Search Results (2,115)

Renal cell carcinoma (RCC) is one of the most common malignant tumors of the urinary system, with clear cell renal cell carcinoma (ccRCC) accounting for more than 75% of RCC cases and representing the primary cause of mortality in renal cancer patients. CDC6 exhibits oncogenic characteristics and plays a significant role in tumor grading and prognosis prediction. Analysis of The Cancer Genome Atlas (TCGA) data shows that the CDC6 gene is significantly overexpressed in 97.22% (70/72) of paired clinical samples in ccRCC tissues compared to adjacent normal tissues. Consistent with this, elevated CDC6 protein levels were observed across all four paired tumor tissues examined. Functional experiments further confirm that CDC6 expression levels directly influence cellular proliferation, as its knockdown suppresses cell viability by ~60% in CCK-8 assays (p < 0.001) and reduces EdU incorporation by ~50%. Mechanistically, in tumor tissues, CDC6 transcription is epigenetically regulated by histone acetylation and methylation, which in turn modulates downstream effectors, e.g., the exosome complex protein EXOSC5. Our findings indicate that in ccRCC, increased histone H3K4 trimethylation near the CDC6 transcriptional start site enhances its expression. The methyltransferase SETD1A may act as a potential upstream regulator mediating the transcriptional activation of CDC6, thereby driving tumor progression through the regulation of EXOSC5. We have further investigated the relationship between the CDC6-associated gene network and tumor development and clarified the diagnostic and prognostic relevance of the SETD1A–CDC6–EXOSC5 axis in ccRCC. The outcomes of this research are expected to provide novel insights into the pathogenesis of renal cell carcinoma and establish a theoretical foundation for new diagnostic strategies. Full article

Protein arginine methyltransferase 5 (PRMT5) mediates arginine methylation of a wide range of proteins and plays context-dependent oncogenic or tumor-suppressive roles. In cancer, PRMT5 represses several tumor suppressor genes, including E-cadherin, TP53BP1, ST7, PTEN, and RB (retinoblastoma). Elevated PRMT5 expression has been reported across multiple cancer types, notably triple-negative breast cancer (TNBC). In TNBC, high PRMT5 levels are associated with enhanced cancer stem cell self-renewal, increased tumor growth and metastasis, and reduced patient survival. Mechanistically, PRMT5 promotes breast cancer stem cell maintenance and proliferation through stabilization of the transcription factors KLF4 and KLF5. Disruption of the PRMT5–KLF4 axis results in significant tumor reduction in TNBC models. Moreover, increased PRMT5 expression has been linked to resistance to chemotherapy and immunotherapy in TNBC. Notably, PRMT5 inhibitors demonstrate synergistic anticancer activity when combined with inhibitors of key oncogenic signaling pathways, including EGFR, PARP, and AKT. While several PRMT5 inhibitors are currently being evaluated in clinical trials for other malignancies, no clinical trials have yet been initiated specifically for TNBC. Full article

Fungal iterative non-reducing polyketide synthases (NR-PKS) contain a unique product template (PT) domain for aromatic cyclization. Among them, some NR-PKSs, such as the sorbicillin NR-PKS (SorB), have an apparently inactive PT. It is unknown what role such PT plays in NR-PKS programming. In this study, the PT domain of SorB was first dissected and engineered. Removal of the PT domain from SorB did not change the product profile, but the yield decreased. Meanwhile, a significantly lower transcriptional level of the ketoacyl synthase (KS) domain was observed in the knockout mutant (UvSorB∆PT). Phylogenetic tree analysis and multiple sequence alignments revealed this PT belongs to group I (C2–C7, monocyclic ring), and mutations were found at catalytic dyad sites when compared with functional fungal PTs. However, mutating these residues back to the conserved ones did not give rise to products corresponding to a functional PT, but rendered the NR-PKS unproductive. Likewise, removal of the C-methyltransferase (CMT) domain from SorB destroyed the polyketide production. Furthermore, in an attempt to alter the methylation pattern, mutations of the key substrate-binding sites of the CMT domain were made. Site-directed mutations of the C-MT led to cessation of the polyketide production. This reveals CMT is vulnerable to engineering in a collaborating NR-PKS (SorB). These results provide additional insights for catalytic reprogramming in fungal NR-PKS. Full article

