Search Results (3,928)

Background: Copper transporters (COPTs) are essential for maintaining copper homeostasis in plants, a process critical for growth, development, and stress adaptation. However, the soybean GmCOPT family remains poorly characterized. Methods: In this study, we performed a genome-wide identification of COPT genes in soybean (Glycine max), conducted phylogenetic, collinearity, and evolutionary analyses, predicted protein motifs, structures, and promoter cis-regulatory elements, and analyzed the expression profiles of the GmCOPT family. Results: We identified ten GmCOPT genes. Phylogenetic analysis of COPT proteins across five plant species revealed that soybean COPTs are more closely related to those from Medicago truncatula. Collinearity analysis suggested that segmental duplication is the primary driver of GmCOPT family expansion, and all duplicated gene pairs exhibited Ka/Ks ratios below 1, indicating purifying selection. Expression profiling revealed tissue-preferential patterns among GmCOPT genes. The presence of ABRE, MBS, and LTR cis-acting regulatory elements in the promoter regions of GmCOPTs suggests their potential involvement in abiotic stress responses. RT-qPCR validation demonstrated that GmCOPT genes responded differentially to salt stress in soybean roots and leaves, with some significantly repressed and others markedly induced. Notably, GmCOPT7 and GmCOPT8 were significantly induced in both tissues in response to salt stress. Conclusions: These findings suggest that GmCOPT genes have undergone duplication-driven expansion and functional diversification, with different expression patterns and salt-inducible responses. This work provides candidate genes for future functional investigations into the roles of GmCOPT genes in abiotic stress tolerance in soybean. Full article

In the filamentous fungus Trichoderma reesei, cellulase production is subject to carbon catabolite repression (CCR) mediated by the key repressors Cre1 and Ace1. In this study, we identified two previously unreported phosphorylation sites—S204 in Cre1 and S145 in Ace1—through phosphoproteomic profiling. Site-directed mutagenesis revealed that dephosphorylation-mimicking mutations (Cre1S204A and Ace1S145A) significantly relieved CCR and promoted cellulase biosynthesis, while phosphomimetic mutations exerted opposite effects. Notably, the Cre1S204A/Ace1S145A double mutant exhibited a combined enhancement in cellulase activity, achieving a 0.7-fold increase in pNPCase activity compared to the parental strain, along with substantially upregulated cellulase gene transcription and increased extracellular CBH1 accumulation. These results demonstrate that S204 and S145 are functionally relevant phosphorylation sites that negatively modulate cellulase production. Our findings provide novel engineering targets for strain improvement and, more broadly, open new avenues for investigating the phosphorylation-based regulatory mechanisms of Cre1 and Ace1 in future studies. From an applied perspective, the work offers a straightforward and effective genetic strategy for the rational design of high-performance fungal strains for lignocellulose bioconversion. Full article

Histone deacetylase inhibitors (HDACis) can enhance responses to DNA-damaging chemotherapy, but how they alter doxorubicin (DOX)-induced transcriptional programs remains incompletely understood. We investigated the effects of valproic acid (VPA) and vorinostat (SAHA) on DOX cytotoxicity and associated molecular responses in HepG2 cells. HDAC inhibition, cell viability, apoptosis, and DOX IC₅₀ values were assessed using histone H3 acetylation, cell counting, Alamar Blue assays, and cleaved caspase-3 immunofluorescence. Transcriptomic responses were analyzed by RNA sequencing, differential expression analysis, and Hallmark gene set enrichment analysis, with selected findings evaluated by RT-qPCR, Western blotting, and comparison with published CRISPR/Cas9 DOX-response data. Both HDAC inhibitors increased histone H3 acetylation and enhanced DOX cytotoxicity, markedly reducing DOX IC₅₀ values. VPA co-treatment also increased DOX-induced cleaved caspase-3 signaling. RNA-seq showed broad transcriptional remodeling, including depletion of the DNA-repair gene set following VPA treatment and attenuation of canonical p53-responsive genes during HDACi–DOX co-treatment. Several HDACi-repressed DNA-repair genes overlapped with genes whose loss sensitized cells to DOX in a published CRISPR screen. HDAC inhibition therefore enhances DOX cytotoxicity and is accompanied by alterations in DNA-repair-associated and p53-responsive transcriptional programs. Full article

