PRMT5 highly expressed on CD16 + CD56- natural killer cells is correlated with NK cells exhaustion in colorectal cancer mesenchymeNie, Chang, Yang
et alCancer Immunol Immunother (2025) 74 (4), 139
Abstract: To investigate the relationships between changes in the phenotype of natural killer cells (NK cells) in the microenvironment of colorectal cancer (CRC) and the expression of important immune checkpoints. To assess the expression level of CD16 bright CD56 negative (CD16 + CD56-) NK cell-associated immune checkpoints, including protein arginine methyltransferase 5 (PRMT5) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), single-immunoglobulin interleukin-1-related receptor (SIGIRR), in CRC mesenchyme.A total of 194 patients who were diagnosed with CRC were screened. The percentage of NK cells and the expression levels of their surface receptors, including PRMT5, CD56, CD69, TIGIT, CD16, IFN-γ, and SIGIRR, in the tumor microenvironment (TME) of CRC were assessed. Immunohistochemical staining, multiplex immunohistochemistry, and single-cell sequencing were performed.Compared with normal mesenchyme, NK cells were less in CRC mesenchyme. The percentage of CD16 + CD56- NK cells in tumor mesenchyme was significantly higher, the number of CD16 + NK cells was more, and the number of CD56 + NK cells was less in CRC mesenchyme. High expression of TIGIT and PRMT5 expression affected the progression of CRC. The expression of PRMT5 and SIGIRR expression was significantly increased in CD16 + CD56- NK cells, and both genes were identified as important morbidity factors. PRMT5 and SIGIRR may contribute to the phenotype changes of NK cells in CRC.The microenvironment of CRC is in an immunosuppressive state characterized mainly by high expression of TIGIT, CD16, PRMT5, and SIGIRR; low expression of CD56, IFN-γ, and CD69; significantly decreased percentage of CD56 + NK cells; and significantly increased percentage of CD16 + CD56- NK cells with weakened killing ability. PRMT5 and TIGIT may be closely related to the formation of CD16 + CD56- NK cells with weakened killing ability.© 2025. The Author(s).
AAV9-delivery of interleukin-37b gene prevents recurrent herpetic stromal keratitis via the SIGIRR pathway in miceWu, Liu, Wang
et alJ Control Release (2025) 381, 113600
Abstract: Ocular herpes simplex virus type I (HSV-1) infection can lead to herpes stromal keratitis (HSK), a condition that may recur throughout a person's life and often results in progressive corneal scarring, which ultimately causes visual impairment. Since existing antiviral agents are ineffective against recurrent HSK, we aimed to explore a strategy to prevent or control recurrent HSK. Adeno-associated virus (AAV) delivery system can transduce target genes into corneal epithelial cells and establish long-term stable gene expression, and providing a promising approach for the prevention and management of recurrent HSK. In this study, interleukin-37 (IL-37), an anti-inflammatory factor, is identified as a therapeutic agent for recurrent HSK via the SIGIRR pathway. AAV9-IL-37bΔ1-45 gene therapy prevents recurrent HSK in HSV-1 latently infected mice and alleviates corneal injury in mice with HSK. In conclusion, our present study establishes a strong foundation for the prevention of recurrent HSK through AAV9-IL-37bΔ1-45 gene therapy.Copyright © 2024. Published by Elsevier B.V.