Nuclear factor erythroid 2-related factor 2 (NRF2) has traditionally been framed as a Kelch-like ECH-associated protein 1 (KEAP1)-regulated stress-response transcription factor, but three observations now require a broader framework: NRF2 turnover is controlled by parallel E3 ligase systems; transcriptional output can be limited by coactivator assembly despite unchanged NRF2 abundance; and NRF2 activation can be beneficial or harmful depending on disease context, as illustrated by lung cancer models in which NRF2 paradoxically promotes metastasis through BTB and CNC homology 1 (BACH1) stabilization. We synthesize these observations into an NRF2 partner-code framework in which NRF2 acts as a context-dependent transcriptional platform assembled through four partly independent modules: a degradation module (KEAP1; β-transducin repeat-containing protein, β-TrCP; HMG-CoA reductase degradation protein 1/synoviolin 1, Hrd1/SYVN1; WD repeat-containing protein 23/DDB1- and CUL4-associated factor 11, WDR23/DCAF11); a cytoplasmic scaffold module (p62/sequestosome 1, p62/SQSTM1; IQ motif-containing GTPase-activating protein 1, IQGAP1; type I phosphatidylinositol 4-phosphate 5-kinase γ/heat shock protein 27, PIPKIγ–HSP27; peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, PIN1; peptidyl-prolyl isomerase A/cyclophilin A, PPIA); a nuclear coactivator module at Neh4/5 (CREB-binding protein/p300, CBP/p300; receptor-associated coactivator 3/steroid receptor coactivator 3, RAC3/SRC-3; protein arginine methyltransferase 1/coactivator-associated arginine methyltransferase 1, PRMT1/CARM1; Mediator complex subunit 16, MED16); and a DNA/chromatin module at Neh1 (small musculoaponeurotic fibrosarcoma [Maf] proteins, BACH1, and chromodomain helicase DNA-binding protein 6, CHD6). Mapping 22 partners onto the Neh-domain architecture identifies approximately 25 pharmacologically addressable interfaces, stratified into four translational tiers. The framework reframes NRF2 pharmacology around one principle: the most actionable target is often a partner rather than NRF2 itself, with disease context dictating the direction of modulation. We close with five testable hypotheses and a partner-code decision matrix linking disease, biomarker, and candidate target. Full article

Transfer RNAs (tRNAs) are chemically matured decoding molecules that are central to protein synthesis. Their post-transcriptional modifications, especially those in the anticodon stem-loop (ASL), shape local RNA structure, codon recognition and translational fidelity at the tRNA-mRNA decoding interface. 2′-O-methylation (Nm) is a conserved ribose modification installed at selected ASL positions, particularly positions 32 and 34, by the modular Trm7/FTSJ1 methyltransferase system. Rather than directly changing base-pairing identity, these marks help prepare the decoder for efficient translation and function within an interconnected 32–34–37 modification network, best illustrated by tRNA^Phe. Loss of Trm7/FTSJ1-mediated Nm may impair selected codon–tRNA decoding pairs; in yeast, Trm7 deficiency is additionally associated with GAAC activation and phenotypes consistent with reduced functional tRNA^Phe availability. In humans, mutations in FTSJ1 are associated with nonsyndromic X-linked intellectual disability (NSXLID), suggesting that disruption of tRNA chemical maturation can affect neuronal translation programs. In this review, we integrate anticodon-loop modifications at positions 32, 34, and 37 into a decoder-centered framework and compare the conserved enzymatic logic of yeast Trm7 and human FTSJ1 with their divergent substrate repertoires. By synthesizing structural, biochemical, genetic, and translational evidence, we distinguish established mechanisms from working models and unresolved questions concerning tRNA modification hierarchies and neuronal vulnerability. Full article

