Comparative and Functional Genomics最新文献

The aim of this study is to compare the effects of different components of Buyang Huanwu Tang (BYHWT) on the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα)/ATP-binding cassette transporter A1 (ABCA1) pathway and its lipid-lowering effects. This study shows that the BYHWT alcohol precipitation and 75% alcohol components can significantly reduce the serum levels of triglycerides (TGs), low-density lipoprotein (LDL), cholesterol (CHO), and hepatic function damage indicators such as glutamic oxaloacetic transaminase (AST) and glutamic pyruvic transaminase (ALT) in hypercholesterolemia mouse model. After treatment, the presence of lipid droplets in liver cells was reduced, and the destruction of adipocytes was improved. The Western blot (WB) results showed that alcohol precipitation and 75% alcohol components can upregulate PPARγ, ABCA1, and LXRα. The expression of these components indicates that PPARγ upregulation can activate LXRα, thus regulating the expression of ABCA1, mediating CHO efflux, promoting reverse cholesterol transport (RCT), and regulating the downstream gene CYP7A1 to participate in bile acid synthesis and metabolism. In summary, the experimental results indicate that the BYHWT alcohol precipitation, 50% alcohol, and 75% alcohol components can modulate the PPARγ/LXRα/ABCA1 pathway in hypercholesterolemia mouse model to promote CHO metabolism.

This study explores the therapeutic potential of the cooling blood and detoxicating formula (CBDF) in the treatment of psoriasis, emphasizing its anti-inflammatory properties and its interaction with RHCG-related mechanisms. Psoriasis, a complex skin disorder characterized by abnormal keratinocyte proliferation and immune system dysregulation, remains challenging to treat effectively. Utilizing advanced techniques including network pharmacology, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics, this research identifies key active components in CBDF—quercetin and kaempferol—that influence critical inflammatory pathways. In experimental models, CBDF significantly alleviates psoriasis symptoms, reducing keratinocyte differentiation abnormalities and dendritic cell (DC) activation. Molecular docking studies demonstrate strong interactions between RHCG and the active ingredients in CBDF. These findings suggest that CBDF exerts its effects through a multifaceted approach, with RHCG identified as a pivotal target. While the results are promising, further clinical validation and mechanistic research are needed. This study underscores the potential of CBDF as a treatment for psoriasis, blending traditional medicine with modern molecular insights.

Background: Colorectal cancer (CRC) is acknowledged as the third leading cause of cancer-related mortality, attributed to its high incidence and fatality rates. Long noncoding RNAs (lncRNAs) have emerged as novel biomarkers for the treatment of colon adenocarcinoma. This study is aimed at investigating the function and underlying mechanisms of the lncRNA fetal-lethal noncoding developmental regulatory RNA (FENDRR) in regulating the malignant phenotype of CRC (COAD) cells.

Methods: This investigation examined FENDRR expression patterns and their association with clinical outcomes in 496 COAD and 173 READ patients from The Cancer Genome Atlas (TCGA) dataset. Additionally, 10 clinical COAD specimens were collected to validate FENDRR expression levels. Using lentiviral-mediated gene delivery, we stably upregulated FENDRR in HCT-116 cells, with transcriptional changes quantified via qPCR. The tumor biological behavior was evaluated using in vitro experiments, including CCK-8, colony formation, wound healing, transwell assays, and immunofluorescence staining. Protein-level alterations were subsequently confirmed by Western blot.

Results: Through bioinformatics evaluation, a notable decrease in FENDRR expression levels was observed in both COAD and READ tissues, with a pronounced link between FENDRR expression and tumor T stage classification in COAD cases. Patients exhibiting diminished FENDRR expression showed worse clinical outcomes in COAD. Enrichment analysis demonstrated significant associations between FENDRR and various signaling cascades, particularly the cAMP pathway. Additionally, immune cell infiltration analysis showed a significant association with FENDRR expression levels. In vitro experiments confirmed that FENDRR overexpression hindered the proliferation, migration, and invasion of cells. Mechanistically, FENDRR has been demonstrated to induce the sinking of the DUSP4/CREB/PRKACB signaling pathway and reverse the epithelial–mesenchymal transition (EMT) pathway, thereby inhibiting tumor growth.

