Search Results (2,074)

Although RNA cytosine-5 methylation (m⁵C) is an important post-transcriptional regulatory mechanism, its contribution to plant antiviral immunity remains unclear. In this study, we identified Thiamine thiazole synthase 2 (TaTHI2) as a host mRNA target of the wheat m⁵C methyltransferase TaNSUN2 during infection by Chinese wheat mosaic virus (CWMV), a soil-borne virus that poses a major threat to wheat production. TaNSUN2 contributes to the m⁵C modification of TaTHI2 transcripts, enhancing mRNA stability and sustaining TaTHI2 accumulation. The disruption of a key m⁵C site markedly reduced methylation, weakened TaNSUN2–RNA binding, and accelerated transcript decay, leading to the compromised production of reactive oxygen species (ROS) and increased viral infection. Mechanistically, the TaNSUN2-dependent m⁵C modification stabilized TaTHI2 mRNA, thereby promoting ROS-mediated antiviral defense. Collectively, our results establish the m⁵C modification of TaTHI2 mRNA as a critical post-transcriptional control point in CWMV resistance and highlight TaNSUN2-dependent RNA methylation as an integral component of host antiviral immunity. Full article

Chlamydia trachomatis has evolved sophisticated mechanisms to manipulate key host cell signaling pathways to facilitate its intracellular reproduction. N6-methyladenosine (m6A) in RNA is known to regulate various physiological and disease processes, and is also involved in the regulation of pathogenic and developmental processes in many pathogens. However, the specific impact of m6A modification on the intracellular growth of C. trachomatis remains poorly understood. In this study, our analysis of the m6A methylation profiles of host cell mRNAs following C. trachomatis infection revealed significant alterations in the distribution of m6A modifications, methylation motifs, and m6A-modified host target genes. We further demonstrate that chlamydial intracellular reproduction is mediated by the host methyltransferase-like (METTL) enzyme METTL14. Silencing METTL14 significantly reduced the reproduction efficiency of C. trachomatis. Mechanistically, C. trachomatis activates the Mitogen-Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/AKT) signaling pathways through METTL14, thereby inhibiting host cell apoptosis and promoting intracellular bacterial reproduction. Collectively, these findings identify METTL14 as a key host factor for chlamydial intracellular reproduction, providing new mechanistic insights and potential targets for therapeutic intervention. Full article

Cancer therapy is increasingly shaped by the need for agents that are both mechanistically precise and clinically tolerable. Sulforaphane (SFN), a dietary isothiocyanate enriched in cabbage-family vegetables such as cauliflower and Brussels sprouts, has emerged as a pleiotropic modulator of tumor biology. This review synthesizes current evidence that SFN regulates diverse cancer-relevant processes, including redox homeostasis, cell-cycle progression, apoptosis, autophagy and epigenetic remodeling, largely through coordinated effects on transcriptional (for example, Nrf2, MAPK, NF-κB and AP-1), post-transcriptional (microRNAs and messenger RNAs) and epigenetic (DNA methyltransferases and histone deacetylases) networks. We then examine how functional nucleic acids, including aptamers, small interfering RNAs, microRNAs and tetrahedral DNA nanostructures, can be engineered to guide SFN to tumor cells, amplify pathway-specific effects and overcome resistance. Particular emphasis is placed on nanotechnology-enabled delivery platforms that enhance SFN stability, bioavailability and tumor selectivity. Finally, we outline key challenges, such as context-dependent Nrf2 activity, inter-individual variability in metabolism and incomplete clinical validation, and propose priorities for translating SFN-based functional nucleic acid systems into rational, combination-ready strategies for precision oncology. Full article

