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Ageing, a leading cause of the decline/deficits in human learning, memory, and cognitive abilities, is a major risk factor for age-associated neurodegenerative disorders such as Alzheimer’s disease. Emerging evidence suggests that epigenetics, an inheritable but reversible biochemical process, plays a crucial role in the pathogenesis of age-related neurological disorders. DNA methylation, the best-known epigenetic mark, has attracted most attention in this regard. DNA methyltransferases (DNMTs) are key enzymes in mediating the DNA methylation process, by which a methyl group is transferred, faithfully or anew, to genomic DNA sequences. Biologically, DNMTs are important for gene imprinting. Accumulating evidence suggests that DNMTs not only play critical roles, including gene imprinting and transcription regulation, in early development stages of the central nervous system (CNS), but also are indispensable in adult learning, memory, and cognition. Therefore, the impact of DNMTs and DNA methylation on age-associated cognitive functions and neurodegenerative diseases has emerged as a pivotal topic in the field. In this review, the effects of each DNMT on CNS development and healthy and pathological ageing are discussed.

Alzheimer’s disease (AD) is a disease characterized by insidious and progressive neurodegeneration, with clinical syndromes of memory and visuospatial skills damage. The pathogenic mechanism of AD is complex in which neural inflammation and neuron death play important roles. Pyroptosis, an inflammatory programmed cell death, has been reported to be involved in neuron death. Pyroptosis is executed by the protein family of gasdermins which punch pores on plasma membrane when activated by the upstream signals including the activation of NLRP3 and caspases, and subsequently triggers the inflammatory cascades featured by the release of interleukin (IL) -1β and IL-18. Herein, we summarized the current research on the roles of neuron pyroptosis in AD, aiming to provide a comprehensive view of the molecular mechanisms underlying AD pathogenesis and potential therapeutic targets for AD.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, with limited treatment options and high recurrence rates. Prognostic biomarkers and predictors of immune checkpoint inhibitor (ICI) response are urgently needed. This study aimed to develop a macrophage-related gene signature to predict patient outcomes and ICI efficacy, with a focus on the functional role of PLAUR. Single-cell RNA sequencing of paired HCC and normal liver tissues was used to identify macrophage subtypes. A prognostic gene signature was constructed based on macrophage-related genes and validated using the TCGA-LIHC cohort. TIDE analysis was performed to assess ICI response prediction. PLAUR-related cell communication was evaluated using CellChat. Functional assays were conducted to assess the effect of PLAUR knockdown on macrophage polarization, tumor cell behavior, and PI3K/AKT/mTOR pathway activity. Tissue microarray immunofluorescence validated PLAUR expression in situ. An eight-gene macrophage-related signature showed strong prognostic and predictive value. High-risk patients had poorer survival and reduced ICI responsiveness. PLAUR was overexpressed in tumor-associated macrophages and correlated with enhanced cell communication in tumors. Knockdown of PLAUR inhibited M2 polarization, reduced tumor cell proliferation and migration, and suppressed PI3K/AKT/mTOR signaling. In vivo, PLAUR silencing significantly reduced tumor growth in a THP-1/SKHep1 co-injection model. We identified a novel macrophage-related gene signature with clinical utility in HCC. PLAUR promotes immunosuppressive polarization and tumor progression via the PI3K/AKT/mTOR pathway, representing a potential therapeutic target and biomarker for immunotherapy response.

Sepsis is associated with immune dysregulated and organ dysfunction due to severe infection. Clinicians aim to restore organ function, rather than prevent diseases that are prone to sepsis, resulting in high mortality and a heavy public health burden. Some chronic diseases can induce sepsis through inflammation cascade reaction and Cytokine Storm (CS). Interleukin (IL)-6, the core of CS, and its related signaling pathways have been considered as contributors to sepsis. Therefore, it is important to study the relationship between IL-6 and its related pathways in sepsis-related chronic diseases. This review generalized the mechanism of sepsis-related chronic diseases via IL-6 related pathways with the purpose to take rational management for these diseases. IL-6 related signaling pathways were sought in Kyoto Encyclopedia of Genes and Genomes (KEGG), and retrieved protein-protein interaction in the Search for Interaction Genes tool (STRING). In PubMed and Google Scholar, the studies were searched out, which correlating to IL-6 related pathways and associating with the pathological process of sepsis. Focused on the interactions of sepsis and IL-6 related pathways, some chronic diseases have been studied for association with sepsis, containing insulin resistance, Alcoholic liver disease (ALD), Alzheimer disease (AD), and atherosclerosis. This article summarized the inflammatory mechanisms of IL-6 cross-talked with other mediators of some chronic diseases in vitro, animal models, and human experiments, leading to the activation of pathways and accelerating the progression of sepsis. The clinicians should be highlight to this kind of diseases and more clinical trials are needed to provide more reliable theoretical basis for health policy formulation.