Conclusion: We establish FENDRR as a tumor-suppressing gene that plays a significant role in suppressing the advancement and metastatic spread of COAD. These findings underscore its diagnostic and prognostic utility in COAD.

Ketosis is a metabolic condition characterized by a shift in energy metabolism, occurring when glucose availability is depleted and fat becomes the alternative primary energy source, resulting in the accumulation of ketone bodies. In dairy cattle, ketosis represents a significant challenge, adversely affecting both animal health and farm productivity. The genetic basis of ketosis in cattle has attracted increasing attention, with genome-wide association studies (GWAS) emerging as a crucial method for identifying relevant genetic factors. This study was aimed at investigating genome-wide regions associated with beta-hydroxybutyrate (BHB) concentrations in Holstein–Friesian cows’ blood before calving in the United Kingdom. BHB measurement data from 253 previously genotyped cows were used in the analyses. The results revealed five significant SNPs on Chromosome 15 (BTA15) and one significant SNP on BTA5 (p < 1.60e − 6). Notably, the SNPs on BTA15 clustered within a genomic region enriched with genes implicated in lipid metabolism and energy balance, highlighting its potential role in ketosis susceptibility. These preliminary findings refine the genetic architecture of ketosis and offer new avenues for improving dairy cattle health and welfare through targeted genetic selection programs while highlighting the need for validation in larger and independent populations.

Background: Autoimmune diseases exhibit familial clustering and co-occurrence, suggesting the presence of shared genetic risk factors. However, the overlapping genetic factors across these diseases have yet to be fully elucidated. This study aimed to identify shared genetic factors across five autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), Sjögren’s syndrome (SS), and polymyalgia rheumatica (PMR).

Methods: A blood tissue–based transcriptome-wide association study (TWAS) was conducted to identify candidate genes. Bayesian colocalization analysis was employed to pinpoint genetic variants shared across diseases. Multiomics summary data–based Mendelian randomization (SMR) was used to identify causal risk genes, while transcriptomic analysis, gene set variation analysis (GSVA), and weighted gene coexpression network analysis (WGCNA) were applied to further investigate the functional roles of these genes.

Results: The TWAS identified 78 candidate genes across the five autoimmune diseases. Bayesian colocalization analysis revealed five genes, GTF2H4, FLOT1, HCP5, IER3, and STK19, that share genetic variants across these disorders. Specifically, RA and AS shared independent variants of GTF2H4 (rs2230365 and rs147708689, respectively). HCP5 variants were shared with SS (rs1800628) and SLE (rs1150757), and rs1800628 was also identified as a shared locus in FLOT1 for SLE. SMR analysis highlighted FLOT1 as a strong causal risk gene for SLE. Transcriptomic analysis showed that FLOT1 is highly expressed in T cells and platelets, with involvement in multiple metabolic pathways. WGCNA identified four key neighboring genes, EHD1, SLC10A3, LMNA, and STXBP2, associated with FLOT1.

Conclusion: This study uncovers shared genetic factors across five autoimmune diseases, with FLOT1 identified as a novel causal risk gene for SLE. These findings suggest that platelet-mediated pathogenic mechanisms may contribute to SLE, providing a potential target for future therapeutic interventions.

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease primarily affecting the joints. The endocannabinoid system plays a crucial role in maintaining immune balance by regulating immune functions. Variations in the CB2 receptor gene (CNR2) can disrupt intracellular signaling, impairing the regulatory functions of endocannabinoids. This dysfunction is associated with an imbalanced immune response and an increased risk of autoimmune inflammatory disorders. This study investigates, for the first time in an Iranian population, the association between the Q63R polymorphism in the CNR2 gene and RA.

