Genes & genomics最新文献

Background: Intracerebral hemorrhage (ICH) is a primary non-traumatic parenchymal hemorrhage of the brain with a high mortality and disability rate. Acupuncture has been proved to alleviate neurological deficits after ICH.

Objective: Our previous study found that UBL4A is up-regulated in the ICH rat treated with acupuncture, and may be a potential molecular target for acupuncture treatment of ICH. However, the molecular mechanism behind UBL4A is unclear.

Methods: UBL4A knockdown was conducted in ICH rats with acupuncture treatment to explore its role in the therapeutic effects of acupuncture on ICH. In vitro, the effects of UBL4A on heme-induced neuronal injury were evaluated using E18 rat embryonic primary cortical neurons. Proteomic experiments were used to verify the regulatory relationship between UBL4A and MAPK14.

Results: UBL4A knockdown has opposite effects to the therapeutic effects of acupuncture on ICH, including increasing corner turn score, brain water content and the number of degenerated and apoptotic neuron in ICH rats. UBL4A knockdown increased the level of ROS, OPA1-S/L, p-MAPK14 and mitochondrial Drp1, and decreased mitochondrial membrane potential, ATP level and MFN2 level in rat brain tissue. In vitro, UBL4A overexpression reduced ROS level and mitochondrial membrane potential and inhibited the activation of the MAPK14/Drp1 signaling pathway. Co-IP verified the binding of UBL4A and MAPK14, and MAPK14 overexpression reversed the effect of UBL4A on hemin-induced neuronal apoptosis and ROS level.

Conclusion: Our study confirms that UBL4A is involved in the therapeutic effect of acupuncture on ICH, and affects mitochondrial damage and oxidative stress through MAPK14 ubiquitination.

Background: Bladder cancer (BCa) is the most frequently seen malignancy of the urinary tract. However, its molecular mechanisms and therapeutic targets are not well established.

Objective: This study aims to investigate the mechanism by which tissue specific transplantation antigen P35B (TSTA3) mediates the suppression of epithelial-mesenchymal transition (EMT) in BCa through targeted regulation of lysosome-associated membrane protein 2 (LAMP2) expression via the mitogen-activated protein kinase (MAPK) signaling pathway.

Methods: Public datasets were analyzed to predict TSTA3 expression and prognosis in BCa. TSTA3 and LAMP2 expression levels were examined in 30 paired BCa and adjacent normal tissues, followed by Pearson correlation analysis of their mRNA levels. TSTA3 expression was quantified in T24, BIU-87 and simian virus 40-immortalized human urothelial cell line-1 (SV-HUC-1). T24 and BIU-87 cells were subjected to TSTA3 knockdown or overexpression. Cell proliferation, migration/invasion (Transwell), apoptosis (flow cytometry), EMT markers (immunofluorescence), and LAMP2/MAPK pathway proteins were evaluated.

Results: TSTA3 upregulation was demonstrated in public databases, BCa patient tissues, and cell strains. TSTA3 knockdown in T24 cells substantially suppressed proliferation, colony formation, invasion, migration, and apoptosis while increasing E-cadherin and decreasing Vimentin expression, whereas TSTA3 overexpression in BIU-87 cells promoted malignant phenotypes. TSTA3 and LAMP2 mRNA levels showed a strongly negative correlation in BCa patients. LAMP2 knockdown reversed the tumor-suppressive effects of TSTA3 silencing. Inhibition of the MAPK pathway rescued the functional deterioration of T24 cells caused by TSTA3 overexpression.

Conclusions: TSTA3 promotes BCa proliferation, migration, invasion, and EMT by regulating LAMP2 to activate the MAPK pathway.

Background: Rhododendron possesses significant ornamental and economic value; however, its limited heat tolerance severely hinders its broader development and application. Heat shock transcription factors (Hsfs) are extensively involved in various abiotic stress responses and play essential roles in plant thermotolerance and other physiological processes.

Objective: To identify Hsf genes in the genome of Rhododendron molle (R. molle) and investigate their regulatory mechanisms underlying heat tolerance in R. molle.

Methods: The Hsf gene family was systematically identified using the genomic data of R. molle, and the expression levels of RmHsf genes under heat stress were analyzed through Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR).

