SEARCH · PubMed Health

Results for “Genes, p53”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed2025

Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.

PURPOSE: Germline pathogenic variants (PV) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC), but the underlying tumor biology of PDAC associated with germline PV in ATM has not been adequately explored. EXPERIMENTAL DESIGN: Whole-genome, whole-exome, and RNA sequencing were performed on PDAC tumors from 25 germline ATM PV carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy-number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated. RESULTS: High-quality whole-exome and whole-genome sequencing were obtained from 21 and 15 tumors, respectively. Biallelic inactivation of ATM was observed in 87%, KRAS PV in 90%, CDKN2A homozygous loss in 60%, and TP53 alterations in <10% of these tumors. A predominant clock-like mutational signature was present in all samples. Whole-transcriptome analysis identified that the aberrantly differentiated endocrine exocrine subtype accounted for 18% of PDAC and was consistently associated with >5-year overall survival. In addition, a 28-gene expression-based signature associated with overall survival was identified and further validated in The Cancer Genome Atlas cohort. Immune landscape analysis through CODEX identified enriched CD4 T-helper cell/tumor interactions and reduced B7H3-high cell/tumor interactions in ATM PV carriers compared with noncarriers. CONCLUSIONS: The observed absence of TP53 PV and enrichment for CDKN2A alterations in ATM tumors, along with differences in the mutational signatures, transcriptomic subtypes and immune landscape, improve our understanding of the mechanistic pathways involved in PDAC development in germline ATM PV carriers and help identify potential targeted therapeutic strategies.

Humans↗

PubMed2026

In silico analysis based on network pharmacology and biomolecular informatics to explore the mechanism of action of Erjing Pills (from Shengji Zonglu) in the treatment of leukotrichia.

This study aimed to explore the core active ingredients and potential molecular mechanisms of Erjing Pills, a prescription in the classic work of Traditional Chinese Medicine, "Shengji Zonglu," in the treatment of leukotrichia by utilizing network pharmacology and biomolecular docking techniques. The chemical components and potential targets of Chinese herbal medicines were analyzed through databases such as the Traditional Chinese Medicine Systems Pharmacology Database. The targets related to leukotrichia were collected using GeneCards. The intersection targets were obtained using RStudio. The protein-protein interaction (PPI) network map and the "drug-component-target-disease" visualization network were generated using Cytoscape and STRING to screen the core components and key targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were carried out using the Database for Annotation, Visualization and Integrated Discovery and RStudio. Finally, molecular docking verification was performed by AutoDock and PyMOL (Schrödinger LLC). The key active ingredients of Erjing Pills in the treatment of leukotrichia are β-sitosterol, quercetin, baicalein, and stigmasterol. The top 5 PPI core target proteins, in order, are AKT serine/threonine kinase 1, interleukin 6, tumor protein p53, cysteine-aspartic acid protease 3, and interleukin 1 beta. The Gene Ontology enrichment analysis suggests that the biological processes mainly include responses to exogenous stimuli, membrane rafts, and DNA-binding transcription factor binding. The Kyoto Encyclopedia of Genes and Genomes pathways involve signal pathways such as lipid and atherosclerosis, hepatitis B, Kaposi sarcoma virus infection, chemical carcinogenesis, and human cytomegalovirus infection. The molecular docking results indicate that most of the main active ingredients in Erjing Pills have relatively stable binding activities with the key targets, such as AKT serine/threonine kinase 1, interleukin 6, tumor protein p53, cysteine-aspartic acid protease 3, and interleukin 1 beta, in the PPI network. The active ingredients of Erjing Pills may interfere with the pathological process of leukotrichia by regulating key targets and signal pathways. This study provides a theoretical basis for the clinical application of Erjing Pills and indicates the direction for subsequent experimental research.

Drugs, Chinese Herbal↗

PubMed2025

Targeting FOXK2 in triple-negative breast cancer: Role of the P53/MCAS1/miR-211-5p regulatory axis.