The meiosis-specific cohesin α-kleisin subunits REC8 and RAD21L regulate higher-order chromatin organization and germline-specific transcription in male germ cells. Rad21l exhibits high, testis-specific expression in mice, but the epigenetic mechanisms governing its promoter activity and those underlying its chromatin targeting and anchoring remain unclear. To address these questions, we investigated Rad21l using dual-luciferase reporter assays, in vitro methylation, bisulfite sequencing, molecular docking, transcriptome sequencing, and co-immunoprecipitation. We identified a distal regulatory region and mapped the core promoter of Rad21l to the −228 to −3 bp region. We further demonstrated that methylation of the promoter CpG islands represses its transcription. Molecular docking simulations suggested that KLF4 could bind a promoter sequence containing CpG5 and that methylation would not disrupt this interaction. Methylation was hypothesized to induce conformational remodeling of KLF4, shift its ability to recruit cofactors, and thereby enable bidirectional transcriptional regulation. Co-immunoprecipitation confirmed the co-occurrence of α-kleisin proteins with the meiosis-specific histone H1t and histone H3, detected modified H3 forms including H3K9me1 and H3S10phos, and showed their association with HP1β. Histone modifications may regulate interaction affinity through long-range allosteric effects. This study proposes a working model for tissue-specific transcriptional regulation of Rad21l involving CpG methylation and KLF4 and establishes a hypothetical model of histone-dependent RAD21L chromatin anchoring, providing a basis for investigating male meiosis and identifying infertility-related targets. Full article

BCOR is a transcriptional corepressor and a core component of Polycomb repressive complex 1.1 (PRC1.1) with diverse roles in development and disease. Germline loss-of-function BCOR mutations cause oculofaciocardiodental syndrome, whereas diverse somatic alterations drive various malignancies. In myeloid neoplasms, loss-of-function truncating mutations disrupt BCOR-mediated transcriptional repression and cooperate with concurrent oncogenic events. Meanwhile, BCOR fusions and internal tandem duplications define distinct tumor entities in sarcomas and brain tumors. Growing evidence indicates that these somatic alterations are not mechanistically equivalent and that the functional impact of BCOR alterations is highly context-dependent, varying across cell types and developmental stages. How these distinct mutations disrupt molecular programs to drive oncogenesis remains a central question in the field. This review summarizes the current knowledge of BCOR domain organization, its epigenetic and physiological functions, and the emerging mutational landscape in human malignancies. Full article

Low-temperature (LT) storage effectively mitigates postharvest deterioration in longan fruit. To investigate the changes in sucrose metabolism underlying this effect, we compared the dynamic changes in sugar metabolism indicators under LT and room-temperature (RT) conditions. This sugar conversion was associated with the increased activities of acid invertase (AI), neutral invertase (NI), sucrose synthase (SS), fructokinase (FRK) and hexokinase (HXK) and the inhibited activity of sucrose phosphate synthase (SPS). Consistently, the transcription levels of DlAI, DlNI, DlSS, DlFRK and DlHXK were upregulated, while the transcriptional level of DlSPS was suppressed. In contrast, LT storage maintained higher sucrose levels with gradual declines in glucose and fructose. Meanwhile, the activities of AI, NI, SS, FRK and HXK were inhibited while SPS activity was promoted, accompanied by transcriptional downregulation of DlAI, DlNI, DlSS, DlSPS, and DlFRK. Pearson correlation and principal component analyses further revealed distinct sugar-metabolite networks between the two storage regimes. Collectively, LT storage preserves sucrose, coinciding with the transcriptional repression of catabolic pathways while maintaining biosynthetic capacity, which may contribute to restraining sugar depletion. These findings advance our understanding of LT-regulated sugar metabolism and offer theoretical support for optimizing postharvest cold-storage strategies. Full article

