Search Results (143)

Bladder cancer remains a major clinical challenge because of its high recurrence rate, marked molecular heterogeneity, frequent progression, and limited durability of current therapeutic strategies. Increasing evidence indicates that acetylation, as a reversible and druggable epigenetic modification, plays a central role in bladder cancer biology by linking chromatin remodeling to transcriptional regulation, DNA damage repair, metabolic adaptation, and immune modulation. Both histone and non-histone acetylation are frequently dysregulated in bladder cancer, and these alterations contribute to multiple malignant phenotypes, including sustained proliferation, defective cell-cycle control, apoptosis evasion, epithelial–mesenchymal transition, metastatic progression, and therapeutic resistance. In this review, we summarize the mechanistic basis of acetylation imbalance in bladder cancer, with particular emphasis on the roles of histone acetyltransferases, histone deacetylases, sirtuins, and acetylation-associated metabolic regulators. We further discuss the emerging evidence that natural products can modulate acetylation-related pathways in bladder cancer, mainly through targeting HDAC-dependent histone deacetylation and SIRT1-associated non-histone deacetylation. Representative compounds, including sulforaphane, erucin, puerarin, capsaicin, curcumin, trichostatin A, trichostatin C, and pinocembrin, highlight the potential of natural products to suppress tumor growth, promote apoptosis, impair migration, and enhance antitumor immunity through acetylation-related mechanisms. Beyond summarizing individual agents, the evidence was evaluated based on the integration of acetylation-related target engagement, acetylation remodeling, and bladder cancer-relevant phenotypic outcomes. The current evidence is heterogeneous. SFN/ECN, capsaicin, and pinocembrin offer the most convincing bladder cancer-specific support, whereas several other compounds remain limited by context-dependent effects, indirect pathway inference, or incomplete validation of the proposed acetylation mechanisms. These findings support an evidence-oriented translational framework that prioritizes natural products according to mechanistic robustness, bladder cancer specificity, and combination potential. Overall, acetylation-targeting natural products represent a promising but still evolving therapeutic strategy for bladder cancer, warranting further subtype-specific, mechanistically rigorous, and translationally oriented investigation. Full article

This study aimed to develop an anther culture protocol for triticale (×Triticosecale Wittmack) and generate a doubled haploid (DH) population combining awnlessness and stripe rust resistance. A wheat anther culture protocol was evaluated on nine triticale varieties, with and without Trichostatin A (TSA), and tested on parental genotypes—an awned, stripe rust–resistant breeding line (AT-45) and an awnless variety (‘1143’)—as well as on ten F₁ plants derived from crosses between AT-45 and ‘1143’. Plant regeneration varied widely among varieties, ranging from 0.8 to 39.7 green plants per 30 anthers (1.6–80 per spike), with an overall mean of 9.9 (20 per spike). TSA did not significantly improve green plant production in this study, though further optimisation of the application method may be warranted. An average of 17.4 green plants per spike was obtained from the F₁ plants, and 1130 regenerant plants were grown to maturity, with a mean spontaneous chromosome doubling rate of 42.5%. A total of 480 DH lines were harvested, comprising 250 awned, 60 reduced awn, and 170 awnless lines. Awned and reduced awn lines were discarded, and 114 awnless lines were advanced for field evaluation of stripe rust resistance and agronomic traits. These results establish an effective anther culture system for DH production in triticale and demonstrate the potential of DH technology to accelerate the development of resilient, high-performing varieties. Full article