Forkhead box K2 (FOXK2) is over-expressed in several human malignancies, yet how it is regulated triple-negative breast cancer (TNBC) remained unclear. We aimed to clarify whether FOXK2 drives TNBC progression, and elucidate the upstream molecular circuitry that controls FOXK2 abundance. FOXK2 mRNA and protein were quantified by qPCR and Western blot in 30 paired TNBC and adjacent tissues. Some assays assessed proliferation, migration and invasion after FOXK2 knockdown or overexpression. Bioinformatics predicted miR-211-5p targeting FOXK2 and lncRNA MCM3AP-AS1 (MCAS1) targeting miR-211-5p. RNA immunoprecipitation (RIP) and dual-luciferase assays validated these interactions. RNA pulldown, mass spectrometry and ChIP identified p53 binding to the MCAS1 promoter. FOXK2 was upregulated in TNBC tissues as opposed to the para-carcinoma tissues. FOXK2 silencing significantly reduced proliferation, migration and invasion, whereas overexpression accelerated these phenotypes. Mechanistically, MCAS1 acts as a sponge for miR-211-5p, ultimately protecting its target gene FOXK2 from degradation. Furthermore, employing RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays, our studies revealed a direct interaction between P53 and the promoter of MCAS1. This interaction resulted in the suppression of MCAS1 transcription. Clinical samples from TNBC patients further confirmed a correlation between FOXK2 expression and tumor size, lymphatic involvement, as well as the expression level of Ki-67. Our findings unveil a novel P53/MCAS1/miR-211-5p/FOXK2 regulatory axis that dictates TNBC aggressiveness. FOXK2 may sever as both a prognostic biomarker and a therapeutic target in TNBC.

Humans↗

PubMed2026

Interaction analysis of miRNA and mRNA reveals the regulatory mechanism of immune response in golden pompano (Trachinotus ovatus) spleen to Streptococcus iniae infection.

Streptococcus iniae is a major warm-water pathogen that cause high mortality and severe economic losses in golden pompano industry. In the present study, we performed the mRNA-miRNA integrated transcriptomic analysis of spleen of golden pompano challenged with S. iniae to explore the possible regulatory mechanism to bacterial infection. In total, we excavated 5072 DEGs, of which 2765 up-regulated and 2307 down-regulated genes. KEGG enrichment analysis indicated that the DEGs were primarily enriched in immune-related pathways, such as proteasome, cytokine-cytokine receptor interaction, p53 signaling pathway, lysosome, phagosome, Herpes simplex virus 1 infection. Additionally, a protein-protein interaction (PPI) network was constructed to extract hub genes. And the result showed that 4 hub genes, comprising cd4, il10, tnfsf2, myd88, may play vital roles in response to S. iniae infection. Furthermore, a total of 46 differentially expressed miRNAs (DEMs) were identified, containing 23 known and 23 novel DEMs. By integrating mRNA and miRNA joint analysis, we established a miRNA-mRNA regulatory network, including 12 miRNAs and 14 genes. Among them, novel-miR-357 were identified as a multi-target hub miRNA. These results provide important insights into the molecular regulatory mechanisms of immune response and inflammation processes in the defense of golden pompano against S. iniae infection.

Integrative interaction↗

PubMed2025

A Subset of Serous Tubal Intraepithelial Carcinoma (STIC)-Like Lesions and Concurrent High-Grade Endometrial Carcinoma Are Genomically Related Entities.

In patients with high-grade endometrial carcinoma (HG-EC), concurrent isolated serous tubal intraepithelial carcinoma (STIC) or STIC-like lesions (STIC-LLs) in the fallopian tube(s) may be found. We sought to determine whether concurrently diagnosed HG-ECs and STIC-LLs are genetically related. Six HG-ECs, including serous carcinomas (n = 4) and carcinosarcomas with serous epithelial component (n = 2), with cooccurring STIC-LLs were identified and subjected to microdissection, DNA extraction, and panel sequencing targeting 468 cancer-related genes or, if DNA quantities were limited, to Sanger sequencing. WT1 and p53 protein expression was assessed by immunohistochemistry. We found that 3 HG-ECs and concurrent STIC-LLs shared pathogenic mutations, such as TP53 hotspot, NF2, FBXW7, and PIK3CA mutations. Immunohistochemical analysis revealed that the HG-EC of case 5 lacked WT1 expression and had aberrant p53 expression, although the matched STIC-LL displayed diffuse WT1 expression. Of the remaining 3 cases that did not show evidence of genetic relatedness based on the targeted sequencing panel, 1 STIC-LL harbored a clonal TP53 missense mutation, whereas the matched HG-EC had a distinct clonal TP53 hotspot mutation, a clonal FBXW7 hotspot mutation, and ERBB2 amplification. At the protein level, the p53 expression patterns of the HG-ECs and STIC-LLs were concordant in these 3 cases. Here, we demonstrate that cooccurring HG-ECs and STIC-LLs are genetically related in a subset of cases.