Methods: A total of 120 RA patients and 120 healthy controls were genotyped using the TaqMan assay. Demographic and clinical data, including gender, age, and ethnicity, were collected through questionnaires. The codominant, dominant, recessive, overdominant, and additive inheritance models were analyzed using SNPStats software.

Results: Logistic regression analysis revealed significant associations under the codominant, dominant, and additive inheritance models, with RR genotype carriers exhibiting more than a 2.5-fold increased risk of developing RA.

Conclusion: The findings of this study suggest a potential role of the CNR2 gene in RA susceptibility among Iranian patients. However, further large-scale studies are required to better understand the contribution of the CB2 receptor to disease susceptibility and its potential clinical applications as a biomarker for diagnosis and therapeutic interventions.

Background: CD8⁺ T cells play pivotal roles in antitumor immunity, where infiltration levels often correlate with favorable prognosis. However, the functional heterogeneity of CD8⁺ T cell subsets within the gastric cancer (GC) tumor microenvironment (TME)—particularly their divergent impacts on tumor progression, immunotherapy response, and clinical outcomes—remains poorly characterized.

Methods: We integrated single-cell RNA sequencing (scRNA-seq) data from 23 GC tissues (GEO: GSE150290) with bulk transcriptomic profiles from TCGA-STAD to dissect CD8⁺ T cell heterogeneity. Analytical pipelines included unsupervised clustering, pseudotime trajectory analysis, and protein–protein interaction (PPI) network construction to identify survival-associated hub genes. Differential gene expression, functional enrichment, and experimental validation were performed to confirm clinical relevance.

Results: scRNA-seq resolved CD8⁺ T cells into five functionally distinct subsets: naïve/memory, exhausted, and three cytotoxic subpopulations. Among these, cytotoxic CD8⁺ T1 cells exhibited the strongest prognostic relevance, with high infiltration correlating to improved survival and enrichment in G2-grade tumors. Pseudotime analysis revealed differentiation trajectories from naïve to exhausted subsets, accompanied by metabolic and immune checkpoint pathway alterations. PPI network analysis identified SELL, CD79B, and RAMP2 as hub genes, all significantly linked to survival and differentially expressed across tumor grades/stages. Experimental validation confirmed that SELL, CD79B, and RAMP2 knockdown suppressed GC cell proliferation, underscoring their functional roles.

Conclusion: Our study unveils the landscape of CD8⁺ T cell heterogeneity in GC and proposes a three-gene signature (SELL/CD79B/RAMP2) with dual prognostic and therapeutic potential. These findings provide actionable insights for stratifying patients, tailoring immunotherapy regimens, and developing novel targets to enhance antitumor immunity in GC.

Aims: The aim of this study was to systematically analyze the role of Brucea javanica in the treatment of cervical cancer (CC) and its underlying mechanisms by means of network pharmacology and molecular docking.

Background:Brucea javanica is a traditional Chinese herbal medicine used for the treatment of malaria and cancers, but its mechanism of action in CC is unknown.

Objective: The objective of the study is screening of active chemical constituents of Brucea javanica by Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and investigating their potential targets involved in CC therapy.

Methods: The GeneCards database was used for the disease targets of CC, the drug–compound–disease target network was constructed by using the Cytoscape 3.8.0 software. Then, the key targets in the protein–protein interaction (PPI) network were identified, and the “clusterProfiler” was used for the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The qRT-PCR, CCK-8, and flow cytometry were used to assess the expression levels of specific target genes in CC cells, as well as their effects on cell proliferation, apoptosis, and reactive oxygen species (ROS) levels, respectively. Protein–compound complex analysis was performed using molecular dynamics simulation.