The innate immune signaling pathway cGAS–STING plays an important role in the recognition of cytosolic nucleic acids and the induction of the interferon-dependent antiviral response. Despite the significant research interest in this cascade in the context of immune system function, the mechanisms regulating cGAS–STING signaling and the switch between its pro-inflammatory and pro-apoptotic effects remain largely underexplored. According to publicly available RNA-seq data and microarray analyses, SETD7 lysine methyltransferase participates in interferon signaling in cancer cells. This study aims to elucidate the role of SETD7 in the regulation of the STING-dependent immune response in human lung adenocarcinoma (LUAD) cells. For this purpose, we developed a reproducible and cost-effective method for inducing the STING cascade by transfecting cells with salmon sperm DNA (sspDNA). We demonstrated that sspDNA efficiently induces phosphorylation of the key components of the STING–TBK1–IRF3 signaling pathway and activates the expression of interferons and pro-inflammatory cytokines. Using this approach, we further demonstrated that SETD7 is involved in the regulation of the IRF3-dependent transcriptional program. Suppression of SETD7 was associated with changes in the expression of genes related to innate immune response and apoptosis, including increased levels of IFNA1, IL1B, BAK1, BBC3 (PUMA), and BCL2. Furthermore, attenuation of SETD7 expression reduced the lentiviral transduction efficacy in H1299 cells. These results suggest that SETD7 may play a role in regulating the switch in STING signaling between pro-inflammatory and pro-apoptotic responses in LUAD cells. Full article

Background: Severe neurocognitive decline is often seen in elderly glioblastoma patients after treatment with radiation and chemotherapy. But the mechanism behind their deterioration is unclear. We describe one such patient with concomitant primary age-related tauopathy (PART) in bilateral hippocampi. Case presentation: An 88-year-old woman experienced unsteadiness, memory loss, and slurred speech that was caused by an epithelioid glioblastoma with wild-type isocitrate dehydrogenase-1 and methylated promoter of O⁶-methylguanine-DNA methyltransferase. She was treated with gross total resection, followed by intensity-modulated radiotherapy and daily temozolomide. Shortly after starting treatment, she developed fatigue, anorexia, and neurocognitive impairment, which were refractory to corticosteroids. After two cycles of adjuvant temozolomide, she experienced impulsivity, disorientation, hallucinations, somnolence, and incontinence despite stable neuroimaging findings. Treatment was subsequently discontinued, and she died 20 months from the time of her glioblastoma diagnosis. Autopsy revealed tau-positive neurofibrillary tangles, but rare Aβ plaques, in the trans-entorhinal and entorhinal cortices of both hippocampi. These findings are consistent with a diagnosis of PART. Conclusions: Undiagnosed tauopathy could be a negative modifier of glioblastoma treatment. The identification of PART and other tauopathies as risk factors in the elderly population may be important to guide treatment decision. Full article

Phellodendron amurense Rupr. is a native tree species in China, well known for its significant medicinal value. Its pharmacological activity mainly derives from the abundant isoquinoline alkaloids in its bark. Berberine serves as the key compound underlying the multiple pharmacological effects of P. amurense and exhibits organ-specific accumulation. However, the genetic mechanisms governing this organ-specific accumulation remain unclear. Genes encoding O-methyltransferase (OMT) and cytochrome P450 (CYP) may play an important role in this regulatory process. In this study, by integrating transcriptomic and metabolomic data from the leaves and stems of P. amurense plantlets, we identified core candidate genes and transcription factors (TFs) that regulate the differential biosynthesis of berberine between these two organs. The results showed that 37 metabolites were significantly upregulated in stems, including main medicinal components such as berberine and jatrorrhizine, while 8497 genes were differentially expressed between leaves and stems. Among these, downstream genes in the berberine biosynthesis pathway, including OMTs and CYPs, were predominantly highly expressed in stems. A co-expression regulatory network identified some TFs such as PaBES1, PaWRKY12/13, PaNAC5, and PaMYB12 as the key nodes regulating the differential biosynthesis of berberine. Phylogenetic analysis classified the 97 PaOMTs into four subgroups. Core candidate genes such as PaOMT7 and PaOMT9 were contained in subgroup IV, potentially contributing to the specific modification of characteristic alkaloids in P. amurense. This study reveals the transcriptional regulatory networks underlying the organ-specific accumulation of berberine in P. amurense plantlets, providing key targets and theoretical support for the targeted improvement and development of elite medicinal varieties. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality, frequently arising from chronic inflammatory states such as metabolic dysfunction-associated steatotic liver disease and cirrhosis. While extensive epidemiological data demonstrate a strong, dose-dependent inverse association between habitual coffee consumption and HCC incidence, the underlying molecular causality remains incompletely understood. In this comprehensive review, we elucidate the “Coffee Paradox” through the lens of nutriepigenomics. We demonstrate how coffee-derived bioactives—specifically chlorogenic acids, diterpenes, and microbially derived short-chain fatty acids—function as a coordinated epigenetic defense system. These compounds actively inhibit DNA methyltransferases, serve as endogenous histone deacetylase inhibitors via the gut–liver axis, and induce post-transcriptional, tumor-suppressive microRNA networks to halt oncogenic progression. However, to provide a critical and balanced perspective, we also address significant translational challenges. We evaluate conflicting null associations from recent Mendelian randomization studies and highlight the profound variability introduced by specific brewing methods, roasting profiles, and individual pharmacogenomics (e.g., CYP1A2 polymorphisms). Finally, we outline the future of precision hepatology, emphasizing the critical transition from observational epidemiology to clinical application via the utilization of circulating exosomal microRNAs as dynamic liquid biopsies and the development of standardized epi-nutraceuticals. Ultimately, this multi-layered epigenetic framework provides a robust foundation for integrating targeted dietary interventions into the primary prevention of HCC. Full article

