Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality rates in patients with rheumatoid arthritis (RA). Currently, the treatment of RA-ILD remains highly challenging. This study aims to identify potential therapeutic targets for RA-ILD through a systematic druggable genome-wide Mendelian randomization (MR) analysis. We performed a genome-wide MR analysis by integrating expression quantitative trait loci (eQLT) of 6888 druggable genes and genetic summary statistics from a genome-wide association study of RA-ILD. A colocalization analysis was performed to prioritize genes strongly associated with RA-ILD. Enrichment analysis, protein-protein interaction network construction, drug prediction, and molecular docking were further conducted to provide valuable guidance for the development of targeted therapies. A total of 33 druggable genes showed significant association with RA-ILD, one of which, CISD1, was robustly validated through colocalization analysis. Notably, three key target genes-CST7, ATN1, and FCER2-were identified as potential mediators of the treatment effect of cyclophosphamide, a current clinical treatment for RA-ILD. This study employed MR and colocalization analysis to identify 33 potential drug-target genes for RA-ILD, including three genes associated with the mechanism of action of cyclophosphamide. These findings offer a promising roadmap for developing targeted therapies, potentially shifting treatment strategies from broad immunosuppression to precise molecular interventions.
The persistence of castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy and androgen receptor (AR) signaling inhibition underscores the need to elucidate resistance mechanisms. The AR signaling pathway plays a central role in the development of prostate cancer. Metabolic reprogramming of androgen synthesis and aberrant activation of AR signaling collectively drive CRPC development. Under therapeutic pressure, AR signaling adapts through AR amplification, ligand-binding domain mutations, splice variants, and alternative activation by cytokines/growth factors, maintaining AR transcriptional activity in low-androgen environments. Concurrently, somatic alterations (like PTEN loss) and crosstalk with key pathways such as PI3K/AKT, coupled with the evolving multifocal spatial heterogeneity, further complicate the role of AR signaling in CRPC treatment resistance. Innovations in single-cell and spatial technologies reveal tumor heterogeneity and lineage plasticity governed by genetic and epigenetic alterations. Current therapeutic innovations, including approaches such as CYP11A1 inhibition, targeting of the AR N-terminal domain, and bipolar androgen therapy, are showing promise in clinical trials. Overcoming CRPC effectively requires cotargeting androgen/AR-associated pathways and suppressing lineage plasticity through dynamic monitoring and precision interventions.
BACKGROUND AND PURPOSE:Microglial activation plays a role in driving chronic migraine (CM). Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in brain microglia and impacts neuroinflammation in nervous system diseases. However, its role in CM is unclear. Here, we have investigated the role of microglial TREM2 in the development of CM. EXPERIMENTAL APPROACH:We used male mice receiving repeated intraperitoneal nitroglycerin (NTG) injections as a CM model. Mechanical and thermal hypersensitivity were assessed by mechanical withdrawal threshold and thermal withdrawal latency. TREM2 knockout mice (TREM2-/-) and systemically administered TREM2 agonist COG1410 were evaluated for TREM2's role in CM. TREM2, calcitonin gene-related peptide (CGRP) and c-fos expression in the trigeminal nucleus caudalis (TNC) were measured for central sensitisation assessment. Immunohistochemical analyses and western blots measured protein expression in the TNC and BV-2 microglia. Quantitative real-time polymerase chain reaction (qRT-PCR) detected inflammatory factor expression. KEY RESULTS:Recurrent NTG injection up-regulated TNC protein levels of TREM2, CGRP and c-fos. TREM2 loss accelerated NTG-induced CM development, increased CGRP and c-fos expression, and inhibited TNC autophagy. Conversely, COG1410 prevented hyperalgesia and reduced CGRP/c-fos expression in the TNC after recurrent NTG administration. In vitro, TREM2 knockdown enhanced the expression of inflammation-related genes and the mTOR/p70s6k pathway activation in lipopolysaccharide (LPS)-stimulated BV-2 microglia, whereas COG1410 significantly inhibited LPS-induced mTOR/p70s6k pathway activation and alleviated inflammatory responses. CONCLUSION AND IMPLICATIONS:These data show that TREM2 plays a protective role in CM by modulating microglial activation and autophagy in the TNC via the mTOR/p70s6k pathway.