Results: A total of 15 active compounds and their 86 treatment targets were obtained from the Brucea javanica analysis, in which 51 target genes were associated with the CC-related disease targets. Then, a PPI analysis identified 12 key genes (including EGFR, TP53, BCL2, AKT1, JUN, TNF, CASP3, IL6, MMP9, ERBB2, CCND1, and PTGS2) that were related to oxidative stress, PI3K-Akt, IL-17, p53, and JAK-STAT pathways, inflammatory response, and apoptosis pathways. In addition, AKT1 showed upregulation at the mRNA level in SiHa cells, and the knockdown of AKT1 significantly reduced the proliferation of CC cells and increased apoptosis and ROS levels. Molecular docking and dynamics simulations revealed a close binding between the active compounds and targets.

Conclusions: The present research comprehensively examined the active compounds, potential targets, and pathways of Brucea javanica in CC treatment, providing a novel insight for CC treatment.

This study investigates the promoter region and regulatory elements of chicken insulin-like growth factor (IGF) and vasoactive intestinal polypeptide (VIP) genes associated with reproductive traits. Several in silico tools, such as Neural Network Promoter Prediction (NNPP), Multiple Expectation maximizations for Motif Elicitation (MEME-Suite), GC-Profiles, microsatellite prediction (MISA-web), CLC Genomics, Multiple Association Network Integration Algorithm (GeneMANIA), and Gene Ontology for Motifs (GOMO), were used to characterize the promoter regions and regulatory elements of IGF and VIP genes. The in silico analysis showed that the highest promoter prediction scores (1.0) for TSS were obtained for three gene sequences (IGFP4, VIP, and VIPR1), while the lowest promoter prediction score (0.8) was obtained for IGF1. The present analysis revealed that the best common motif, Motif II, resembles three major transcription factor families: zinc finger family, homeobox transcription factor family, and high-mobility group factor family, accounting for about 79.17%. This study found that 62.5% of the candidate transcription factors have interaction with the Wnt signalling pathway to regulate transcription. Key regulatory elements identified in this study, such as CPEB1, MAFB, SOX15, TCF7L2, TCF3, and TCF7, play critical roles in activating and repressing transcription, with significant implications for embryonic and nervous system development. In the current study, very rich CpG islands were identified in the gene body and promoter regions of IGF and VIP genes. Generally, in silico analysis of gene promoter regions and regulatory elements in IGF and VIP genes can be helpful for comprehending regulatory networks and gene expression patterns in promoter regions, which will guide new experimental studies in gene expression assays.

Background: Glioblastoma (GBM) represents an aggressive malignancy in the central nervous system, with a poor prognosis. Despite ongoing research efforts, there is still a lack of effective treatments, leading to the need for new therapeutic targets. Collagen plays a crucial role in the extracellular matrix and can impact the progression of cancer. Yet the potential involvement of COL22A1 (Collagen Type XXII Alpha 1 chain) in GBM has not been investigated.

Materials and Methods: The expression of COL22A1 was evaluated in both clinical GBM samples and the Gene Expression Profiling Interactive Analysis (GEPIA) database. Following COL22A1 knockdown in GBM cells, functional assays were conducted to assess proliferation, migration, and invasion. The influence of COL22A1 on oncogenic signaling pathways was analyzed through luciferase reporter assays and interventions with pharmacological agents. In vivo experiments were performed using a nude mouse xenograft model.

Results: COL22A1 expression was significantly higher in GBM tissues and was linked with a poor prognosis. Silencing COL22A1 suppressed proliferation, migration, and invasion of GBM cells and impeded tumorigenesis in vivo. On a mechanistic level, COL22A1 impacted the PI3K/AKT signaling cascade, demonstrated by decreased FOXO transcriptional activity and lower levels of phosphorylated PI3K (p-PI3K) and phosphorylated AKT (p-AKT). Furthermore, stimulating the PI3K/AKT pathway partially mitigated the impact of COL22A1 silencing.

Conclusion: COL22A1 plays a crucial role in dictating the malignancy of GBM through regulating the PI3K/AKT signaling pathway. Targeting COL22A1 could present a novel approach for GBM management.