Lung cancer is among the most fatal malignancies worldwide, with approximately 85% of diagnosed cases being non-small-cell lung cancer (NSCLC). Despite the considerable progress in surgical, chemotherapeutic, radiotherapeutic, and immunological treatments, the prognosis of NSCLC remains poor due to late-stage diagnosis, molecular heterogeneity, treatment resistance, recurrence, and systemic toxicity. Therefore, there is an urgent need to develop more effective and less toxic therapies, and cancer nanotechnology has emerged as a promising approach. Selenium nanoparticles (SeNPs) are a viable option for lung cancer treatment because of their unique physicochemical and biochemical properties. They can be used for targeted drug delivery into cancer cells, as selenium possesses inherent anti-cancer properties, such as the induction of reactive oxygen species (ROS), mitochondrial disruption, DNA damage, cell-cycle arrest, and modulation of several signaling pathways, including PI3K/Akt, MAPK, NF-κβ, STAT3, and p53, leading to cancer cell death and repression of tumor progression. Green synthesis of SeNPs using plant-derived phytochemicals is a sustainable strategy as it allows for simultaneous reduction and stabilization of nanoparticles, with an additional therapeutic phytochemical effect against cancer. Various phytochemicals, such as flavonoids, polyphenols, terpenoids, and alkaloids, have the ability to chelate metal ions and act as reducing agents and stabilizers in the synthesis of SeNPs. The antioxidant, anti-inflammatory, anti-proliferative, and anti-metastatic activities of phytochemicals, along with their ability to inhibit the overexpressed enzymes, e.g., matrix metalloproteinases, in cancer cells, could provide an additional therapeutic benefit. However, the application of SeNPs in practice is limited by their low targeting ability, which results in poor bioavailability due to fast clearance from the bloodstream, reduced tumor accumulation, and poor cellular uptake. Conjugation of SeNPs with tumor-targeting peptides could enhance their delivery into the cancer cells. There is a variety of cell surface receptors that are overexpressed in lung cancer cells and can be used for targeted drug delivery. The most common receptors are EGFR, integrins, gastrin-releasing peptide receptor, neuropilin-1, and transferrin receptor. The ligands for these receptors, including the GE11 peptide for EGFR (epidermal growth factor receptor), RGD for integrins, bombesin for GRPR, and iRGD for neuropilin-1, could be used for targeting, as well as cell-penetrating peptides, such as TAT. This review discusses the current knowledge on the application of functionalized SeNPs for lung cancer treatment, specifically synthetic methods, physicochemical properties, mechanisms of action, and targeting strategies. Particular attention is paid to the combination of the anti-cancer effects of selenium and phytochemicals and their synergistic impact on tumor cell death. In addition, the challenges of the application of SeNPs for lung cancer treatment and possible future developments for functionalized SeNPs as novel therapeutic nanocarriers are discussed. Full article

Salidroside is a bioactive compound extracted from the traditional Chinese medicinal plant Rhodiola rosea that exerts differential regulatory effects on cell viability depending on cell type and physiological state. Sertoli cells are important testicular somatic cells that play multiple roles in nourishing, protecting, and supporting spermatogenic cells. Currently, the regulatory effects and underlying mechanisms of salidroside on Sertoli cells remain unclear. This study investigated the effects of different concentrations of salidroside on the viability and regulatory mechanisms of TM4 cells (mouse Sertoli cell line). The results showed that within the range of 25–600 μM, cell viability decreased with increasing salidroside concentration. Treatment with 600 μM salidroside inhibited proliferation, promoted apoptosis, and suppressed the expression of key genes related to Sertoli cell function. Transcriptome sequencing revealed that several glycolysis-related genes, including Ldha, Pfkl, Eno3, and Eno1b, were significantly downregulated in salidroside-treated cells, accompanied by marked reductions in key glycolytic metabolites, including fructose-1,6-diphosphate (FDP), pyruvate, lactic acid, and ATP. Notably, overexpression of lactate dehydrogenase A (Ldha) rescued cell viability and proliferation, suppressed apoptosis, elevated both intracellular and extracellular lactate and ATP levels, and partially restored functional gene expression in 600 μM salidroside-treated cells. Overall, this study provides hitherto undocumented evidence of the regulatory effects and mechanisms of salidroside on TM4 cells, identifying the Ldha–glycolytic axis as an in vitro cellular target of high-dose salidroside in Sertoli cells, which may inform future in vivo reproductive safety profiling pending pharmacokinetic validation. Full article