Maize plant height and stalk mechanical strength are critical traits that influence planting density, yield, and lodging resistance. Although numerous dwarf mutants have been characterized in maize, most cannot be directly utilized in breeding programs due to associated developmental and reproductive deficiencies. In a previous study, we demonstrated that ZmNAC17 regulates mesocotyl elongation by mediating auxin and reactive oxygen species (ROS) biosynthetic pathways. Here, we characterize the role of ZmNAC17 in maize stalk development using both zmnac17 mutants and ZmNAC17-overexpressing (OE) lines. Plant height, stalk diameter, and internode length were reduced in both the zmnac17-1 EMS mutant and the zmnac17-3 CRISPR mutant. Internode cell length and cell area were decreased, whereas cell number was increased in zmnac17-1. Cellulose and lignin contents were elevated in zmnac17-1. Stalk bending force was diminished in zmnac17-3 but enhanced in the OE lines. The ratio of syringyl to guaiacyl (S/G), a key lignin monomer composition, was increased in zmnac17-3 while reduced in the OE lines. ZmNAC17 functions as a transcription factor, with its downstream targets implicated in phytohormone biosynthesis, phytohormone signaling, and lignin biosynthesis. CUT&Tag binding profile, EMSA, and dual-luciferase reporter assay demonstrate that ZmNAC17 promotes the expression of caffeoyl-CoA O-methyltransferase (CCoAOMT). IP-MS, Co-IP, and GST pull-down assays reveal that ZmNAC17 interacts with Beta glucosidase aggregating factor1 (BGAF1). Collectively, our findings indicate that ZmNAC17 regulates maize stalk development through transcriptional activation and protein–protein interactions, thereby providing new genetic resources for modifying plant architecture and mechanical strength in maize. Full article

Background/Objectives: No study has investigated the effect of the catechol-O-methyltransferase (COMT) Val158Met rs4680 polymorphism in cognitive and executive performance in migraine. The current study investigated the potential influence of the Val158Met rs4680 polymorphism in cognitive performance/executive function in women with migraine. Methods: One hundred and forty women with migraine (70 chronic and 70 episodic) and 70 healthy controls completed the following neurocognitive tests (D2 Attention test and Rey–Osterrieth Complex Figure) and executive functions (subtest “Digits D/R/I” of the Wechsler Adult Intelligence Scale WAIS-IV battery for, the 5-Digit test, the Symbol Search for and the Zoo Test) for evaluating selective attention, visual perception, working memory, mental inhibition, processing speed and planning/decision making, respectively. Thus, three genotypes (Val/Val, Val/Met, and Met/Met) of the Val158Met polymorphism were identified by polymerase chain reaction. The effect of group and Val158Met genotype in neurocognitive tests and executive functions was evaluated with multivariate analysis of covariance (MANCOVA). Results: The MANCOVA revealed a significant Val158Met polymorphism* group interaction on neurocognitive performance (Wilk’s λ = 0.393, F [76,688] = 2.425, p < 0.001, n2p = 0.208, 1 − β = 0.999), not influenced by age (Wilk’s λ = 0.920, F [19,174] = 0.743, p = 0.734, n2p = 0.035, 1 − β = 0.120), educational level (Wilk’s λ = 0.875, F [19,174] = 1.024, p = 0.440, n2p = 0.047, 1 − β = 0.190) and prophylactic medication (Wilk’s λ = 0.855, F [19,174]= 1.000, p = 0.467, n2p= 0.145, 1 − β = 0.686). Post hoc analyses revealed that women with chronic migraine with the Met/Met genotype exhibited domain-specific better performance (i.e., higher selective attention, visuospatial memory) and executive functioning (i.e., working memory, planning/decision making) than those women with chronic migraine carrying Val/Val or Val/Met genotypes. Conclusions: We found an association of the Met/Met genotype with neurocognitive performance/executive functioning, particularly in women with chronic migraine since women with chronic migraine carrying the Met/Met genotype showed domain-specific better cognitive performance/executive functioning than those with the Val allele. Future studies including large sample sizes from different geographic locations are needed to better generalizability and validity of the current results. Full article

m⁶A is an important RNA modification involved in post-transcriptional regulation in plants. However, putative m⁶A writers and erasers in G. biloba remain poorly characterized. In this study, a total of 17 candidate m⁶A regulatory genes, including 8 writers and 9 erasers, were identified through genome-wide analysis. Phylogenetic and structural analyses indicated that these proteins are generally conserved, with some members showing potential functional divergence. Promoter analysis revealed abundant hormone- and stress-responsive cis-elements, and expression profiling showed tissue-specific patterns and dynamic responses to ABA, MeJA, and NaCl treatments, with erasers exhibiting greater transcriptional responsiveness than writers. In addition, protein interaction network and phase separation predictions suggested potential roles in RNA methylation-related processes. These results provide a foundation for further functional studies of m⁶A regulation in G. biloba. Full article