Humans↗

PubMed2026

Virtual Tumors Enable Prediction of Personalized Therapeutic Combinations for Non-Small Cell Lung Cancer.

UNLABELLED: The disease burden from non-small cell lung cancer (NSCLC) adenocarcinoma is substantial, with a million new cases diagnosed globally each year and a 5-year survival rate of less than 20%. The lack of therapeutic options personalized to individual patients leads to high variation in survival. The combination of patient stratification with personalized treatment has the potential to improve outcomes; however, the variation in mutations found in patients with NSCLC adenocarcinoma makes experimentally determining treatment combinations time-consuming and expensive. In this study, we developed an interpretable mechanistic model to decipher complex signaling interplay and guide personalized therapy in NSCLC adenocarcinoma. This "virtual tumor" model encompassed key tumor-intrinsic oncogenic signaling pathways for efficiently predicting rational drug-drug and drug-radiotherapy combination therapies in NSCLC. Diverse genetic profiles were simulated for testing more than 10,000 therapeutic strategies to identify optimal approaches to overcome resistance mechanisms specific to genetic profiles and p53 status. The virtual tumor model reproduced drug additivity screens, predicted radiosensitizing genes validated in a CRISPR screen, and identified 53BP1 as a potential drug target that improved the therapeutic window during radiotherapy. A 19-gene signature derived from the virtual tumor framework stratified patients most likely to benefit from radiotherapy, which was validated using The Cancer Genome Atlas (TCGA) data. These results show the utility of virtual tumors to predict effective therapeutic combinations and present a computational resource for large-scale screening of personalized therapies to guide clinical decision-making in patients with NSCLC. SIGNIFICANCE: A computational framework that simulates thousands of personalized treatment strategies offers a scalable, cost-effective way to tailor therapies and improve outcomes for patients with genetically diverse NSCLC.

Humans↗

PubMed2025

USP2 reversed cisplatin resistance through p53-mediated ferroptosis in NSCLC.

BACKGROUND: It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance. METHODS: Ubiquitin-specific protease mRNA expression, was detected through RT-qPCR. In vitro functional assays assessed the effects of USP2 overexpression on DDP resistance, cell proliferation capability, and ferroptosis markers in A549/DDP and H1299/DDP cells. Ubiquitination assays evaluated the ubiquitination levels of p53 following USP2 overexpression. Co-immunoprecipitation (Co-IP) assays confirmed the binding relationship between USP2 and p53. In vivo experiments in mice explored the specific role of the USP2-p53 axis in a xenograft tumor model. RESULTS: USP2 expression was suppressed in cisplatin-resistant NSCLC cells. USP2 overexpression inhibited cell viability in cisplatin-resistant cells. Among the ferroptosis markers, the results showed that USP2 overexpression promoted LDH release, Fe2+ level, MDA and Lipid ROS, while inhibited GPX4 activity and GSH levels. The WB results revealed that USP2 overexpression inhibited GPX4, SLC7A11 and cytoplasm p53 protein expression, while promoted the nucleus p53 protein expression. Moreover, USP2 directly bound to p53 and USP2 overexpression stabilized p53 protein by suppressing its ubiquitination. In vivo experiments further suggest that the USP2-p53 pathway plays a crucial role in regulating cisplatin sensitivity in A549/DDP cells. CONCLUSION: USP2 acted on the K305R site of p53, which resulted in its deubiquitination. This cellular process could modulate cisplatin resistance through ferroptosis in NSCLC. This study could provide a potential therapeutic target to NSCLC.

Ferroptosis↗

PubMed1994

Description of a human papillary thyroid carcinoma cell line. Morphologic study and expression of tumoral markers.