Drought is a major abiotic stress limiting rice (Oryza sativa L.) production, and identifying genes that balance drought resistance with growth is a priority for molecular breeding. We previously identified the MATE transporter OsMATE6 as a negative regulator of drought resistance in rice. Here, we characterized its closest paralog, OsMATE19. OsMATE19 was predominantly expressed in roots, guard cells, and vascular tissues, and the OsMATE19–eGFP fusion protein localized to the plasma membrane. Two independent osmate19 knockout lines showed reduced leaf water loss, elevated leaf surface temperature under dehydration, improved seedling survival after PEG (polyethylene glycol)-simulated and soil drought, and 32.0–41.1% higher grain yield than the wild type under field drought conditions, without a yield penalty under irrigation. The osmate6/osmate19 double mutant showed the strongest drought resistance but, unlike either single mutant, exhibited dwarfism and significant reductions in grain yield, tiller number, plant height, and panicle architecture under normal paddy conditions. Transcriptome analysis revealed coordinated upregulation of ABA (abscisic acid)- and stress-responsive genes and repression of growth- and metabolism-related genes, with the greatest changes in the double mutant. These results reveal a dosage-dependent trade-off: disruption of either gene alone enhances drought performance without yield cost, whereas simultaneous loss of both genes over-activates stress responses at the expense of growth. Our findings provide candidate gene targets and a genetic framework for balancing drought adaptation and productivity in rice breeding. Full article

WRKY transcription factors play crucial roles in plant growth, development, and stress responses. However, their systematic evolution and functions within the genus Rubus remain incompletely understood. In this study, genome-wide identification, evolutionary analysis and functional characterization of the WRKY gene family were conducted in five Rubus species. A total of 37–67 members were identified and classified into three groups by phylogenetic analysis. The collinearity result, gene family expansion and contraction analyses revealed a contraction trend within the Rubus lineage compared with the outgroup sweet cherry. Promoter cis-acting element analysis predicted widespread involvement of these genes in hormone and stress responses. Expression profiling revealed tissue-specific patterns among WRKY genes, with most members down-regulated during fruit development and differentially regulated by biotic and abiotic stresses. Further correlation analysis and experimental validation were focused on RiWRKY48 in red raspberry (Rubus idaeus L.). This protein was localized to the nucleus and lacked transcriptional activation activity. Combined in silico modeling (AlphaFold3) and dual-luciferase reporter assays revealed that RiWRKY48 may repressed the promoter activity of RiUFGT4, a key anthocyanin biosynthetic gene, suggesting a putative interaction with the W-box element. In summary, this study systematically characterized the evolutionary features of the Rubus WRKY family and provided evidence for a potential regulatory role of RiWRKY48 in anthocyanin biosynthesis through modulation of RiUFGT4 promoter activity. These findings provided new insights into the regulatory roles of WRKY transcription factors in fruit quality development in Rubus species. Full article

The potent redox-cycling Pseudomonas aeruginosa secondary metabolite pyocyanin induces acute and persistent oxidative stress in diseased airways. Pyocyanin promotes goblet cell hyperplasia and metaplasia and exacerbates the mucus burden. Forkhead Box A2 (FOXA2) is a key pioneer factor that governs the transition of airway basal epithelial and club cells to goblet cells by transcriptionally repressing the expression of MUC5AC and MUC5B mucin genes. FOXA2 activity is negatively regulated by Thr156 phosphorylation in various cell types. However, how post-translational modifications modulate the transcriptional repression of FOXA2 on airway mucin genes remains uncharacterized. Here, we demonstrate that the interaction between SIRT1 and FOXA2 is significantly increased within pyocyanin-exposed MUC5AC-expressing human bronchial epithelial cells, and in human COPD and pyocyanin-exposed mouse lungs. Pyocyanin promotes SIRT1-mediated deacetylation of FOXA2, which serves as a prerequisite for subsequent phosphorylation, inactivation, and MUC5AC derepression. Specifically, under pyocyanin-imposed oxidative stress, SIRT1 deacetylates FOXA2 at Lys259, which dictates phosphorylation at Thr156, leading to nuclear exclusion, ubiquitination, and proteasome-mediated degradation, initiating airway goblet cell transdifferentiation. By contrast, inactivation of SIRT1 by transient knockdown and chemical inhibition impedes pyocyanin-induced FOXA2 phosphorylation and MUC5AC expression. Our results uncover a novel role of SIRT1 in regulating FOXA2 expression dynamics governing airway mucus homeostasis. Full article