DNA methylation, the covalent addition of methyl groups to cytosine (5mC) or adenine (6mA) in DNA, is a fundamental mechanism of epigenetic inheritance conserved from bacteria to humans. Fungi provide a uniquely informative window into the evolutionary logic of methylation systems. Spanning more than 1 billion years of diversification, the kingdom encompasses species that have lost cytosine methylation entirely, lineages that use 5mC to silence transposons and drive the irreversible genome-defense process known as repeat-induced point mutation (RIP), and early-diverging lineages, in which 6mA has emerged as a prominent chromatin mark. The methyltransferases underlying these strategies (DIM-2, RID, DNMT1-RFD, DNMT5, and the MT-A70 complex) and the recently characterized demethylases Dmt1 and CcTet are structurally and mechanistically distinct from their mammalian counterparts. Here we review the mechanisms, targets, and biological functions of fungal DNA methyltransferases and demethylases, incorporating cryo-EM structural insights into DIM-2 and DNMT5 catalysis, analyses of DNMT gene loss as a continuous evolutionary process, the antiviral role of DIM-2 in vegetative hyphae, and the emerging model of 6mA as a heritable regulatory mark in early-diverging lineages. By integrating these advances, this review offers the updated and comprehensive account of DNA methylation across fungi. Full article

The role of the catechol-O-methyltransferase (COMT) Val158Met rs4680 polymorphism in altered pain processing in headaches is controversial. The aim of this study was to investigate the influence of the Val158Met rs4680 polymorphism in conditioned pain modulation (CPM) in women with migraine. A case-control study including 70 women with chronic migraine, 70 with episodic migraine and 70 pain-free women was conducted. Pressure pain thresholds (PPTs) at the temporalis muscle, lateral epicondyle, and tibialis anterior were bilaterally assessed. Heat (HPT) and cold (CPT) pain thresholds at the frontalis muscle were also assessed. Subsequently, CPM was evaluated immediately after a one-minute cold-pressor test paradigm on changes obtained in PPTs, HPT and CPT. Thus, after amplifying Val158Met polymorphism by polymerase chain reaction, genotype frequencies (Val/Val, Val/Met, or Met/Met) and allele distributions were identified. The distribution of Val158Met genotypes (p = 0.097) was not significantly different among women with episodic migraine, chronic migraine and pain-free controls. The results revealed significant group*time*Val 158Met interactions for PPTs at the temporalis (Wilk’s λ = 0.917, F [4, 193] = 4.377, p = 0.002, n²p = 0.083, 1 − β = 0.930) and lateral epicondyle (Wilk’s λ = 0.892, F [4, 193] = 5.870, p < 0.001, n²p = 0.108, 1 − β = 0.982), as well as CPT (Wilk’s λ = 0.872, F [4, 193] = 7.111, p < 0.001, n²p = 0.128, 1 − β = 0.995) or HPT (Wilk’s λ = 0.921, F [4, 193] = 4.133, p = 0.003, n²p = 0.079, β − 1 = 0.914), but not for the PPT at tibialis anterior (Wilk’s λ = 0.983, F [4, 193] = 0.834, p = 0.505, n²p = 0.017, 1 − β = 0.263). Women with chronic migraine with the Met/Met genotype exhibited reduced CPM indexes for PPT, CPT, or HPT at the temporalis (trigeminal area) than those with the Val/Val genotype. This study showed that CPM deficit is higher in women with migraine with the Met/Met genotype, but this association is mostly present in the symptomatic (trigeminal) area in the chronic form of the disease. No association of the Met/Met genotype with CPM was seen in healthy controls. Full article

