Search Results (705)

The conserved protein SetDB1 has been identified in various vertebrate and invertebrate groups. It plays key roles in vital processes such as germline and nervous system development, immune response, tumorigenesis, cell cycle progression, and others. SetDB1 is initially characterized as an enzyme that methylates lysine 9 on histone H3, leading to gene silencing, which is traditionally considered its primary function. However, SetDB1 also targets about a dozen nuclear, cytoplasmic, and membrane proteins as substrates. Moreover, some functions of SetDB1 do not require methyltransferase activity. Due to its SUMO-interacting motif, Tudor domain, and methyl-binding domains, SetDB1 interacts with a wide range of complexes that regulate protein stability and activity, signal transduction pathways, and chromatin spatial organization. In this review, we aim to expand the classical view of SetDB1 as solely a histone methyltransferase and to highlight the broader diversity of its functions. Full article

Neonicotinoids are widely used pesticides that have caused a catastrophic decrease in bee and bumblebee populations worldwide. In addition to insects, neonicotinoids induce toxic effects in other species, including lizards, birds, and mammals. Previous studies have shown that gestational exposure to thiacloprid promotes transgenerational effects in the testes and thyroid. In this project, we described the epigenetic effects of thiacloprid on prostate tissue in directly exposed F1 and non-directly exposed F3 outbred Swiss male mice. We used paraffin sections for morphological analysis and frozen tissue for immunofluorescence analysis, RT–qPCR, and protein analysis. We purified histones and analyzed them through Western blot. We used ChIP–qPCR for histone H3K4me3 occupancy analysis. A tendency to increase in epithelial hyperplasia in F1 but not in F3 prostate was detected. Elevated levels of phosphorylated histone H3 at serine 10, a marker of mitosis, in both the F1 and F3 prostates were noted. A significant increase in the level of the Ki-67 marker of proliferation was detected in the F1 but not in the F3 anterior prostate. Hox gene expression was upregulated in the F1 and downregulated in the F3 prostate. The changes in gene expression were positively associated with histone H3K4me3 alterations at the promoters of the Hoxa and Hoxb13 genes. We determined that regions of Hox genes that play important roles in prostate development had altered DNA methylation in the sperm of F1 and F3. These alterations in DNA methylation were negatively related to gene expression. This is an observational study, as it was part of our previous research on the effects of thiacloprid on the testis and thyroid. Our analysis revealed that gestational exposure to thiacloprid induced an increase in cell proliferation in the prostates of directly exposed F1. Some persistent epigenetic alterations in the prostate of F3 males were not associated with phenotypic changes. Full article

This study presents the experimental characterization of the volumetric and transport properties of pseudo-binary mixtures of commercial diesel and residual chicken fat methyl ester biodiesel over the temperature range of 293.15–353.15 K at 0.078 MPa. Density measurements were performed using a U-shaped vibrating-tube densimeter; kinematic viscosities were obtained using Cannon–Fenske capillary viscometers. The results show that density decreased with increasing temperature and diesel content. The excess molar volume (V^E) was negative for all mixtures; the strongest volumetric contraction took place at around x₁ ≈ 0.4–0.6. The Redlich–Kister equation and the Prigogine–Flory–Patterson (PFP) model were applied to represent excess molar volumes, with an absolute average deviation (AAD) lower than 14.92%. The thermal expansion coefficient (${\alpha }_P$) and its excess property (${\alpha }_P^E$) further confirmed the existence of non-ideal mixing driven by polar–apolar interactions. The kinematic viscosity ($\nu$) was confirmed to be temperature-dependent and increased with the amount of FAMEs; this effect can be associated with the greater polarity and structural rigidity of esters. The McAllister model also adequately reproduced the dynamic viscosity ($\eta$) with an AAD < 4.2%. Furthermore, an increase in the activation enthalpy (${\Delta H}^{\ne }$) was observed at higher FAME fractions, indicating a high energy demand is required to overcome the internal energy barrier for the initial displacement of the molecules. Full article