To overcome the seasonal constraints of explant availability and facilitate genetic improvement in Catalpa ovata, this study established a dual-pathway in vitro regeneration system (encompassing adventitious shoot organogenesis and somatic embryogenesis) using mature zygotic embryos. We systematically evaluated the synergistic effects of maternal genotypes, plant growth regulators (PGRs), basal media, and the histone deacetylase inhibitor Trichostatin A (TSA). Genotype screening revealed significant divergence in regenerative potential, with the half-sib family 32F17 exhibiting superior responsiveness (84.7% callus induction). A high cytokinin-to-auxin ratio (ZA3 medium) optimally drove direct shoot organogenesis. For adventitious shoot proliferation, the addition of TDZ significantly improved the multiplication coefficient (up to 2.99 on ZB4 medium), although a physiological trade-off with shoot elongation was observed. In parallel, the application of 10 µM TSA significantly enhanced somatic embryogenesis from embryogenic calli, effectively alleviating the inhibitory constraints of exogenous PGRs. For rhizogenesis, the DKW basal medium proved superior to half-strength MS, with the ZE3 treatment (0.1 mg·L⁻¹ NAA + 0.1 mg·L⁻¹ IBA) yielding the highest rooting frequency (69.6%) and robust root architecture. Notably, while somatic embryo conversion remained recalcitrant, plantlets derived exclusively from the adventitious shoot organogenesis pathway were successfully acclimatized ex vitro. These transplanted plantlets exhibited consistently high survival rates (83.1–84.4%) across all tested genotypes, effectively overcoming the initial genotype-dependent recalcitrance. Collectively, this optimized protocol provides a reliable technical platform for the large-scale clonal propagation and biotechnological breeding of C. ovata. Full article

Dendritic cells (DCs) play a crucial role in immune protection against myocardial infarction (MI). Through multiple experimental methods including bioinformatics, qPCR, Western blotting, immunofluorescence, MTT assays, echocardiography, TTC staining, and flow cytometry, this study found that metabolism was demonstrated to be markedly altered under oxygen–glucose deprivation (OGD) conditions in DCs. Pyruvate kinase M2 (PKM2) is a key protein in metabolism, and PKM2 was upregulated under OGD conditions in DCs. Trichostatin A (TSA) alleviated the OGD-induced cellular damage in DCs. Furthermore, TSA was shown to modulate DCs’ function by enhancing glycolysis while suppressing fatty acid synthesis and oxidation pathways. The metabolic changes caused by TSA and OGD were mechanistically mediated by PKM2. Mechanistically, PKM2 modulates glucose and lipid metabolism via its dimer formation. These results deepen our understanding of the interplay among TSA, glucose and lipid metabolism and DC functions in MI. Full article

Chromatin architecture is highly dynamic, undergoing nanoscale rearrangements throughout the cell cycle and in response to environmental cues. In this study, we employed high-resolution stochastic optical reconstruction microscopy (STORM) to visualize chromatin organization and cellular plasticity at the nanoscale in two osteosarcoma cell lines, U2OS and MG63. To promote a tumor-suppressive bone microenvironment, we applied three biophysical modalities, namely mechanical vibration, electrical stimulation, and optical pulses, each previously linked to altered tumor behavior by reprogramming cells and generating induced tumor-suppressing (iTS) cells. These stimuli enlarged nuclear size and disrupted nuclear envelope integrity, as revealed by increased surface roughness. Critically, all three modalities transiently scattered nucleosome clusters, indicating chromatin decondensation as a hallmark of iTS cell generation. iTS cells exhibited elevated expression of histone demethylases lysine demethylase 3A (KDM3A) and lysine demethylase 4 (KDM4), accompanied by reduced levels of trimethylated histone H3 lysine 9 (H3K9me3). Consistently, pharmacological agents—Trichostatin A as a histone deacetylase inhibitor and chaetocin as a histone methyltransferase inhibitor—induced nucleosome scattering and converted U2OS cells into iTS cells, whose conditioned media exerted tumor-suppressive effects. Our findings highlight nucleosome clustering as a key epigenetic feature responsive to both biophysical and chemical cues, underscoring its role in microscale chromatin remodeling and reprogramming of the tumor microenvironment. Full article