Methylated flavonoids are abundant phytochemicals in Eucalyptus and are of interest because methylation can alter flavonoid diversity, bioactivity, and stability. However, the enzymes responsible for flavonoid methylation in eucalypts remain largely uncharacterised. We used comparative leaf transcriptomics of two species with contrasting flavanone profiles, together with protein-structure-guided candidate selection, to identify prospective O-methyltransferases involved in methylated flavonoid biosynthesis. Five candidate methyltransferases from E. eugenioides were cloned, heterologously expressed, and assayed against a panel of flavonoids and a chalcone precursor. The enzymes showed distinct substrate preferences and regioselectivities. EeOMT1 acted as a broad 7-O-methyltransferase, whereas EeOMT3–EeOMT5 preferentially methylated B- and C-ring hydroxyl groups, with differing capacities for sequential methylations at different sites. EeOMT2 was of particular interest because it methylated pinocembrin chalcone to alpinetin chalcone more efficiently than it converted the flavanone pinocembrin to alpinetin. Expression–metabolite analyses across E. eugenioides genotypes were consistent with roles for EeOMT2 and EeOMT1 in the in planta accumulation of 5-O- and 7-O-methylated flavanones, respectively. These findings support a revised model in which alpinetin biosynthesis proceeds, at least in part, through methylation of a chalcone precursor before flavanone formation. This work provides a foundation for elucidating flavonoid methylation pathways in plants and for engineering the production of tailored methylated flavonoids. Full article

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in older adults and is characterized by progressive dysfunction of the retinal pigment epithelium (RPE). Although genetic susceptibility and environmental exposure both contribute to disease risk, the mechanisms through which chronic metabolic and oxidative stress are integrated into sustained RPE dysfunction remain incompletely understood. Increasing evidence from human AMD donor tissue and experimental RPE models indicates that epigenetic regulation operates at the interface between mitochondrial dysfunction, redox imbalance, and transcriptional remodeling. This review synthesizes current findings on DNA methylation, chromatin accessibility, histone modification, and RNA-based regulation in AMD, with emphasis on their metabolic and mitochondrial context. Studies in human AMD-RPE demonstrate that epigenetic alterations are generally selective rather than global and frequently involve pathways related to mitochondrial maintenance, lipid metabolism, oxidative stress responses, and cellular homeostasis. Mechanistically, mitochondrial dysfunction and reactive oxygen species (ROS) may influence epigenetic regulation through altered Nicotinamide adenine dinucleotide (NAD⁺) availability, acetyl-CoA metabolism, redox-sensitive chromatin regulation, and modulation of DNA methyltransferase and histone deacetylase activity. Redox-sensitive pathways, including antioxidant signaling, further connect mitochondrial stress to adaptive or maladaptive transcriptional responses in the RPE. Importantly, while several interactions discussed are supported by findings in human AMD tissue, other components of the proposed epigenetic–mitochondrial–redox framework remain inferential or model-based and require further validation. Rather than acting as isolated disease triggers, epigenetic changes are more likely to function as stress-responsive regulatory layers that stabilize transcriptional states over time in a long-lived post-mitotic tissue. We further discuss unresolved questions regarding causality, reversibility, therapeutic feasibility, and stage-specific intervention strategies. Collectively, this framework positions the epigenetic–mitochondrial–redox axis as a unifying model for understanding RPE vulnerability and AMD progression. Full article

The SARS-CoV-2 non-structural proteome remains the most clinically validated and strategically important landscape for direct-acting small-molecule antiviral drug discovery. The success of inhibitors targeting the main protease (M^pro, Nsp5) and RNA-dependent RNA polymerase (RdRp, Nsp12) has firmly established viral replication enzymes as tractable, druggable, and therapeutically relevant targets, while setting clear benchmarks for translational antiviral development. Building on this foundation, a second wave of non-structural protein (Nsp) targets has emerged with increasing translational promise, including the papain-like protease (PL^pro), the bifunctional Nsp14 proofreading and capping machinery, Nsp16 2′-O-methyltransferase, Nsp13 helicase, and Nsp15 endoribonuclease. In parallel, additional components such as Nsp1 and the Mac1 domain of Nsp3 continue to expand the antiviral design space, although they remain at earlier stages of chemical validation. In this review, we comprehensively assess SARS-CoV-2 non-structural proteins through a medicinal chemistry and translational lens, with an emphasis on structural tractability, mechanism of action, quality of chemical matter, cellular and in vivo antiviral evidence, evolutionary conservation, resistance liabilities, and developability. Particular attention is given to the features that distinguish tool compounds from genuinely actionable leads and to the opportunities for rational combination regimens that extend beyond first-generation protease- and polymerase-centred therapy. Collectively, the non-structural proteome offers the strongest foundation for next-generation and potentially broader-spectrum coronavirus antivirals with improved resilience to viral evolution. Full article