Glypican-3 (GPC3)-targeted chimeric antigen receptor T (CAR-T) cell therapy is a promising approach for hepatocellular carcinoma (HCC), but marked interpatient variability and antigen heterogeneity limit its broader application. Here, we established a patient-derived organoid (PDO)-based platform to functionally evaluate autologous GPC3-targeted CAR-T cell activity in HCC. HCC PDOs preserved key histologic features and heterogeneous GPC3 expression patterns of the original tumors. In co-culture assays, CAR-T cell cytotoxicity was associated with GPC3 expression levels and was accompanied by IFN-γ and IL-2 release, supporting the feasibility of using PDOs for functional assessment of CAR-T cell sensitivity. We further found that matrix conditions strongly influenced organoid architecture, viral transduction, CAR-T cell infiltration, and killing efficiency, with lower Matrigel concentrations providing a more permissive setting for functional assessment. Importantly, in GPC3-low PDOs, pretreatment with the DNA methyltransferase inhibitor 5-azacytidine (5-AZA) reduced DNA methyltransferase 3 alpha (DNMT3A) expression, increased surface GPC3 expression, and significantly enhanced CAR-T-mediated cytotoxicity. Together, these findings provide proof-of-concept evidence supporting the use of HCC PDOs as a patient-derived platform for modeling selected determinants of GPC3-targeted CAR-T cell activity and for exploring combination strategies to improve therapeutic efficacy. Full article

Objectives: This study aimed to investigate the biological role and molecular mechanism of the RNA m⁵C methyltransferase NSUN4 in cervical cancer progression, with a focus on its involvement in ferroptosis regulation. Methods: Differential expression and survival analyses were performed using TCGA and GEPIA datasets. Functional enrichment and GSEA identified pathways associated with NSUN4 dysregulation. NSUN4 expression was validated in clinical tissues by qRT-PCR, Western blot, and immunohistochemistry. Gain- and loss-of-function assays, including CCK-8, colony formation, and Transwell assays, were conducted to assess cell proliferation and invasion. Furthermore, a nude mouse subcutaneous xenograft model was established to validate the oncogenic role of NSUN4 in vivo. Ferroptosis was evaluated using specific inhibitors and measurement of GSH and ferroptosis-related proteins. RIP, m⁵C-RIP, RNA stability, and dual-luciferase assays were performed to explore the underlying mechanism. Results: NSUN4 was markedly upregulated in cervical cancer tissues and correlated with poor prognosis. Functionally, NSUN4 enhanced tumor cell growth, migration, and invasion while inhibiting ferroptosis. Mechanistically, NSUN4 bound to and stabilized C-MYC mRNA via m⁵C methylation, activating the PI3K/Akt signaling pathway and promoting ferroptosis resistance. Conclusions: NSUN4 promotes cervical cancer progression by stabilizing C-MYC mRNA through m⁵C modification, leading to PI3K/Akt activation and suppression of ferroptosis. These findings identify NSUN4 as a novel oncogenic regulator and potential therapeutic target in cervical cancer. Full article