Age-Related Integrative Transcriptomic Profiling of Human Granulosa Cells Reveals mRNA-microRNA Regulatory Network Associated with Key Ovulation DynamicsRogers, Gad, Cork
et alBiol Reprod (2025)
Abstract: Advanced maternal age (AMA) patients experience decreased success from assisted reproductive technologies (ART), attributed to the quantity and quality of oocytes, which is significantly influenced by the intrafollicular granulosa cells (GCs). In this study, we compared the mRNA and microRNA (miRNA) transcriptomes between young (< 32 y.o.) and AMA (> 38 y.o.) patients' GCs to identify potential ovarian aging-related molecular signatures. We identified 293 and 21 differentially expressed genes (DEGs) and miRNAs (DE miRNAs), respectively, between young and aged GCs. Highly expressed mitochondrial-encoded genes, MT-ND3, MT-ND6, and MT-CYB, were downregulated in aged GCs, indicating potential mitochondrial insufficiency. Additionally, pathway analysis indicates DEGs are involved in inflammation, cytokine signaling, extracellular matrix (ECM) remodeling, and angiogenesis. Key DEGs related to these processes include CXCL8, IL1B, NLRP3, SIGIRR, ANGPT2, ADAM8, and ADAMTS14. Additionally, target gene prediction and pathway analysis of DE miRNAs indicates their potential post-transcriptional regulation of genes associated with cell signaling, mitochondrial function, oxidative stress, apoptosis, and senescence pathways in addition to cytokine signaling, angiogenesis, and ECM remodeling. To investigate regulatory mechanisms further, we looked at the DEGs' convergence with the DE miRNAs predicted target genes and we identified miR-483-3p, miR-1268a, miR-4497, miR-7704, miR-135a-5p, miR-1261, and miR-4791 as potential crucial regulators of genes involved in pathways associated with inflammation, ECM, and angiogenesis. This data suggests that aged GCs have an impaired ability to elicit the same pro-inflammatory response combined with dysregulation of angiogenesis and ECM remodeling compared to young GCs, and miRNA may play a role in regulating key ovulatory processes. While this study identifies potential regulatory relationships between DE miRNAs and DEGs, experimental validation is necessary to confirm the relationships and biological relevance.© The Author(s) 2025. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
NEK4: prediction of available drug targets and common genetic linkages in bipolar disorder and major depressive disorderGong, Xiao, Feng
et alFront Psychiatry (2025) 16, 1414015
Abstract: Bipolar disorder (BD) is a mental illness characterized by alternating episodes of elevated mood and depression, while major depressive disorder (MDD) is a debilitating condition that ranks second globally in terms of disease burden. Pharmacotherapy plays a crucial role in managing both BD and MDD. We investigated the genetic differences in populations of individuals with MDD and BD, and from a genetic perspective, we offered new insights into potential drug targets. This will provide clues to potential drug targets.This study employed genome-wide association studies (GWAS) and summary-data-based Mendelian randomization (SMR) methods to investigate the genetic underpinnings of patients with bipolar disorder (BD) and major depressive disorder (MDD) and to predict potential drug target genes. Genetic variants associated with BD and MDD were identified through large-scale GWAS datasets. For BD, the study utilized a comprehensive meta-analysis comprising 57 BD cohorts from Europe, North America, and Australia, including 41,917 BD cases and 371,549 controls of European ancestry. This dataset included both type 1 and type 2 BD cases diagnosed based on DSM-IV, ICD-9, or ICD-10 criteria through standardized assessments. For MDD, we used data from a meta-analysis by Howard DM et al., which integrated the largest GWAS studies of MDD, totaling 246,363 cases and 561,190 controls. The SMR approach, combined with expression quantitative trait loci (eQTL) data, was then applied to assess causal associations between these genetic variants and gene expression, aiming to identify genetic markers and potential drug targets associated with BD and MDD. Furthermore, two-sample Mendelian randomization (TSMR) analyses were performed to explore causal links between protein quantitative trait loci (pQTL) and these disorders.The SMR analysis revealed 41 druggable genes associated with BD, of which five genes appeared in both brain tissue and blood eQTL datasets and were significantly associated with BD risk. Furthermore, 45 druggable genes were found to be associated with MDD by SMR analysis, of which three genes appeared simultaneously in both datasets and were significantly associated with MDD risk. NEK4, a common drug candidate gene for BD and MDD, was also significantly associated with a high risk of both diseases and may help differentiate between type 1 and type 2 BD. Specifically, NEK4 showed a strong association with BD (β brain=0.126, P FDR=0.001; βblood=1.158, P FDR=0.003) and MDD (β brain=0.0316, P FDR=0.022; βblood=0.254, P FDR=0.045). Additionally, NEK4 was notably linked to BD type 1 (βbrain=0.123, P FDR=2.97E-05; βblood=1.018, P FDR=0.002), but showed no significant association with BD type 2.Moreover, TSMR analysis identified four proteins (BMP1, F9, ITIH3, and SIGIRR) affecting the risk of BD, and PSMB4 affecting the risk of MDD.Our study identified NEK4 as a key gene linked to both bipolar disorder (BD) and major depressive disorder (MDD), suggesting its potential as a drug target and a biomarker for differentiating BD subtypes. Using GWAS, SMR, and TSMR approaches, we revealed multiple druggable genes and protein associations with BD and MDD risk, providing new insights into the genetic basis of these disorders. These findings offer promising directions for precision medicine and novel therapeutic strategies in mental health treatment.Copyright © 2025 Gong, Xiao, Feng and Shen.
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