Development of a Novel 11-Gene Signature Related to Immune Subtypes for FibromyalgiaZhao, Wang
Endocr Metab Immune Disord Drug Targets (2025)
Abstract: The purpose of this study was to identify molecular subtypes and hub genes in fibromyalgia [FM] based on immune-related genes [IRGs].FM is a chronic disease featuring widespread pain, and the immune system may be involved in the FM progression.The objectives of this study are as follows: 1] To identify the molecular subtypes of FM based on IRGs. 2] To screen and validate the hub genes in FM. 3] To predict the transcription factor [TF] targeting hub genes and 4] To evaluate the correlation between immune cell infiltration, hallmark pathways, and hub genes.Two FM datasets were acquired from the Gene Expression Omnibus [GEO] database. IRGs were collected from the ImmPort database. Molecular subtypes of FM were identified using the "ConsensusClusterPlus" package. IRGs score and differentially expressed genes [DEGs] between different FM subtypes and control samples were obtained using "GSVA" and "limma" packages. Key module genes related to FM subtypes were identified using the "WGCNA" package. Hub genes were screened and verified using "glmnet" and "pROC" packages. TF-hub gene regulatory network was constructed by Cytoscape software. The correlation between immune cells, hallmark pathways, and hub genes was analyzed by the Spearman method. Finally, the DSigDB database was used to obtain associations between characterized genes and drugs, and the expression of key genes was verified using qRT-PCR.FM samples were classified into two subtypes, and the IRGs score of the C2 subtype was lower than that of the C1 subtype. Then, 184 module genes were obtained and mainly enriched in immune-related pathways. Next, 11 hub genes [TSPAN16, RILPL2, RASSF5, PGAP2, PADI2, NACC1, LRRC25, ITGAD, HIPK1, ATP6V0D1, AP1M2] were screened with good diagnostic performance. Besides, 45 TFs targeting hub genes were predicted. Most hub genes were negatively associated with CD4/CD8 T cells while positively correlated with macrophages, mast cell, monocyte, and neutrophil, as well as inflammatory response, angiogenesis pathways, etc. Molecular docking suggests that chloroquine and L-citrulline may be potent agents for the treatment of NACC1 and PADI2. RILPL2 and ITGAD were significantly differentially expressed in control and FM group mouse models.This study identified two subtypes and 11 hub genes of FM based on IRGs, providing a reference for the clinical diagnosis of FM.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
Identification of the immune infiltration and biomarkers in ulcerative colitis based on liquid-liquid phase separation-related genesHong, Fang, Nie
et alSci Rep (2025) 15 (1), 4484
Abstract: Liquid-liquid phase separation (LLPS) associates with immune infiltration in multiple diseases. Nonetheless, the role of LLPS-related genes (LLPS-RGs) in immune infiltration of ulcerative colitis (UC) is still elusive. We identified the hub LLPS-RGs (DE-LLPS-RGs) (HSPB3, SLC16A1, TRIM22, SRI, PLEKHG6, GBP1, PADI2) by machine learning algorithms. Hub genes were screened that displayed high prediction accuracy of UC patients. Both the microarray and scRNA-seq datasets showed a strong correlation with immune cell infiltration and cytokines, especially GBP1, TRIM22, SRI. And qRT-PCR analysis showed that GBP1 play a pro-inflammatory role in UC. Two distinct clusters were identified, in which cluster A displayed higher immune infiltration level compared with the cluster B. The top targeted biological pathways of two clusters were distinct, glutamate receptor antagonist ranked top for cluster A while HDAC inhibitor ranked top in cluster B. External cohort and UC cell model validation indicated the similar immune infiltration levels, gene expression and cytokine expression patterns. We determined the seven high accuracy diagnostic genes of UC patients and provide a new perspective on immunoregulation in UC pathogenesis. And suggest patient stratification and candidate targets for precision treatment based on hub genes screened.© 2025. The Author(s).