Background:Obesity, a chronic condition affecting multiple physiological systems, poses major public health challenges. Dietary interventions are widely recognized as effective strategies for weight management. With over 4 billion Internet users worldwide, an increasing number of individuals rely on online platforms for health information. In China, TikTok, Bilibili, and Kwai are major channels for disseminating health-related content. However, the quality of dietary weight loss information on these platforms remains unclear. Objective:This study aims to assess the reliability and quality of the information in Chinese videos on dietary weight loss shared on the BiliBili, TikTok, and Kwai, three video-sharing platforms. Methods:We identified the top 100 dietary weight-loss videos on each platform in February 2024, resulting in a total of 300 videos. Video information quality and reliability were assessed using the Global Quality Score (GQS) and modified DISCERN (mDISCERN). Correlations between video quality and video characteristics were also analyzed. Results:The average GQS scores for BiliBili, TikTok, and Kwai were 2.04, 1.81, and 1.70, respectively, while the average mDISCERN scores were 2.01, 1.81, and 1.73. Median scores for both tools across all platforms were 2. BiliBili showed significantly higher GQS scores than TikTok and Kwai (p < 0.01 and p < 0.05, respectively). Regarding mDISCERN, BiliBili scored significantly higher than TikTok (p < 0.05), while the difference with Kwai was not statistically significant (p = 0.08). Nevertheless, none of the platforms achieved scores above 3, indicating generally low information quality and reliability. Significant positive correlations were found between video duration and both GQS (r = 0.41, p < 0.01) and mDISCERN (r = 0.32, p < 0.01). Additionally, strong correlations were observed between likes and saves (r = 0.90, p < 0.01), likes and comments (r = 0.92, p < 0.01), and saves and comments (r = 0.86, p < 0.01). Conclusion:While acknowledging limitations regarding cross-sectional design and specific sampling of single keyword and Chinese platforms, our findings highlight that the prevalence of low-quality videos on Chinese social media exposes viewers to significant risks of misinformation and inappropriate dieting. These findings underscore the need to promote digital health literacy and improve strategies for digital health communication.
Patients with uremia undergoing long-term hemodialysis are prone to multi-organ complications, but the underlying molecular mechanisms remain unclear. Ferroptosis, an iron-dependent form of cell death, has been linked to inflammation and organ damage. Its role in hemodialysis-related pathology, however, has not been well characterized. In this study, we systematically profiled low-abundance plasma proteins from six hemodialysis patients and eight healthy controls using a protein corona–based enrichment technique to enhance detection sensitivity. A total of 183 differentially expressed proteins (DEPs) were defined based on a fold-change threshold (≤ 0.25 or ≥ 4), including 101 upregulated and 82 downregulated proteins. Notably, pathway enrichment analysis highlighted the ferroptosis pathway, with altered abundance of proteins including TFRC, ALOX15, PRNP, CYBB, and ACSL1, suggesting a potential association of ferroptosis-related signals with hemodialysis-related complications. To complement the proteomic analysis, enzyme-linked immunosorbent assay (ELISA) was performed in an independent cohort. ALOX15 showed a significant and reproducible increase in plasma levels (P < 0.0001), consistent with the proteomic results. Other ferroptosis-related candidates warrant further evaluation and independent validation in larger cohorts. Furthermore, drug target prediction based on DEP data identified N-oleoyldopamine, luteolin, and catechol as potential compounds targeting the five ferroptosis-related molecules. Collectively, this study provides an exploratory plasma proteomic resource and suggests that ferroptosis-associated plasma protein changes may be relevant to hemodialysis-related complications, warranting further validation. Collectively, this study provides an exploratory plasma proteomic resource and offers initial insights into ferroptosis-associated plasma protein changes in hemodialysis patients.