Beckwith–Wiedemann syndrome (BWS) is an overgrowth disorder caused by genetic and epigenetic alterations at chromosome 11p15.5. Increasing evidence suggests that imprinting defects may be accompanied by broader epigenomic perturbations affecting repetitive elements such as human endogenous retroviruses (HERVs). We quantified the transcriptional levels of the HERV-H, HERV-K, and HERV-W-pol genes, the HERV-derived env genes, Syncytin-1 (SYN1) and Syncytin-2 (SYN2), and the epigenetic regulators, TRIM28 and SETDB1, in whole blood from children and adolescents with BWS, stratified by molecular subtype (ICR2 loss of methylation, n = 14; UPD(11)pat, n = 10), and compared with age-matched healthy controls using quantitative real-time PCR. The BWS samples showed significantly increased transcription of HERV-H and HERV-K relative to controls, whereas HERV-W was unchanged. The SYN1 transcripts were significantly higher in UPD(11)pat compared with controls, while SYN2 did not differ between groups. TRIM28 and SETDB1 were significantly overexpressed in BWS, irrespective of molecular subtype, and no significant differences were observed between ICR2 and UPD(11)pat for HERV-H, HERV-K, HERV-W, TRIM28, or SETDB1. These findings indicate selective dysregulation of endogenous retroelements and key repressors in BWS, consistent with epigenetic alterations extending beyond canonical imprinted loci. Full article

Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), mediates histone H3 lysine 27 trimethylation (H3K27me3), an epigenetic modification associated with transcriptional repression. EZH2 inhibitors (EZH2is) gained attention after the first-in-class drug Tazemetostat received FDA approval for treating epithelioid sarcoma. Preclinical studies suggest that EZH2is could be effective against melanoma, but their general inability to cross the blood–brain barrier (BBB), among others, limits the treatment of secondary brain metastases. Based on these limitations, we designed SG-8, a novel compound derived from TDI-6118 (a known brain-penetrant EZH2i). In silico docking predicted that SG-8 may exhibit high affinity for EZH2 as well as for another PRC2 subunit, Embryonic Ectoderm Development (EED). In addition, in vitro PAMPA assays suggested passive BBB permeability of SG-8. In cell-based assays, SG-8 and the structurally related EZH2i PF-06726304 displayed lower cytotoxicity than Tazemetostat in both primary (A375) and metastatic (Colo-679) human melanoma cells. Western blot analysis showed that SG-8 and PF-06726304 markedly reduced EED protein levels and, to a lesser extent, EZH2 levels, without affecting total H3K27me3, consistent with preserved canonical PRC2 activity. Instead, treatment with both compounds—most prominently SG-8—was associated with reduced phosphorylation levels of EZH2 (Ser21) and its upstream regulator Akt (Ser473), suggesting that modulation of the Akt–EZH2 signaling axis may at least partially contribute to their anti-melanoma activity. Full article

Background/Objectives: Genome-wide studies of differential DNA methylation often focus on its role in turning transcription on or off. Here we report some atypical epigenetic/transcription relationships for 92 genes that are highly and preferentially expressed in primary human myoblasts relative to heterologous cell cultures. Methods: We compared methylomes and myoblast-specific differentially methylated regions (DMRs) with methylomes, chromatin profiles, and transcriptomes for many different cell populations. Results: We found that myoblast-associated promoter hypomethylation was unusually prevalent among the 92 myoblast-preferential genes. Sometimes this promoter hypomethylation was seen as a myoblast-associated extension of their constitutively unmethylated region at a CpG island. All 92 genes showed some myoblast-specific hypomethylation, including 32 genes at tissue-specific super-enhancers or broad H3K4-trimethylated promoters. Myoblast hypermethylated DMRs were also associated with almost half of the myoblast-preferential genes. These hypermethylated DMRs were often in intragenic locations embedded in H3K36-trimethylated chromatin in myoblasts. Conclusions: Our analysis suggests that some of the hypermethylated DMRs repress cryptic, alternative, or adjacent promoters. Myoblast hypermethylated DMRs may also downmodulate expression in myoblasts to avoid yet higher RNA levels found in adult or fetal skeletal muscle tissue. The epigenetic insights that were obtained can help elucidate the transcription regulation of some of these genes (e.g., MUSK, RAPSN, HEYL, SYNPO2, SYNPO2L, STAC3, PITX2, and TPPP3) that are implicated in congenital myasthenic syndromes, myasthenia gravis, muscle repair, heart dysfunction, or cancer. This study supports cell type-specific roles for DNA hypo- and hypermethylation as a modulator of transcription levels, in addition to being an on–off switch during differentiation. Full article