BACKGROUND: The establishment of cell lines from thyroid carcinomas can provide an in vitro model of oncogenesis. B-CPAP is a new cell line that has been obtained from a differentiated papillary thyroid carcinoma. The data presented give a broader characterization and expression of tumoral markers of this cell line and identify the differentiated functions that are preserved. METHODS: An ultrastructural study was performed to confirm the thyroid nature of the new cell line. The cellular markers (thyroglobulin, S100, neuron-specific enolase [NSE]) and the oncogenes (mutated p53, H-ras, c-myc, PTC, trk) were studied by immunohistochemistry, Southern blot, or in situ hybridization. RESULTS: The cells were of a differentiated ultrastructural thyroid type. All of the cells proved immunoreactive with antibodies specific to thyroglobulin, S100 proteins, NSE, and mutant p53 protein. Mutations of H-ras, PTC, and trk were not observed. The c-myc gene was not amplified. CONCLUSIONS: The cell line described in these data provides a suitable model for the study of thyroid carcinogenesis, given that the cells present thyroid characteristics, and metabolic disorders not previously found in such cell lines. In addition, the coexpression of S100 proteins and mutant p53 proteins in the cells should permit the study of the interaction between these two proteins.

Aged↗

PubMed2025

Genome-wide association meta-regression identifies stem cell lineage orchestration as a key driver of acne risk.

Over 85% of the population experience acne at some point in their lives, with its severity spanning a quantitative spectrum, from mild, transient outbreaks to more persistent, severe forms of the condition. Moderate to severe disease poses a substantial global burden arising from both the physical and psychological impacts of this highly visible condition. The analytical approach taken in this study aimed to address the impact of variation in the dichotomisation of acne case control status, driven by ascertainment and study design, on effect size estimates across independent genetic association studies of acne. Through a fixed intercept meta-regression framework, we combined evidence genome-wide for association with acne across studies in which case-control status had been ascertained in different settings, allowing for different severity threshold definitions. Across a combined sample of 73,997 cases and 1,103,940 controls of European, South Asian and African American ancestry we identify genetic variation at 165 genomic loci that influence acne risk. There is evidence for both shared and ancestry specific components to the genetic susceptibility to acne and for sex differences in the magnitude of effect of risk alleles at three loci. We observe that common genetic variation explains 13.4% of acne heritability on the liability scale. Consistent with the hypothesis that genetic risk primarily operates at the level of individual pilosebaceous units, a polygenic score derived from this case-control study of acne susceptibility is associated with both self-reported and clinically assessed acne severity in adolescence, further strengthening the link between genetic risk and disease severity. Prioritisation of causal genes at the identified acne risk loci, provides genetic validation of the targets of established and emerging acne therapies, including retinoid treatments. The identified acne risk loci are enriched for genes encoding downstream effectors of RXRA signalling, including SOX9 and components of the WNT and p53 pathways. Illustrating that the control of stem cell lineage plasticity and cellular fate are important mechanisms through which genetic variation influences acne susceptibility within the pilosebaceous unit.

Journal Article↗

PubMed2026

Minimizing Off-Target Effects of CRISPR-Cas9 With Optimized sgRNA: Evaluation of Efficiency and Specificity in the Tumor Protein 53 (TP53) Region.

CRISPR-Cas9 is a widely used genetic tool with therapeutic potential in molecular biology. CRISPR-Cas9 enables precise genome editing by its ability to target specific DNA sequence. After off-target and on-target regions are identified, CRISPR-Cas9 is applied to these regions based on the match between the guide RNA (gRNA) and target DNA sequence. This study points to the off-target impact of mismatches between the gRNA and target DNA on exon regions of the TP53 gene, which are involved in regulating multiple genes and cellular functions. Off-target positions are typically evaluated using scoring methods. In this study, we have used latent class analysis to reveal subclasses of off-target positions. Thus, we have created the levels of off-target positions and evaluated the effects of mismatching positions within these classes using machine learning classifiers. The results revealed that mismatching positions could be categorized into three levels: low, middle, and high off-target positions. We have improved a computational framework to minimize off-target effects and to identify the PAM sequences in the gRNA design. Thus, carefully designed gRNAs will ensure that desired genetic edits are performed and target variants are achieved. This work will avail the future research aimed at optimizing genome editing by customizing CRISPR-Cas9 to target specific protospacer DNA through gRNA.

CRISPR-Cas Systems↗

PubMed2026

Regulation of the lncRNA NEAT1 by p53-ΔNp63 crosstalk modulates the DNA damage response and therapeutic efficacy in HNSCC.