Polycomb repressive complex 2 (PRC2) regulates the expression of pluripotency genes in embryonic stem cells (ESCs) and suppresses multiple genes associated with development, cell fate determination, and differentiation. Mouse embryonic stem cells (mESCs) derived from protein kinase C inhibition (PKCi) exhibit self-renewal and pluripotency comparable to those ESCs captured by the classical 2iL (CHIR99021, PD0325901, and leukemia inhibitory factor) system. However, the dynamic expression pattern of PRC2 in PKCi-mESCs and its role in regulating pluripotency remain unclear. This study demonstrated that the expression level of the enhancer of zeste 2 gene (Ezh2), of which protein is the catalytic subunit of PRC2 responsible for the trimethylation of lysine 27 on nucleosome histone H3 subunit (H3K27me3), is significantly higher in PKCi-mESCs than in 2iL-mESCs. EZH2 knockdown enhances the self-renewal capacity of PKCi-mESCs, as evidenced by a significant increase in the number of undifferentiated mESCs colonies. The effect of an EZH2 reduced expression is accompanied by the upregulation of specific core pluripotency gene Nanog, along with the general downregulation of differentiational genes representing the three germ layers. Conversely, EZH2 overexpression promotes a significant differentiation of PKCi-mESCs, resulting in the downregulation of pluripotency genes, including core pluripotency genes Nanog and Sox2, as well as naïve pluripotency genes Klf4, Fgf4, and Esrrb, while with a wide upregulation of three germ layer associated genes. Importantly, Cleavage Under Targets and Tagmentation (CUT&Tag) demonstrates that EZH2 directly controls H3K27me3 enrichment at the Nanog promoter near the transcription start site. Thus, EZH2, a core subunit of PRC2, exhibits the distinct regulatory functions orchestrating mESCs at a poised state between self-renewal and differentiation under PKC inhibition. EZH2 exerts histone H3 methyltransferase activity to regulate Nanog expression as one of its key targets, thereby modulating the transcriptional regulatory network that maintains pluripotency and lineage specification in mESCs. Full article

Objective: To investigate the association between genetic polymorphisms of the vitamin D receptor (VDR: rs1544410, rs2228570, rs731236), methylenetetrahydrofolate reductase (MTHFR: rs1801131), and DNA methyltransferase (DNMT1: rs2228611, DNMT3A: rs7590760, DNMT3B: rs6087990) genes and the coexistence of periodontitis and systemic lupus erythematosus (SLE). Methods: Systematically healthy individuals and patients with SLE of both sexes, aged over 20 years, were recruited and divided into four groups: healthy, periodontitis, SLE, and SLE with periodontitis. Seven polymorphisms in the VDR, MTHFR, DNMT1, DNMT3A, and DNMT3B genes were analyzed. Results: The frequency of the rs1801131 (MTHFR) AA genotype was higher in the healthy group than in the periodontitis group. The B allele of rs1544410 (VDR) was more frequent in patients with SLE, regardless of the presence of periodontitis. The t allele of rs731236 (VDR) was more frequent in patients with SLE without periodontitis. Conclusions: The polymorphisms studied do not show an exclusive association with the coexistence of periodontitis and SLE. However, the MTHFR rs1801131 polymorphism may be a protective factor against periodontitis, but not when it coexists with SLE. VDR rs1544410 is associated with SLE regardless of the presence of periodontitis, and rs731236 is associated with SLE, but not in coexistence with periodontitis. These data provide insights into the genetics of periodontitis and lupus; however, they are currently exploratory, as they were obtained from a single-center study in which it was not possible to adjust for demographic variables (age and sex) between groups due to the modest sample size. Full article