Background/Objectives: SETD2 is a dual-function methyltransferase important for methylation of histone H3 at lysine 36 and α-tubulin in spindle microtubules. Genetic inactivation of SETD2 during oncogenesis drives loss of H3K36me3, genomic instability, and cancer progression. This study asked if disruption of genomic stability was a canonical feature of SETD2 inactivation via different pathways. Methods: We evaluated the impact of EPZ-719, a pharmacologic SETD2 inhibitor, and an H3.3K36M mutant histone (“oncohistone”) that binds and sequesters SETD2, on methylation activity and genomic stability in human cell lines. SETD2 activity was measured using in vitro methylation assays, H3K36me3 loss confirmed by Western analysis, and mitotic defects, specifically micronuclei and chromatin bridges, quantified with cytogenetic analysis. Results: EPZ-719 caused a dose- and time-dependent reduction in SETD2 activity on both histone and tubulin substrates, accompanied by significant increases in chromatin bridges and micronuclei in retinal pigmented epithelial (RPE-1) and 786-O ccRCC cells. Similarly, oncohistone expression markedly decreased SETD2 function, as determined by H3K36me3 levels, and induced comparable mitotic defects in 786-O cells, and aneuploidy in two chondrocyte cell lines expressing the H3.3K36M oncohistone. Combining EPZ-719 with H3.3K36M expression did not exacerbate mitotic defects beyond either oncohistone or pharmacologic inhibition alone, consistent with inhibition of SETD2 as their shared underlying mechanism of action. Conclusions: Pharmacologic inhibition and oncohistone-mediated sequestration of SETD2 converge on the induction of mitotic defects, underscoring SETD2’s essential role in maintaining genomic stability. Identification of loss of genomic stability as a canonical feature of SETD2 inactivation points to a potential therapeutic liability associated with targeting SETD2 in cancers where it is overexpressed and reveals a mechanism that could contribute to the progression of cancers expressing oncohistone mutations. Full article

The resource utilization of keratin waste has garnered significant attention, yet the processing of yak hair keratin in underdeveloped regions such as Tibet and Qinghai in China remains challenging. This study addresses these concerns by carbonizing yak hair keratin waste using a steam flash explosion (SFE) technique for 150 s, which is followed by activation with KOH at various ratios and subsequent to produce activated carbon (AC) samples. The AC was then combined with sodium alginate (Alg) at different ratios, pH and applied voltage to yield AC−Alg gel microbeads using an electrospinning method. The characterization of the AC and AC–Alg gel microbeads was conducted using SEM, BET, TG, and FT-IR analysis. In adsorption studies, AC−Alg_0.5U gel microbeads prepared with optimized conditions (pH 7, 11 kV, 19 G needle) were used to remove dyes (methylene blue (MB) and methyl orange (MO)) and antibiotic minocycline hydrochloride (MH). Various parameters such as temperature, pH, and adsorbent dose were optimized to obtain the maximum adsorption performance under model concentrations. The experimental results showed that the AC−Alg_0.5U gel microbeads can effectively adsorb MB and MO with adsorption capacities of 1038.9 mg/g and 206.2 mg/g, respectively. Moreover, the microbeads had the best adsorption performance for MH (1694.2 mg/g), with the kinetics most accurately represented by the pseudo-second-order kinetic model (R² = 0.999), and the isotherm followed the Langmuir model (R² = 0.984). The microbeads maintained a high adsorption capacity of 75% after six cycles. The composite gel microbeads not only utilize yak hair keratin waste but also will be used as durable and favorable adsorbents for the removal of pollutants. Full article