Head and neck squamous cell carcinomas (HNSCCs) are characterized by recurrent genetic alterations, including the inactivation of the tumor suppressor TP53 gene and dysregulation of the TP63 gene. The TP63 gene encodes multiple isoforms, among which the N-terminal truncated isoform ΔNp63 is fundamental for the integrity of stratified epithelial tissues. We previously demonstrated that ΔNp63 represses the expression of the lncRNA NEAT1. Here, we investigated the functional crosstalk between p53 and ΔNp63 in modulating NEAT1 expression following genotoxic stress. We found that upon genotoxic insults, p53 activation and the concomitant downregulation of ΔNp63 promote NEAT1 transcription. In p53-proficient HNSCC cells, NEAT1 targeting leads to increased DNA damage, highlighting its potential role in maintaining genomic stability and facilitating efficient DNA repair. Importantly, we showed that histone deacetylase inhibitors (HDACis) upregulate NEAT1 expression independently of p53, and NEAT1 silencing enhances HDACis-induced DNA damage. Overall, our findings establish NEAT1 as an early regulator of the DNA damage response in HNSCCs and suggest that combining NEAT1 targeting with HDAC inhibition may potentiate therapeutic efficacy, particularly in TP53-mutant HNSCCs.

DNA damage↗

PubMed2026

Identification of putative causal associations between MicroRNAs and breast cancer via Mendelian randomization and bioinformatic analysis.

MicroRNAs (miRNAs) are implicated in breast cancer progression and prognosis. This study employed a Mendelian randomization (MR) framework to investigate causal relationships between plasma circulating miRNAs and breast cancer. miRNA expression quantitative trait loci were extracted from 2 independent cohorts. High-confidence miRNAs and their associated single-nucleotide polymorphisms were selected for 2-sample MR analyses using inverse-variance weighted and MR-Egger methods. Differential expression analysis and univariate Cox regression identified survival-associated genes in breast cancer, while enrichment analyses revealed pathways and biological processes linked to candidate targets. Pan-cancer analyses of miRNAs and targets were conducted via the ENCORI platform. Initial MR analyses in the discovery phase identified hsa-miR-100-5p, hsa-miR-125b-5p, and hsa-miR-339-5p as significantly associated with reduced breast cancer risk (P < .05), suggesting potential protective roles. A total of 1291 survival-associated differentially expressed genes were identified, with 39 overlapping targets implicated in miRNA-mediated breast cancer intervention. Enrichment analyses highlighted their involvement in cell cycle regulation and p53 signaling pathway. In the validation cohort, only hsa-miR-339-5p confirmed a protective effect on breast cancer risk, while hsa-miR-100-5p and hsa-miR-125b-5p did not reach significance. Pan-cancer profiling demonstrated aberrant miRNA expression across malignancies, prognostic relevance in multiple cancers, and significant negative correlations between miRNAs and target genes in breast tumors. Our findings provide novel insights into the causal roles of miRNAs in breast cancer pathogenesis and underscore their potential as noninvasive biomarkers and therapeutic targets. Future studies should prioritize functional validation and clinical translation of these miRNAs.

Humans↗

PubMed2026

Long-term heat exposure reshapes muscle molecular regulation and enhances thermal tolerance in Clarias fuscus.

Rapid fluctuations in water temperature driven by global warming have become a major abiotic stressor affecting muscle function in teleost fish. This study examined the effects of long-term thermal conditions on heat tolerance in Clarias fuscus. Fish were maintained for 90 days at either a normal temperature group (NT, 26 °C) or a high-temperature group (HT, 34 °C). Subsequently, muscle histology, and transcriptomic profiles were observed following acute high-temperature exposure (34 °C) and after temperature recovery (26 °C). Histological analysis showed that fish from the NT under acute high-temperature stress exhibited severe muscle damage (atrophy, myofilament disruption, and myolysis), whereas fish from the HT displayed markedly reduced lesions. RNA-seq profiling revealed 5769 differentially expressed genes (DEGs) in the NT and 3292 DEGs in the HT following acute temperature challenges. Functional enrichment indicated that, in the HT, modulation of key cell cycle regulators (e.g., ccna, ccnb, cdk1, cdk2) contributed to alleviating muscle damage caused by temperature fluctuations. In the NT, genes associated with ribosome biogenesis (e.g., nop56, riok2, riok1) were up-regulated and then down-regulated during temperature fluctuation, whereas p53 in the cell cycle pathway showed the opposite expression pattern. These findings demonstrate long-term heat exposure reshapes molecular expression and regulatory mechanisms in the muscle of C. fuscus, thereby enhancing thermal tolerance and adaptability, and providing a theoretical basis for breeding heat-resistant, high-quality aquaculture strains.