Metastatic breast cancer is driven by reversible cell-state programs shaped by transcription factors (TFs) and microRNAs (miRNAs). Dysregulated TFs integrate oncogenic signaling, hypoxia, inflammation, lineage identity, mechanical cues, and chromatin state, whereas miRNAs buffer or reinforce these programs through post-transcriptional repression. Their reciprocal interactions form dynamic regulatory circuits controlling epithelial–mesenchymal plasticity, stem-like behavior, invasion, dissemination, dormancy, organ-specific colonization, immune escape, and treatment resistance. This narrative review examines major TF-miRNA modules implicated in breast cancer metastasis, including ZEB1/2-miR-200/miR-205, TWIST1-miR-10b, MYC-miR-9, FRA-1-miR-34, FOXM1-miR-671-5p, HIF-1α-miR-18a, mutant p53/HIF-1α-miR-30d, STAT3-miR-21/miR-34a, and the context-dependent FOXP3-miR-200c/miR-141 network. Evidence from experimental models, paired primary-metastatic tissues, circulating tumor cells, extracellular vesicles, and plasma cohorts is integrated with emphasis on disease stage, molecular subtype, and biological compartment. Tissue and circulating miRNA signals are not interchangeable, and FOXP3-miR-200c relationships appear compartment- and model-dependent. Clinical translation remains limited by tumor heterogeneity, pre-analytical variability, incomplete cellular resolution, and limited causal validation. Prospective, subtype-stratified studies integrating spatial, single-cell, metastatic-tissue, and standardized liquid-biopsy analyses are required before TF-miRNA signatures can guide clinical management. Full article

Background/Objectives: Papillary thyroid cancer (PTC) is the most common endocrine malignancy and is generally associated with favorable clinical outcomes. However, a subset of tumors develops aggressive phenotypes characterized by increased proliferation, migration, therapeutic resistance, and disease progression. Long non-coding RNAs (lncRNAs) have emerged as important regulators of tumor biology, yet the role of Long Intergenic Non-Protein Coding RNA 1614 (LINC01614) in PTC remains poorly understood. This study investigated the functional role of LINC01614 in PTC and its potential involvement in ferroptosis-associated molecular pathways. Methods: RNA sequencing data from a repository of 44 paired PTC and adjacent normal thyroid tissue samples were analyzed to identify differentially expressed lncRNAs. LINC01614 expression was evaluated in thyroid cell lines, and CRISPR interference (CRISPRi) was used to generate stable LINC01614 knockdown K1 cell lines. Cellular proliferation, migration, clonogenicity, intracellular iron accumulation, lipid peroxidation, cytokine secretion, and ferroptosis-associated gene expression were assessed using qRT-PCR, RNA sequencing, Western blotting, cytokine array analysis, iron quantification assays, and BODIPY C11 lipid peroxidation imaging. Results: LINC01614 was significantly overexpressed in PTC tissues and thyroid cancer cell lines. CRISPRi-mediated repression of LINC01614 reduced cellular proliferation, migration, and clonogenic capacity. Mechanistically, LINC01614 knockdown resulted in an 8.8-fold increase in miR-4521 expression and a 23-fold decrease in IGF2 expression, supporting a potential competing endogenous RNA mechanism. Reduced LINC01614 expression was associated with decreased AKT, GPX4, SLC7A11, and SLC3A2 expression, increased IL-6 secretion, a 3.4-fold increase in intracellular ferrous iron accumulation, and a marked increase in lipid peroxidation following erastin treatment, indicating enhanced sensitivity to ferroptosis. Conclusions: These findings identify LINC01614 as a novel regulator of aggressive PTC phenotypes and ferroptosis resistance. The data support a model in which LINC01614 contributes to thyroid cancer progression through modulation of a miR-4521/IGF2/PI3K/AKT signaling axis and downstream anti-ferroptotic pathways. LINC01614 may represent a promising biomarker and potential therapeutic target in papillary thyroid cancer. Full article