Cancer is one of the leading causes of mortality worldwide, with breast and colon cancers being among the most common neoplasms in men and women, respectively. Despite significant advancements in treatment, there is a pressing need to enhance specificity and reduce systemic side effects. Importantly, a distinctive feature of cancer cells is their acidic extracellular environment, which profoundly influences cancer progression. In this study, we evaluated the anticancer activity of a pH-sensitive nanocomposite based on silver nanoparticles and pegylated carboxymethyl chitosan (AgNPs-CMC-PEG) in breast cancer (MCF-7) and colon cancer (HCT 116) cell lines. To achieve this, we synthesized and characterized the nanocomposite using UV-Vis spectroscopy, Dynamic Light Scattering (DLS), Fourier-Transform Infrared Spectroscopy (FT-IR), and Scanning Electron Microscopy (STEM-in-SEM). Furthermore, we assessed cytotoxic effects, apoptosis, and reactive oxygen species (ROS) generation using MTT, DAPI, and H2DCFDA assays. Additionally, we analyzed the expression of DNA methyltransferases (DNMT3a) and histone acetyltransferases (MYST4, GCN5) at the mRNA level using RT-qPCR, along with the acetylation and methylation of H3K9ac and H3K9me2 through Western blot analysis. The synthesized nanocomposite demonstrated an average hydrodynamic diameter of approximately 175.4 nm. In contrast, STEM-in-SEM analyses revealed well-dispersed nanoparticles with an average core size of about 14 nm. Additionally, Fourier-transform infrared (FTIR) spectroscopy verified the successful surface functionalization of the nanocomposite with polyethylene glycol (PEG), indicating effective conjugation and structural stability. The nanocomposite exhibited a pH and concentration dependent cytotoxic effect, with enhanced activity observed at an acidic pH 6.5 and at concentrations of 150 µg/ml, 75 µg/ml, and 37.5 µg/ml for both cell lines. Notably, the nanocomposite preferentially induced apoptosis accompanied by ROS generation. Moreover, expression analysis revealed a decrease in H3K9me2 and H3K9ac in both cell lines, with a more pronounced effect in MCF-7 at an acidic pH. Furthermore, the expression of DNMT3a at the mRNA level significantly decreased, particularly at acidic pH. Regarding histone acetyltransferases, GCN5 expression decreased in the HCT 116 line, while MYST4 expression increased in the MCF-7 line. These findings demonstrate that the AgNPs-CMC-PEG nanocomposite has therapeutic potential as a pH-responsive nanocomposite, capable of inducing significant cytotoxic effects and altering epigenetic markers, particularly under the acidic conditions of the tumor microenvironment. Overall, this study highlights the advantages of utilizing pH-sensitive materials in cancer therapy, paving the way for more effective and targeted treatment strategies. Full article

This study demonstrates that sunflower plants display integrated, multilevel responses to excessive lithium (Li) exposure. Li concentrations above 5 mM markedly impair germination, growth, and biomass accumulation. Li is preferentially accumulated in the shoots, showing high translocation and bioaccumulation factors, and disrupts mineral nutrient homeostasis, particularly potassium (K) and sodium (Na) uptake, while inducing oxidative stress. Although photosynthetic pigment contents decline, photosynthetic efficiency is largely maintained, except at 10 mM Li. Li treatment enhances superoxide anion (O₂^.−) and hydrogen peroxide (H₂O₂) production exclusively in leaves. Consequently, activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR), monodehydroascorbate reductase (MDHAR), and glutathione reductase (GR) increase in leaves, whereas only APX and GR are stimulated in the roots. Nitric oxide (NO) accumulation is detected only in leaves, while hydrogen sulfide (H₂S) and glutathione (GSH) contents decline. Leaf ascorbate (AsA) levels decrease concomitantly with dehydroascorbate (DHA) accumulation. Expression analyses of catalase, DHAR, DHAR-like, and glutathione S-transferase (GST) genes confirm their involvement in Li stress responses. Moreover, global DNA methylation analyses reveal hypomethylation in leaves and hypermethylation in the roots. Overall, Li exposure induces dose- and organ-specific physiological, molecular, and epigenetic adjustments in sunflower plants under environmentally relevant concentrations and controlled experimental conditions in this study. Full article