Animals↗

PubMed2024

L3MBTL1, a polycomb protein, promotes Osimertinib acquired resistance through epigenetic regulation of DNA damage response in lung adenocarcinoma.

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

Humans↗

PubMed2026

Noise-Induced Hepatic Stress Is Associated with Transglutaminase Activation and TG7 Upregulation in Rats.

OBJECTIVE: Environmental noise is increasingly recognized as a systemic stressor capable of inducing oxidative and inflammatory responses beyond the auditory system. This study aimed to investigate the effects of chronic noise exposure on transglutaminase (TG) activation, particularly TG7, and its association with hepatic stress responses in rat liver tissue. METHODS: Thirty adult male Wistar albino rats were randomly assigned to control, short-term noise exposure (LT1), and long-term noise exposure (LT2) groups. Gene expression of TG isoforms (TG1, TG2, TG3, TG6, and TG7), inflammatory markers (IL6 and TNF-α), and apoptotic markers (CASP3 and P53) was evaluated using quantitative real-time PCR. Total TG enzymatic activity was assessed colorimetrically. TG7 protein expression and localization were examined by immunohistochemistry and immunofluorescence. DNA integrity was evaluated by agarose gel electrophoresis. Biochemical parameters, including serum malondialdehyde (MDA), interleukin-1 beta (IL1β), cortisone, aspartate aminotransferase, alanine aminotransferase, glucose, insulin, and total cholesterol, were also measured. RESULTS: Noise exposure induced selective upregulation of TG isoforms, with TG7 showing the highest increase (∼10-12-fold). Total transglutaminase enzymatic activity was significantly increased in both noise-exposed groups, with a higher increase in LT1 (*** P < 0.001) and a significant increase in LT2 (** P < 0.01) compared with control, while no significant difference was observed between LT1 and LT2. IL6 and TNF-α increased progressively, particularly in LT2, whereas CASP3 expression was elevated in LT1 but reduced in LT2. DNA analysis revealed mild alterations in genomic integrity without clear internucleosomal fragmentation. TG7 protein showed strong localization within hepatocyte cytoplasm and perisinusoidal regions. Biochemical analysis demonstrated significant increases in MDA (up to 61.28%), IL1β, cortisone, liver enzymes, glucose, insulin, and total cholesterol. CONCLUSION: Chronic noise exposure induces early TG activation, particularly TG7, accompanied by sustained oxidative stress and inflammatory responses in liver tissue. These findings identify TG7 as a potential stress-responsive mediator in noise-induced hepatic injury.

Animals↗

PubMed2026

Methylation-Associated Differentiation Features Define Biological and Prognostic Heterogeneity in CMS4 Colorectal Cancer.

Consensus molecular subtype 4 (CMS4) colorectal cancer (CRC) is associated with an aggressive clinical course and poor survival, yet the biological basis of heterogeneity within this subtype remains incompletely understood. DNA methylation is an epigenetic mechanism involved in transcriptional regulation, cellular differentiation, and colorectal tumorigenesis. Here, we integrated single-cell RNA sequencing (scRNA-seq), bulk data, and promoter DNA methylation data to characterize CMS4-associated cancer cell states and methylation-related features. Using the scAB algorithm, we integrated scRNA-seq with bulk CMS4 data and identified CMS4-related cells distributed across multiple patients. Single-cell analyses of cell-cell communication and transcriptional regulation revealed a CMS4-related cancer cell population characterized by macrophage migration inhibitory factor (MIF)-centered intercellular communication, enhanced caudal type homeobox 1 (CDX1) and Kruppel-like factor 5 (KLF5) regulon activity, and gene modules enriched in differentiation-related pathways. CytoTRACE analysis further stratified CMS4 cancer cells into poorly and well-differentiated states, yielding 802 differentially expressed genes (DEGs). Linking these differentiation-associated DEGs with bulk expression and promoter methylation data identified 218 methylation-associated DEGs showing significant inverse methylation expression correlations, suggesting a link between differentiation-related heterogeneity and promoter methylation. Univariable Cox regression followed by LASSO regression further prioritized eight genes for construction of the methylation and differentiation-related prognostic model (MeDiff-PM). MeDiff-PM consistently stratified overall survival in the TCGA CMS4 cohort and two independent validation cohorts, with cutoff-independent continuous Cox analyses further supporting its prognostic association across cohorts. And MeDiff-PM remained prognostically significant after adjustment for available clinical variables. High MeDiff-PM risk scores were associated with activation of P53, WNT, and ubiquitin-mediated proteolysis pathways and with consistent predicted drug response differences for compounds across three CMS4 cohorts. While individual in silico knockout analysis suggested links between MeDiff-PM genes and metallothionein-related and immune-associated transcriptional responses. Collectively, these findings indicate that methylation-associated differentiation features represent a molecular dimension of intra-CMS4 heterogeneity and provide a biologically informed framework for prognostic stratification within CMS4 CRC.