Background Clear cell renal cell carcinoma (ccRCC) frequently exhibits transcriptional reprogramming driven by oncogenic C-Myc. Fibrillarin (FBL), a nucleolar C-Myc target, is markedly upregulated in ccRCC, correlating with poor prognosis and essential for tumor cell survival. Methods Integrated single-cell RNA sequencing, bulk transcriptomics, and proteomics were used to identify FBL as a key target. Functional assays, immunoprecipitation–mass spectrometry, and molecular docking were performed to investigate FBL's oncogenic mechanisms and interaction with TRIM21. Results FBL promotes ccRCC cell proliferation, migration, and tumor growth via PI3K/AKT pathway activation. TRIM21 was identified as a novel FBL-binding E3 ubiquitin ligase that catalyzes K48-linked polyubiquitination of FBL at lysine 292, accelerating its proteasomal degradation. TRIM21 overexpression reduces FBL levels, inhibits PI3K/AKT signaling, and reverses FBL-induced oncogenic phenotypes. TRIM21 is downregulated in ccRCC tissues and associated with unfavorable prognosis. Conclusions The TRIM21–FBL axis regulates ccRCC progression by modulating PI3K/AKT signaling, providing mechanistic insight and potential therapeutic targets for ribosome biogenesis and oncogenic signaling.

The protein Talin1 encoded by the TLN1 gene is a focal adhesion-related protein that binds to various cytoskeletal proteins and plays an important role in cell adhesion and movement. Recent studies have shown that it is overexpressed in prostate cancer, liver cancer, and oral squamous cell carcinoma, and is closely related to tumor progression and metastasis. This study integrated bioinformatics and functional analysis to reveal the prognosis and potential functions of TLN1 in AML. The results showed that the expression level of TLN1 was abnormally increased in AML and localized in the cell membrane and cytoplasm, and TLN1 is a significant prognostic indicator of overall survival (OS). Enrichment analysis of related genes showed that TLN1 is related to neutrophil mediated immunity, neutrophil activation and may regulate important signal pathways in hematological tumors including tyrosine kinase receptor, FLT3 and PIK3/AKT. The PPI network shows that TLN1 and MYH9 may be involved in the process of AML tumors together with PIP5K1C, ROCK1, S100A4, MY01A and WAC . Immune infiltration analysis explains that TLN1 is associated with multiple immune cells and may be an important immune marker in AML. Furthermore, molecular biology experiments confirmed that TLN1 is related to the proliferation, differentiation and cycle of AML cells. Silencing TLN1 can inhibit the proliferation of AML cells and promote differentiation through the Talin1/P-AKT/CREB signaling pathway.

Myeloid-derived suppressor cells (MDSCs) possess immunosuppressive activities, which allow cancers to escape immune surveillance and become non-responsive to immune checkpoints blockade. Here we report hypoxia as a cause of MDSC accumulation. Using hepatocellular carcinoma (HCC) as a cancer model, we show that hypoxia, through stabilization of hypoxia-inducible factor-1 (HIF-1), induces ectoenzyme, ectonucleoside triphosphate diphosphohydrolase 2 (ENTPD2/CD39L1), in cancer cells, causing its overexpression in HCC clinical specimens. Overexpression of ENTPD2 is found as a poor prognostic indicator for HCC. Mechanistically, we demonstrate that ENTPD2 converts extracellular ATP to 5′-AMP, which prevents the differentiation of MDSCs and therefore promotes the maintenance of MDSCs. We further find that ENTPD2 inhibition is able to mitigate cancer growth and enhance the efficiency and efficacy of immune checkpoint inhibitors. Our data suggest that ENTPD2 may be a good prognostic marker and therapeutic target for cancer patients, especially those receiving immune therapy. Myeloid-derived suppressor cells (MDSCs) promote tumor immune escape. Here, the authors show that in hepatocellular carcinoma, hypoxia induces the expression of ENTPD2 on cancer cells leading to elevated extracellular 5′-AMP, which in turn promote the maintenance of MDSCs by preventing their differentiation.

