytes are specialized cells in synovial joint cartilage, responsible for maintaining and regenerating the extracellular matrix. Inflammation disrupts the balance between matrix synthesis and degradation, leading to cartilage breakdown. This process, commonly observed in conditions such as osteoarthritis, results in chondrocyte dysfunction and accelerates joint degeneration. Since TRPA1 channels are implicated in inflammatory processes, this study investigates the expression of TRPA1 channels in freshly dissociated rat articular chondrocytes and their modulation by anti-inflammatory agents. Methods: We used the whole-cell patch-clamp method to assess TRPA1 channel expression and modulation. Results: Freshly dissociated chondrocytes exhibit ion currents attributable to TRPA1 channel expression, with higher magnitudes observed in medium-sized cells. These currents decrease over time in primary culture. Treatment with pro-inflammatory agents (IL-1α, IL-1β, and LPS) increases TRPA1's current magnitude. IL-1β treatment directly induces transient TRPA1 currents. Several signaling components activated during inflammation contribute to the IL-1β-induced enhancement of TRPA1 current density, including IL-1 R1, the adaptor protein MyD88, and the downstream kinases IRAK1 and IRAK4. Conclusions: Our findings demonstrate that healthy rat chondrocytes express functional TRPA1 channels and that inflammatory processes modulate their expression.
The causal effects of 2,821 protein level ratios on non-small cell lung cancer: a two-sample Mendelian randomization studyZou, Shen, Li
et alTransl Cancer Res (2025) 14 (2), 1101-1110
Abstract: Non-small cell lung cancer (NSCLC) has a complex etiology, making early diagnosis difficult and leading to high mortality rates, thus necessitating personalized treatment strategies. While protein level ratios have shown potential as biomarkers or therapeutic targets, their causal relationship with NSCLC remains unclear. This study aimed to investigate these causal links using Mendelian randomization (MR), providing insights into potential biomarkers and therapeutic avenues.We executed an intricate two-sample MR study to explore the stochastic causal links between 2,821 protein level ratios and NSCLC. The genome-wide association study (GWAS) statistics for NSCLC and protein level ratios were sourced from the Finnish Database (version 10) and the UK Biobank, respectively. For the instrumental variables (IVs) related to protein level ratios, we selected IVs with a P value <1.0×10-5. Throughout this analysis, we applied five established MR techniques.Our study identified causal relationships between 142 protein level ratios and NSCLC. Notably, the AKR1B1/SUGT1 protein level ratio and the PLPBP/STIP1 protein level ratio demonstrated the most significant negative correlations with NSCLC risk. On the other hand, the ARHGEF12/IRAK4 protein level ratio and the BANK1/LBR protein level ratio exhibited the most significant positive correlations. Furthermore, sensitivity analyses did not reveal any significant heterogeneity or horizontal pleiotropy.Studying specific protein level ratios in patients can reveal the molecular mechanisms and pathological processes of NSCLC, which has certain clinical significance for early diagnosis of NSCLC, understanding drug resistance mechanisms and developing personalized treatment strategies. However, these findings necessitate further validation through extensive clinical research.Copyright © 2025 AME Publishing Company. All rights reserved.
Preliminary results and a theoretical perspective of co‑treatment using a miR‑93‑5p mimic and aged garlic extract to inhibit the expression of the pro‑inflammatory interleukin‑8 geneGambari, Papi, Gasparello
et alExp Ther Med (2025) 29 (4), 85
Abstract: The coronavirus disease-19 (COVID-19) pandemic has been a very significant health issue in the period between 2020 and 2023, forcing research to characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequences and to develop novel therapeutic approaches. Interleukin-6 (IL-6) and IL-8 are considered significant therapeutic targets for COVID-19 and emerging evidence has suggested that microRNAs (miRNAs/miRs) serve a key role in regulating these genes. MiRNAs are short, 19-25 nucleotides in length, non-coding RNAs that regulate gene expression at the post-transcriptional level through the sequence-selective recognition of the 3'-untranslated region (3'-UTR) of the regulated mRNAs, eventually repressing translation, commonly, via mRNA degradation. For example, among several miRNAs involved in the regulation of the COVID-19 'cytokine storm', miR-93-5p can inhibit IL-8 gene expression by directly targeting the 3'-UTR of IL-8 mRNA. In addition, miR-93-5p can regulate Toll-like receptor-4 (TLR4) and interleukin-1 receptor-associated kinase 4 (IRAK4) expression, thus affecting the nuclear factor-κB (NF-κB) pathway and the expression of NF-κB-regulated genes, such as IL-6, IL-1β and other hyper-expressed genes during the COVID-19 'cytokine storm'. In the present study, the results provided preliminary evidence suggesting that the miR-93-5p-based miRNA therapeutics could be combined with the anti-inflammatory aged garlic extract (AGE) to more effectively inhibit IL-8 gene expression. The human bronchial epithelial IB3-1 cell line was employed as experimental model system. IB3-1 cells were stimulated with the BNT162b2 COVID-19 vaccine and transfected with pre-miR-93-5p in the absence or in the presence of AGE, to verify the inhibitory effects on the BNT162b2-induced expression of the IL-8 gene. The accumulation of IL-8 mRNA was assessed by RT-qPCR; the release of IL-8 protein was determined by Bio-Plex assay. In addition, the possible applications of TLR4/NF-κB inhibitory agents (such as miR-93-5p and AGE) for treating human pathologies at a hyperinflammatory state, such as COVID-19, cystic fibrosis and other respiratory diseases, were summarized.Copyright: © 2025 Gambari et al.
BAP1 Represses Sequential Activation of IRAKs and NF-κB Signaling in Pancreatic CancerZhao, Liang, Wei
et alInt J Biol Sci (2025) 21 (5), 1949-1965
Abstract: The deubiquitinating enzyme BRCA1 Associated Protein-1 (BAP1) has been reported to be shallowly deleted in a subset of pancreatic ductal adenocarcinomas (PDAC) and is believed to play a significant role in the development of chronic pancreatitis-driven PDAC. However, evidence suggests that BAP1 may also be involved in the progression and metastasis of PDAC, though the underlying mechanism remains unclear. Here, we demonstrate that BAP1 deletion leads to the overactivation of the nuclear factor-κB (NF-κB) signaling in PDAC, thereby promoting the proliferation, migration, and invasion of PDAC models both in vivo and in vitro. Mechanistically, BAP1 inhibits the sequential activation of interleukin-1 receptor-associated kinases (IRAKs) in an enzyme-independent manner. BAP1 binds to IRAK1 and inhibits the interaction between IRAK4 and IRAK1, as well as the IRAK4-mediated initiation of IRAK1 phosphorylation and autophosphorylation. This, in turn, prevents the dissociation of IRAK1 from the Myddosome complex and sequential activation of NF-κB. Based on this, we further identified that dual-target inhibitors of IRAK1/4 exhibited significant inhibitory effects on BAP1-deficient tumors in both in vivo and in vitro PDAC models. Our findings elucidate the mechanism by which BAP1 inhibits the NF-κB signaling and present a promising strategy for the targeted treatment of BAP1-deficient pancreatic cancer.© The author(s).
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