Humans↗

PubMed2025

A tumorigenesis threshold for endogenous Myc revealed by dosage-compensation for Myc-haploinsufficiency in the absence of p53.

The MYC proto-oncogene is crucial for neoplasia in most tumors. Overexpressed, oncogenic MYC amplifies the flux through most major processes but does not specify a unique carcinogenic pathway. This "amplifier" model suggests that MYC must exceed an expression threshold to become oncogenic. We designed a genetic test of this model, using the mouse Trp53 null mutant (p53KO) as a highly robust tumor generator to examine the effect of a modest change in the endogenous Myc level (Myc +/-). Strikingly, tumor-free survival is greatly extended in p53KO mice with haploid Myc gene-dosage, yet in the tumors that do develop (mainly hemangiosarcomas and thymic lymphomas), their Myc deficit has been invariably compensated either by increasing Myc genomic dosage (hemangiosarcomas) or expression (lymphomas). Furthermore, acutely halving the endogenous Myc gene-dosage in established tumor allografts curtails growth rates. These results indicate that even an incremental reduction of MYC activity can be salutary in cancer and that one of the major tumor suppressor functions of p53 derives from its ability to prevent MYC overexpression. Myc generates acute DNA damage by several mechanisms and accordingly, p53's anti-Myc function may be inextricably linked to its role in genome integrity surveillance.

Myc haplo-insufficiency↗

PubMed2026

Diosmetin Inhibits Bladder Cancer through Suppression of the PI3K-AKT Signaling Pathway and Activation of the p53 Signal Pathway Revealed by Network Pharmacology and In Vitro Experimental Verification.

INTRODUCTION: Diosmetin, a naturally occurring flavonoid abundant in plants such as chrysanthemums, lemons, and oranges, has been reported to exhibit diverse antitumor properties. However, its potential efficacy against bladder cancer remains unexplored. This study aims to investigate the anti-bladder cancer effects of Diosmetin and elucidate the underlying mechanisms using network pharmacology combined with in vitro experiments. METHODS: Public databases were employed to identify shared targets between Diosmetin and bladder cancer. A Protein-Protein Interaction (PPI) network was constructed, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses to predict core targets and signaling pathways. The predicted mechanisms were subsequently validated through in vitro assays. RESULTS: A total of 48 common targets were identified. PPI network analysis revealed 22 hub genes, including AKT1 and MDM2. GO analysis indicated enrichment in 208 biological processes, 23 cellular components, and 38 molecular functions. KEGG analysis suggested that Diosmetin exerts anti-bladder cancer effects primarily through pathways such as Pathways in cancer, PI3K-AKT signaling, and Proteoglycans in cancer. Notably, the PI3K-AKT pathway showed the highest gene enrichment, indicating its potential prominence. In vitro experiments demonstrated that Diosmetin suppresses bladder cancer cell proliferation and induces apoptosis. Additionally, Diosmetin reduced the expression of p-PI3K, p-AKT, and MDM2, while upregulating p53 expression, suggesting involvement of both the PI3K-AKT and p53 pathways. DISCUSSION: These findings align with network pharmacology predictions and highlight the potential of Diosmetin as a multi-target agent against bladder cancer, warranting further in vivo investigation. CONCLUSION: Diosmetin inhibits bladder cancer cell proliferation and promotes apoptosis by suppressing the PI3K-AKT pathway and activating the p53 pathway.

Diosmetin↗