Background Hepatocellular carcinoma (HCC) is the most common type of malignant liver tumor with poor prognosis. In this study, we investigated the expression of transforming growth factor beta regulator 4 (TBRG4) in HCC and its effects on the proliferation, invasion, and metastasis of HCC cells, and analyzed the possible molecular mechanisms. Method Downloading the expression and clinical information of HCC samples in the TCGA database, analyzing the expression differences of TBRG4 by bioinformatics methods, analyzing the clinical relevance and prognostic significance. Performing GO, KEGG and GSEA enrichment analysis on the TBRG4-related gene set in patient HCC tissues. Applying cell counting, scratch test and Transwell experiment to study the biological function of TBRG4 in HCC. Mitochondrial membrane potential, apoptosis and ROS levels were evaluated to assess cell iron death. Western blot, RT-PCR, laser confocal microscopy and co-immunoprecipitation were used to detect and analyze the downstream signaling pathways and interacting molecules of TBRG4. Results Bioinformatics analysis revealed that TBRG4 was abnormally highly expressed in HCC tumor tissues and was associated with poor prognosis and metastasis in HCC patients. GO and KEGG functional enrichment analysis showed that TBRG4 was related to oxidative stress and NADH dehydrogenase (ubiquinone) activity. GSEA enrichment analysis showed that TBRG4 was associated with Beta catenin independent wnt signaling and B cell receptor. Functional experiments confirmed that knocking down TBRG4 could inhibit the proliferation, migration, and invasion of HCC cells. Mechanistically, TBRG4 inhibited the function of HCC cells through the DDX56/p-AKT/GSK3β signaling pathway. In addition, interference with TBRG4 expression could reduce the mitochondrial membrane potential and accumulate ROS in HCC cells, leading to increased ferroptosis. Co-IP analysis showed that TBRG4 specifically bound to Beclin1. Conclusion TBRG4 is highly expressed in HCC tumor tissues and is associated with poor prognosis. It may regulate the proliferation, invasion, and metastasis of HCC cells through the DDX56/p-AKT/GSK3β signaling pathway. TBRG4 may interact with Beclin1 to regulate the ferroptosis of HCC cells.

Spinal muscular atrophy (SMA) is the second most common fatal genetic disease in infancy. It is caused by deletion or intragenic pathogenic variants of the causative gene SMN1 , which degenerates anterior horn motor neurons and leads to progressive myasthenia and muscle atrophy. Early treatment improves motor function and prognosis in patients with SMA, but drugs are expensive and do not cure the disease. Therefore, carrier screening seems to be the most effective way to prevent SMA birth defects. In this study, we genetically analyzed 1400 samples using multiplex ligation-dependent probe amplification (MLPA) and quantitative polymerase chain reaction (qPCR), and compared the consistency of the results. We randomly selected 44 samples with consistent MLPA and qPCR results for comprehensive SMA analysis (CASMA) using a long-read sequencing (LRS)-based approach. CASMA results showed 100% consistency, visually and intuitively explained the inconsistency between exons 7 and 8 copy numbers detected by MLPA in 13 samples. A total of 16 samples showed inconsistent MLPA and qPCR results for SMN1 exon 7. CASMA was performed on all samples and the results were consistent with those of resampling for MLPA and qPCR detection. CASMA also detected an additional intragenic variant c.-39A>G in a sample with two copies of SMN1 (RT02). Finally, we detected 23 SMA carriers, with an estimated carrier rate of 1/61 in this cohort. In addition, CASMA identified the “2 + 0” carrier status of SMN1 and SMN2 in a family by analyzing the genotypes of only three samples (parents and one sibling). CASMA has great advantages over MLPA and qPCR assays, and could become a powerful technical support for large-scale screening of SMA.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a complex tumor ecosystem that contributes to its progression. Deubiquitinases (DUBs) are vital regulators in cancer. However, the overall activity of DUBs and their role in driving PDAC progression within immune microenvironment remain largely unknown. We employed an integrative multi-omics strategy combining machine learning (ML) on bulk transcriptomic data, single-cell RNA sequencing and spatial transcriptomic profiling. We applied Coxnet and Fuzzy SVM for prognostic modeling, inferCNV for malignant cell identification, SCENIC for transcription factor regulon analysis, LIANA for inferring inter-cellular communication networks and cell2location for spatial deconvolution. USP54 expression was detected by real-time quantitative PCR, western blotting and immunohistochemistry. USP54 function was validated through and assays. ML-based pathway analysis revealed post-translational modification as a major prognostic category, within which elevated DUBs activity emerged as an independent adverse prognostic factor. At the single-cell level, USP54 was upregulated along the trajectory of malignant ductal cells and correlated with an inflamed tumor microenvironment. Cell-cell communication analysis predicted signaling from monocytes/macrophages to tumor cells via the THBS1-integrin ligand-receptor pair. This immune-derived signaling potentially converged on KLF5-positive tumor cells, with KLF5 identified as a putative transcriptional activator of USP54. Spatial transcriptomics validated the co-localization of USP54 expression, elevated DUB activity, and KRAS signaling within specific tumor niches adjacent to THBS1-enriched immune regions. High USP54 expression was frequently observed in PDAC tissues and associated with poor patient survival. More importantly, in both BxPC-3 and PANC-1 cell lines, USP54 knockdown suppressed cell proliferation and metastasis, whereas its overexpression enhanced these malignant phenotypes. Subcutaneous xenograft growth and tail vein injection experiments validated these findings . Our comprehensive multi-omics analysis and experimental validation identify the deubiquitinase USP54 as a novel promoter of PDAC progression within a spatially organized tumor-immune microenvironment. These findings suggest USP54 as both a candidate prognostic biomarker and a potential therapeutic target for this lethal malignancy.