Background: Tumor invasion is the central barrier to effective immunotherapy in lung adenocarcinoma (LUAD) and glioblastoma. Cell adhesion signaling critically shapes tumor–microenvironment interactions, yet the upstream regulators coordinating these invasive programs at single-cell resolution remain incompletely understood. Methyltransferase Like protein 7B (METTL7B) has recently emerged as a candidate oncogenic regulator, but its lineage-specific functions and the potential downstream effectors are unclear. Methods: We integrated publicly available single-cell RNA sequencing datasets from LUAD and glioblastoma with The Cancer Genome Atlas (TCGA) transcriptomic analyses to resolve METTL7B-associated malignant cell states and microenvironmental interactions. Functional enrichment analyses identified invasion- and focal adhesion pathways linked to METTL7B expression. Gain- and loss-of-function experiments were conducted in LUAD and glioblastoma cell lines to validate downstream cell adhesion effectors. Spatial expression patterns were examined using immunofluorescence, and transwell assays were used to assess migratory and invasive phenotypes. Results: Single-cell analyses revealed that METTL7B was selectively enriched in malignant epithelial cells in LUAD and glioblastoma and defined a transcriptional program characterized by cell adhesion signaling. Integrin Alpha 3 (ITGA3) emerged as a conserved downstream effector of METTL7B, with progressive upregulation from minimally invasive to invasive LUAD and glioblastoma. Functional perturbation confirmed that METTL7B enhances tumor cell migration and invasion through integrin-associated pathways. Conclusions: METTL7B acts as a potential lineage-enriched regulator of invasive tumor states by activating cell adhesion signaling in LUAD and glioblastoma. These findings position METTL7B as a putative prognostic factor for strategies aimed at limiting invasion in lung cancer and glioblastoma. Full article

Glioblastoma (GB) classical treatment with the alkylating drug temozolomide (TMZ) is not effective mainly due to chemoresistance mechanisms, particularly those mediated by O6-methylguanine-DNA methyltransferase (MGMT). In this context, polyethylene glycol (PEG)-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed to deliver tamoxifen (TAX), a clinically approved non-alkylating drug with reported anti-GB activity. The NP formulation was optimized using a factorial design and subsequently functionalized with lactoferrin (Lf) to enhance GB targeting. The Lf-conjugated optimized formulation exhibited a mean diameter of 193 ± 6 nm, a polydispersity index (PDI) of 0.11 ± 0.04, a zeta potential of −18.2 ± 6.8 mV, and an encapsulation efficiency (EE) of 68.6 ± 1.8%. The NPs exhibited a sustained release profile for up to 23 days, and remained stable under physiological conditions. Cell uptake studies, conducted in human GB cells (U87, U251, and T98G) and healthy astrocytes, demonstrated enhanced internalization of Lf-NPs in GB cells compared with non-conjugated NPs, suggesting uptake through Lf-binding site-mediated endocytosis. Cytotoxicity assays further indicated that Lf-conjugation improved the antiproliferative efficacy of TAX-loaded NPs relative to non-functionalized formulations, particularly in GB cells. Moreover, combination studies with TMZ showed that the developed NPs were able to sensitize GB cells to treatment with this alkylating agent. In sum, this work supports the potential of the developed Lf-decorated TAX-loaded PLGA NPs as a nanoplatform for targeted delivery against GB. Full article