Harvest maturity critically determines the balance between eating quality (evaluated by soluble solids, sugars, acidity, and firmness) and nutritional bioactive compounds in fleshy fruits, yet the optimal window for ‘Fengtang’ plum—a high-sugar cultivar from Guizhou—remains unclear. This study systematically investigated the dynamic changes in fruit quality traits, flavonoid accumulation, antioxidant activity, and their underlying regulatory mechanisms across three on-tree maturity stages (PG, PB, and PY) using integrated metabolomic and transcriptomic approaches. As ripening progressed, soluble solids, soluble sugars, and reducing sugars increased significantly while firmness and titratable acidity declined, optimizing fresh-eating quality at the PY stage, whereas total flavonoid content and DPPH/ABTS antioxidant activities continuously decreased, peaking at the PG stage. Metabolomic analysis identified 35 differentially accumulated flavonoid-related metabolites, comprising 32 reliably annotated flavonoids and 3 tentatively annotated xanthones (MSI Level 3); the reliably annotated flavonoids, particularly flavan-3-ols and flavonols, exhibited persistent downregulation, whereas only a few, including dihydromyricetin-3-O-glucoside and apigenin-5-O-glucoside, showed PY-specific upregulation. Transcriptomic profiling revealed systemic reprogramming of the R2R3-MYB transcription factor family: the progressive downregulation of positive regulators, coupled with the PY-stage upregulation of repressive MYBs, was associated with the overall decline in flavonoid biosynthesis, while certain branch-specific MYBs positively correlated with the few upregulated flavonoid components, suggesting a possible association with localized activation of specific metabolic branches against a background of global downregulation. Collectively, these findings delineate a trade-off pattern between edible quality improvement and bioactive compound decline during ‘Fengtang’ plum ripening and establish a MYB-mediated regulatory network model, providing a theoretical basis for tailoring harvest timing according to industrial end-use and offering candidate gene resources for molecular breeding aimed at nutritional quality enhancement. Full article

Background: Pediatric solid tumors respond poorly to T-cell-directed immunotherapy despite expressing developmentally restricted, cancer-testis, fusion-derived, and lineage-associated antigens, suggesting that therapeutic failure may reflect defective conversion of intracellular antigen expression into surface peptide–major histocompatibility complex class I (pMHC-I) display. This review examines the antigen-presentation bottleneck as a framework for tumor immune invisibility and therapeutic resistance. Methods: We conducted a narrative mechanistic synthesis of pediatric and translational evidence on antigen repertoires, MHC-I and antigen-processing machinery dysfunction, mechanisms of presentation loss, therapeutic restoration, pMHC-directed immunotherapy, and MHC-independent bypass strategies. Results: Antigen expression does not reliably predict natural presentation. Presentation failure may result from HLA loss, coordinated transcriptional repression, developmental and epigenetic states, altered trafficking, SUMOylation, and autophagy-mediated MHC-I degradation. Potentially reversible defects can be targeted through cytokine signaling, NF-κB/IRF1/NLRC5 reactivation, epigenetic or lineage reprogramming, and inhibition of post-translational MHC-I loss; irreversible defects favor MHC-independent surface targeting. Conclusions: Pediatric solid tumors may be antigen-invisible rather than antigen-poor. Therapeutic matching should assess antigen abundance, HLA integrity, antigen-processing competence, natural peptide presentation, quantitative pMHC density, and spatial and longitudinal heterogeneity, then restore presentation or deliberately bypass it. The framework distinguishes the presentation phenotype (quantitative pMHC insufficiency versus qualitative loss or functional absence of a required HLA/APM element) from the underlying mechanism (soft/potentially reversible versus hard/structural) because these dimensions have different biomarker and therapeutic implications. Full article