DNA double-strand breaks (DSBs) can be induced by cellular byproducts or genotoxic agents. Improper processing of these lesions leads to increased genome instability, which constitutes a hallmark of pathological conditions and fuels carcinogenesis. DSBs are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ) and the proper balance between these two pathways is finely modulated by specific molecular events. Here, we report that the histone chaperone DAXX plays a fundamental role in the response to DSBs. Indeed, in human cells, DSBs induce ATM/ATR-dependent phosphorylation of DAXX on serine 424 and 712 and promote its binding to chromatin and the deposition of the histone variant H3.3 in proximity to DNA breaks. Enrichment of H3.3 at DSBs promotes 53BP1 recruitment to these lesions and the repair of DNA breaks by HR pathways. Moreover, H3.3-specific post translational modifications, particularly K36 tri-methylation, play a key role in these processes. Altogether, these findings indicate that DAXX and H3.3 mutations may contribute to tumorigenesis-enhancing genome instability. Full article

Background: In nuclear medicine, numerous cancer types are treated via internal irradiation with radiopharmaceuticals, including low-LET (linear energy transfer) beta-emitting radionuclides like Lu-177. In most cases, such treatments lead to low-dose exposure of organ systems with β-irradiation, which induces only few isolated DSBs (double-strand breaks) in the nuclei of hit cells, the most threatening DNA damage type. That damaging effect contrasts with the clustering of DNA damage and DSBs in nuclei traversed by high-LET particles (α particles, ions, etc.). Methods: After in-solution β-irradiation for 1 h with Lu-177 leading to an absorbed dose of about 100 mGy, we investigated the spatial nano-organization of chromatin at DSB damage sites, of repair proteins and of heterochromatin marks via single-molecule localization microscopy (SMLM) in PBMCs. For evaluation, mathematical approaches were used (Ripley distance frequency statistics, DBScan clustering, persistent homology and similarity measurements). Results: We analyzed, at the nanoscale, the distribution of the DNA damage response (DDR) proteins γH2AX, 53BP1, MRE11 and pATM in the chromatin regions surrounding a DSB. Furthermore, local changes in spatial H3K9me3 heterochromatin organization were analyzed relative to γH2AX distribution. SMLM measurements of the different fluorescent molecule tags revealed characteristic clustering of the DDR markers around one or two damage foci per PBMC cell nucleus. Ripley distance histograms suggested the concentration of MRE11 molecules inside γH2AX-clusters, while 53BP1 was present throughout the entire γH2AX clusters. Persistent homology comparisons for 53BP1, MRE11 and γH2AX by Jaccard index calculation revealed significant topological similarities for each of these markers. Since the heterochromatin organization of cell nuclei determines the identity of cell nuclei and correlates to genome activity, it also influences DNA repair. Therefore, the histone H3 tri methyl mark H3K9me3 was analyzed for its topology. In contrast to typical results obtained through photon irradiation, where γH2AX and H3K9me3 markers were well separated, the results obtained here also showed a close spatial proximity (“co-localization”) in many cases (minimum distance of markers = marker size), even with the strictest co-localization distance threshold (20 nm) for γH2AX and H3K9me3. The data support the results from the literature where only one DSB induced by low-dose low LET irradiation (<100 mGy) can remain without heterochromatin relaxation for subsequent repair. Full article