Results: The RmHsf gene family consists of 25 members distributed across 12 chromosomes. Phylogenetic analysis demonstrated that the RmHsf genes are classified into three subfamilies: A, B and C. Most genes within the same subfamily share similar conserved motifs and gene structures. The cis-acting elements in the promoter regions of RmHsf genes are associated with plant hormone signaling and stress response pathways. Collinearity analysis revealed that the expansion of the RmHsf gene family primarily occurred through segmental and tandem duplication events. RT-qPCR results showed that RmHsfA2, RmHsfA3, RmHsfA7a, and RmHsfA7b were significantly upregulated under heat stress, suggesting that they may serve as key genes in the heat stress response of R. molle. Among them, RmHsfA2 and RmHsfA3 were notably induced by exogenous ethylene.

Conclusion: This study conducted a comprehensive genome-wide analysis of the Hsf gene family in R. molle, laying a solid foundation for functional validation of Hsf genes and the breeding of heat-tolerant cultivars.

Background: Acute myeloid leukemia (AML) is characterized by extensive immunometabolic rewiring that drives leukemic progression and fosters immune evasion.

Objective: This study investigates regulatory role of CD36 as an immunometabolic mediator in AML pathogenesis.

Methods: Integrated bulk transcriptomics, single-cell RNA sequencing, and in-vitro validation were performed. Macrophage co-localization was validated using colorectal cancer (CRC) spatial transcriptomics.

Results: CD36 was identified as a central hub in preserved immunometabolic modules, enriched for TLR signaling, lipid metabolism, antigen-presenting pathways, and cytokine-cytokine receptor interactions. Drug sensitivity analysis revealed that high CD36 expression showed greater sensitivity to venetoclax and GSK626616AC. CD36 drives AML immune cycle and revealed a strong association with AML functional states, including inflammation, differentiation, apoptosis, invasion, quiescence, and hypoxia. Single-cell analysis indicated CD36 upregulation in monocyte and macrophage clusters, facilitating ligand-receptor communication with T cells, which emphasizes CD36's role in shaping immune microenvironment. Spatial transcriptomics analysis of colorectal cancer confirmed a significant CD36-CD68 colocalization in macrophages. CD36 also influenced monocyte to macrophage differentiation in AML cells. CD36 deficiency significantly reduces AML cells' proliferation and leads to G0/G1 phase expansion, accompanied by E2F4/E2F5/RB1 modulation. Hallmark enrichment analysis unveiled that CD36-high expression leukemic cells, CD36 immune signatures, and monocytes/macrophages showed enrichment in key immune and inflammatory pathways, including TNFα/NF-κB, IL6/JAK/STAT3, and IL2/STAT5 signaling, mTORC1 activation, interferon alpha and gamma responses, and reactive oxygen species pathways.

Conclusion: Integration of transcriptomics and spatial validation revealed robust CD36-mediated immunometabolic signaling in AML, which further requires comprehensive in-vitro and in-vivo validation.

Background: Acute myocardial infarction (AMI) is a leading cause of mortality worldwide, with sterile inflammation and immune dysregulation driving cardiac injury. Itaconate, a mitochondria-derived immunometabolite synthesized by ACOD1, has emerged as a key regulator of myeloid cell function, exhibiting anti-inflammatory and metabolic effects. However, its role and downstream targets in sterile myocardial inflammation remain poorly understood.

Objective: This study aimed to systematically dissect the immunometabolic role of itaconate in AMI by identifying itaconate-responsive genes, uncovering their cell-type specificity and functional dynamics, and evaluating their diagnostic and therapeutic potential.

Methods: We established a novel systems-level framework that integrates bulk and single-cell/single-nucleus transcriptomics, network pharmacology, machine learning-based feature selection, and molecular docking. This multi-layered strategy was applied to human and murine datasets covering infarcted cardiac tissue and peripheral immune compartments to identify robust, itaconate-responsive immune targets in AMI.

Results: Single-cell data show that ACOD1 induction is disease-specific and characteristic of AMI. And we identified 36 itaconate-associated genes enriched in myeloid populations and dynamically regulated during infarction. Among them, MMP9, TLR2, and ANPEP were consistently prioritized by multiply machine learning algorithms, showed robust diagnostic performance across independent cohorts, and exhibited potential binding to itaconate in silico. Single-cell analyses confirmed spatial and temporal regulation of these targets in infarcted myocardium. Functional analyses revealed that 4-octyl-itaconate (4-OI) induced dose- and context-dependent transcriptional programs in myeloid cells, including NRF2 and ATF3 activation.

Conclusions: This study identifies a core immunometabolic program downstream of itaconate in myeloid cells and highlights MMP9, TLR2, and ANPEP as key effectors linking metabolic sensing to inflammation and tissue remodeling in AMI. Our integrative approach offers new insights into context-specific immunomodulation and supports the development of metabolite-guided therapeutic strategies for cardiovascular inflammation.