Viruses are key regulators of marine microbial communities, yet their temporal dynamics in tropical intertidal sediments remain poorly characterized. We conducted a year-long metagenomic survey of sandy intertidal sediments in Sanya Bay (60 monthly samples from five sites) to examine viral taxonomy, community structure, lytic proteins, and auxiliary metabolic genes (AMGs). Within the classifiable fraction, the assemblages were consistently dominated by Assiduviridae. However, NMDS analysis revealed a significant overall seasonal shift, with October–December samples separating from the rest of the year. Co-occurrence network analysis identified five co-occurrence modules with distinct temporal patterns, alongside a concurrent decline in module abundance and lytic proteins in October. Functional annotation showed that cysteine and methionine metabolism, primarily driven by DNA methyltransferases, was identified as a highly represented AMG category among the annotated functions, while other pathways displayed seasonal variability. Collectively, these findings suggest that although characterized by a classifiable fraction dominated by Assiduviridae, the highly complex tropical intertidal viral communities undergo substantial seasonal reorganization in structure and functional potential. Full article

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers. Full article

Background: Clinical target volume (CTV) delineation in glioblastoma remains debated, particularly in the era of modern chemoradiation and image-guided radiotherapy. Whether reduced CTV margins can preserve oncological outcomes without increasing marginal or out-of-field failures remains uncertain. We evaluated the association of the gross tumor volume (GTV)-to-CTV margin with survival, patterns of failure, and its interaction with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Materials and Methods: We retrospectively analyzed a single-center cohort of patients with glioblastoma treated with conventionally fractionated chemoradiation (58–60 Gy in 29–33 fractions). Patients were categorized into two predefined margin groups: <1.5 cm and 1.5 cm. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and patterns of failure. Survival was assessed using Kaplan–Meier estimates and Cox regression, including an interaction term with MGMT status. Results: Among 102 eligible patients, 95 were included in the margin-based OS analysis. Reduced margins (<1.5 cm; applied range 1.0–1.4 cm) were not associated with worse OS, either overall or within MGMT subgroups. No significant differences were observed in PFS or recurrence patterns, with overlapping distributions and no increase in marginal or out-of-field recurrences. MGMT methylation and gross total resection were independently associated with improved survival, while no statistically significant interaction between margin and MGMT status was detected. Conclusions: In this retrospective exploratory cohort, reduced GTV-to-CTV margins were not associated with a clear signal of worse survival or less favorable recurrence patterns. These findings are consistent with the oncological adequacy of margins around 15 mm and justify cautious prospective evaluation of whether further reduction can be achieved safely, including formal assessment of toxicity, neurocognitive outcomes, and quality of life. Full article

Maternal infection (MI) can increase the risk of neurodevelopmental and behavioural changes. This study examined MI-induced changes in motor coordination through the inflammatory-pathway-mediated epigenetic status of Reln. On gestational day (GD) 10, rats were assigned as (i) Control (Ctrl); (ii) Cronobacter sakazakii (CS) infection on GD-10 through recto-vaginal colonization; (iii) Negative Control (NC) [infected with C. sakazakii and treated with dimethyl sulfoxide (DMSO) 1 h before and 24 h after infection]; and (iv) C. sakazakii-infected rats treated with matrix metalloproteinase inhibitor (MMPI), 1 h before and 24 h after infection (CS + MMPI). Offspring were subjected to footprint analysis and the ladder rung walking test, which revealed that MI caused significant deficits in motor coordination. In addition, MI activated complement components—a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1, C5a)—as well as proinflammatory cytokines such as interleukin-6 (IL-6) and matrix metalloproteinases (MMP-2, MMP-3, and MMP-9). Furthermore, the levels of DNA methyltransferase 3 alpha (DNMT3A), methyl-CpG-binding protein 2 (MeCP2), and histone H3 lysine 4 trimethylation (H3K4me3) were elevated in the CS and NC groups. Concurrently, the level of Reln promoter methylation increased; as a result, mRNA and protein, as well as postsynaptic density protein-95 (PSD-95), levels were decreased. Overall, the findings suggest that MI altered MMP-2/3/9 activity, H3K4me3, and the methylation of Reln, thereby affecting reelin, synaptic protein expression, and motor coordination in an experimental meningitis rat model. Full article