[The effects and mechanisms of PAD2 inhibitor AFM-30a attenuates pulmonary fibrosis in silicotic mice]Zhang, Jin, Gao
et alZhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi (2025) 43 (1), 1-13
Abstract: Objective: To observe the effects of peptidylarginine deiminase 2 (PAD2) inhibitor AFM-30a on silicotic mice and its possible mechanisms. Methods: In May 2022, 40 SPF male C57BL/6J mice were randomly divided into control group, AFM-30a group, silicosis model group and AFM-30a treatment group, with 10 mice in each group. Silicosis model group and AFM-30a treatment group were perfused with silicon dioxide (SiO(2)) suspension (10 mg/piece, 50 μl), and the other groups were perfused with an equal amount of sodium chloride solution. After 2 weeks, AFM-30a group and AFM-30a treatment group were intraperitoneally injected AFM-30a (20 mg/kg, 100 μl) daily, and mice of other groups were injected with equal amounts of sodium chloride solution for 4 weeks. Mouse RAW264.7 monocytes/macrophages were cultured in vitro and divided into blank control group, AFM-30a group (5 μmol/L), SiO(2) group (200 μg/ml), and SiO(2)+AFM-30a group (200 μg/ml SiO(2) induction for 12 h, followed by 5 μmol/L AFM-30a treatment for 12 h). As well as blank control group, vimentin (Vim) group (2 μg/ml), citrullinated vimentin (Cit-Vim) group (2 μg/ml), and Cit-Vim+TLR4-C34 group (10 μmol/L TLR4-C34 treatment for 1 h, followed by 2 μg/ml Cit-Vim induction for 24 h). Hematoxylin Eosin (HE) and Masson staining were used to observe the pathological morphology of lung. The lung fieldclarity and lung texture of each group was observed by micro-CT. The number of positive cells was detected by tartrate resistant acid phosphatase (TRAP) staining. The localization and expression levels of PAD2, Cit-Vim, toll-like receptor 4 (TLR4) signaling and receptor activator of nuclear factor-κB ligand (RANKL) signaling proteins were measured by Immunofluorescence staining and Western blotting in vitro and in vivo. The experimental data were all presented as Mean±SD. A completely random design of one-way analysis of variance was used among the groups. The pduo comparison was performed using LSD test for homogeneity of variance and Tamhane's test for inconsistency. Results: Compared with the control group, the silicosis model group showed the formation of silicon nodules accompanied by collagen deposition, the silicosis model group showed thickened, and several high-density shadows of varying sizes in the lung field, and the number of TRAP positive cells in silicosis model group were increased significantly, the expression levels of PAD2, Cit-Vim, TLR4 and RANKL signal-related proteins were also significantly increased in silicosis groupmodel (P<0.05). Compared with the silicosis model group, the AFM-30a treatment group reduced deposition of collagen in lung, and the number of TRAP positive cells was decreased in AFM-30a treatment group. The expression levels of PAD2, Cit-Vim, TLR4 and RANKL signaling related proteins were significantly decreased in AFM-30a treatment group (P<0.05). In vitro, compared with the blank control group, the number of TRAP positive cells and the expression levels of PAD2, Cit-Vim, TLR4 and RANKL signaling related proteins in the SiO(2) group were significantly increased (P<0.05). Compared with the SiO(2) group, the number of TRAP positive cells and the expression levels of PAD2, Cit-Vim, TLR4 and RANKL signaling related proteins in the SiO(2)+AFM-30a group were significantly decreased (P<0.05). Compared with the blank control group, the expression levels of TLR4 and RANKL signaling related proteins in the Cit-Vim group were significantly increased (P<0.05). Compared with the Cit-Vim group, the expression levels of TLR4 and RANKL signaling related proteins in the Cit-Vim+TLR4-C34 group were significantly decreased (P<0.05) . Conclusion: PAD2 inhibitor AFM-30a may play an antagonisticrole in silicotic fibrosis in mice by potentialregulating TLR4 and RANKL signaling pathways.
Circulating levels of PADs and citrullinated histone H3 in SARS-CoV-2 infection: Influence of genetic polymorphismsAdriana Gutiérrez-Pérez, Pérez-Rubio, Rafael Villafan-Bernal
et alClin Chim Acta (2025) 569, 120180
Abstract: Peptidyl arginine deiminases (PADs) and citrullinated H3 histone (H3Cit) play a crucial role in the inflammatory response. These components determine various clinical situations in COVID-2019 associated pneumonia. Single nucleotide polymorphisms (SNPs) in the genes PADI2 and PADI4 may influence the outcome of poorer patient outcomes. We analyze the association of circulating levels NETs biomarkers (PAD2, PAD4, and H3Cit) and the SNPs on PADI2 (rs1005753 and rs2235926) and PADI4 (rs11203366, rs11203367, and rs874881) in hospitalized patients with severe acute respiratory distress syndrome (ARDs) by SARS-CoV-2 pneumonia.A cross-sectional study in 160 hospitalized patients with ARDs by SARS-CoV-2 pneumonia. The plasma levels of PAD2, PAD4, and H3Cit were determined by ELISA method. The SNPs were determined by qPCR using TaqMan probes. Logistic regression models and receiver operating characteristics (ROC) curve were used to assess the association and predictive value of PAD2, PAD4, and H3Cit plasma levels in outcome by ARDs by SARS-CoV-2 pneumonia.PAD2, PAD4, and H3Cit concentrations were predictors of invasive mechanical ventilation (IMV) requirement and non-survival. PAD2 were associated with non-survival, while PAD4 and H3Cit were associated with requirement IMV. In addition, PAD2 and PAD4 concentrations were related with inflammation markers such as NLR, MLR, dNLR, SII, SIRI, AISI, and NHL. In the carriers of TT genotype of rs1005753 of PADI2 were associated with increased of H3Cit, while, the carriers of GTG/GTG haplotype of PADI4 was related to the presence of increased of PAD4 circulating levels.SNPs in PADI2 and PADI4 have a significant influence on concentrations of PAD2, PAD4, and H3Cit, which are predictor markers of requirement IMV and non-survival in severe ARDS by SARS-CoV-2 pneumonia.Copyright © 2025. Published by Elsevier B.V.
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