Understanding how supercritical CO₂ and water interact with mineral surfaces is essential for predicting the stability and sealing performance of geological storage formations. Yet, the combined effects of mineral surface chemistry and confined pore geometry on interfacial structure and fluid dynamics remain insufficiently resolved at the molecular scale. In this study, molecular dynamics simulations were employed to quantify how methylated SiO₂, hydroxylated SiO₂, and kaolinite regulate CO₂–H₂O interfacial behavior through variations in wettability and electrostatic interactions. The results show a clear hierarchy in water affinity across the three minerals. On methylated SiO₂, the water cluster remains spherical and poorly anchored, with a contact angle of ~140°, consistent with the weakest water–surface Coulomb attractions (only −400 to −1400 kJ/mol). Hydroxylated SiO₂ significantly enhances hydration, forming a cylindrical water layer with a reduced contact angle of ~61.3° and strong surface–water electrostatic binding (~−18,000 to −20,000 kJ/mol). Kaolinite exhibits the highest hydrophilicity, where water forms a continuous bridge between the two walls and the contact angle further decreases to ~24.5°, supported by the strongest mineral–water electrostatic interactions (−23,000 to −25,000 kJ/mol). Meanwhile, CO₂–water attractions remain moderate (typically −2800 to −3500 kJ/mol) but are sufficient to influence CO₂ distribution within the confined domain. These findings collectively reveal that surface functionalization and mineral type govern interfacial morphology, fluid confinement, and electrostatic stabilization in the sequence methylated SiO₂ < hydroxylated SiO₂ < kaolinite. This molecular-level understanding provides mechanistic insight into how mineral wettability controls CO₂ trapping, fluid segregation, and pore-scale sealing behavior in subsurface carbon-storage environments. Full article

(1) Background: Modifications of histone methylation could alter chromatin structure and thereby have an impact on gene expressions. (2) Methods: To investigate whether ORY-1001 delay retinal photoreceptor degeneration, rd10 mice were intraperitoneally injected with ORY-1001 (0.075 mg/kg) every second day from the 14th to the 24th day after birth. Full-field electroretinogram detection (ff ERG), optical coherence tomography (OCT), visual behavioral testing, retinal tissue morphology observation, and protein expression detection experiments were performed on the 25th day. Simultaneously, ATAC-seq and RNA-seq were used to test the mice’s retinal tissues, and metabolomics detection and quantitative real-time polymerase chain reaction (qRT-PCR) were carried out. (3) Results: Compared with the rd10 group, in the treatment group, the function in the electroretinogram response and the visual behavioral responses were improved, the nuclear layer morphology of retinal tissue was reserved more, and the protein expression of H3K4me2 and CoREST was increased. Conjoint analysis of our ATAC-seq and RNA-seq results showed that chromatin accessibility was changed, as was gene expression which was involved in metabolism changes. In addition, the effector gene in the retina was Gnat1. (4) Conclusions: ORY-1001 delays retinal photoreceptor degeneration by inhibiting H3K4me2 demethylation in rd10 mice, which suggests that ORY-1001, as a novel epigenetic modifier, has potential for treating RP. Full article

The influence of 5-Methyl-1H-benzotriazole (MHBTZ) on the corrosion of pure iron (Fe) and aluminum (Al) in 1 M HCl was investigated in this study. The experimental and theoretical aspects of MHBTZ adsorption onto pure iron (Fe) and aluminum metal (Al) surfaces, as well as the stability of adsorbed layers based on the metal type, were also studied. Different electrochemical measurements were performed to explore the corrosion rates and inhibition efficiencies on the Fe and Al surfaces at 298 K. Optical profilometry was used to obtain the 3D surface topography of Fe and Al metals after immersion with and without the MHBTZ molecule. The results showed that MHBTZ exhibited excellent inhibition properties for both metals. Electrochemical impedance spectroscopy (EIS) achieved inhibition efficiencies of 98.1% and 98.5% for Fe and Al, respectively, at a concentration of 2500 ppm. Potentiodynamic polarization (PDP) indicated that MHBTZ acted as a mixed-type inhibitor. Density functional theory (DFT) analysis and molecular dynamics (MD) simulations were used to explore the relationship between the molecular structure of MHBTZ and its inhibition efficiency at the atomic level. Full article