Intratumoral heterogeneity poses significant challenges to the efficacy of cancer immunotherapy. Melanoma-associated antigen D4 (MAGED4) has been proposed as a potential immunotherapeutic target in oral squamous cell carcinoma (OSCC). This study aims to investigate the expression of MAGED4, focusing on its intratumoral expression heterogeneity and the underlying epigenetic regulation mechanism. Utilizing public online databases, immunohistochemical analyses of clinical specimens, and single-cell RNA sequencing data, we found that MAGED4 was overexpressed with significant intratumoral heterogeneity in OSCC tissues. Methylation-promoter luciferase reporter assays revealed that MAGED4 transcription was suppressed by DNA methylation at its promoter region. Additionally, co-expression analysis implicated a potential role for histone acetylation in regulating MAGED4. To functionally validate these findings, we treated OSCC cells with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) and histone deacetylase inhibitors trichostatin A (TSA) and valproic acid (VPA). The triple-drug combination treatment resulted in the most robust reactivation of MAGED4 expression, correlating with promoter DNA demethylation and enhanced acetylation of H3K9 and H3K27 at the MAGED4 promoter. Our findings elucidate critical epigenetic mechanisms contributing to MAGED4 heterogeneity in OSCC and highlight the potential of combination epigenetic therapies to reverse this heterogeneity, thereby providing a foundation for exploring such approaches to improve immunotherapeutic outcomes. Full article

Cellular mechanical properties are critical indicators of cellular state and promising disease biomarkers. This study introduces a novel microhand system, featuring chopstick-like plate-shaped end-effectors, designed for stable and high-precision single-cell mechanical characterization. First, we automated the force sensor calibration to overcome the inefficiency and unreliability of conventional manual methods. To validate the system’s sensitivity, we precisely quantified the mechanical contributions of subcellular components, such as the actin cytoskeleton and chromatin, by measuring stiffness reductions after treatment with Cytochalasin D and Trichostatin A, respectively. Notably, when applied to a cellular model of Hutchinson–Gilford progeria syndrome, we successfully captured disease-induced mechanical alterations. A distinct population of high-stiffness cells was detected in progerin-overexpressing cells, a feature not observed in the control groups. Furthermore, by controlling the indentation speed and depth, the mechanical properties of the cytoplasm and nucleus could be distinctly evaluated. These results demonstrate that our microhand system is a highly sensitive and robust platform, capable of detecting subtle, disease-related changes and elucidating the contributions of specific subcellular structures to cell mechanics. Full article

MICA/B molecules (MICs) are stress-induced molecules expressed by infected and tumor cells. Their expression also characterizes trophoblast cells. Cytotoxic lymphocytes, including natural killer (NK) cells, express the NKG2D receptor, aiding them in the recognition and destruction of target cells that present MICs. To evade destruction, target cells employ various defense mechanisms, including the secretion of soluble forms of MICs. Choriocarcinoma JEG-3 cells and NK-92 cells were used to assess the expression of MICs and NKG2D. The cytotoxicity of NK-92 cells against JEG-3 cells in the presence of trichostatin A (TSA), anti-MICA/B antibodies (anti-MICA/B), and recombinant MIC proteins (rMICA/B) was evaluated. JEG-3 cells and NK-92 cells express MICs. Additionally, NK-92 cells exhibit high levels of NKG2D receptor expression. TSA treatment reduced the surface expression of MICs on choriocarcinoma cells, and was also associated with the release of soluble MICB. However, the TSA-induced decrease in MIC expression by choriocarcinoma cells did not protect them from the cytotoxic effects of NK cells. Only the activation of NK cells by IL-12 resulted in a decline in susceptibility of TSA-treated choriocarcinoma cells to NK cell-mediated cytotoxicity. Thus, NK cells activated by IL-12 lose their ability to effectively kill TSA-treated choriocarcinoma cells through the MIC-mediated mechanisms. Full article

Objectives: High-calorie diets are linked to increased risks of chronic inflammation and immune dysfunction, yet their role in modulating pneumonia severity remains unclear. Focusing on the interactions among gut-originating short-chain fatty acids (SCFAs), neutrophil function, and histone deacetylases (HDACs), this research examined the exacerbating effects of a high-calorie diet on pneumonia in rats. Methods: Male Sprague-Dawley rats (3 weeks old, 110 ± 10 g) were allocated among four groups: normal diet (N), high-calorie diet (G), LPS-induced pneumonia (P), and high-calorie diet combined with lipopolysaccharide (LPS)-induced pneumonia (GP). LPS was administered via aerosolization for three days. Fecal, serum, and lung SCFA levels were quantified via GC-MS. Neutrophil extracellular traps (NETs) formation, neutrophil apoptosis, and HDAC activity were assessed using immunofluorescence, TUNEL assays, and qRT-PCR. Propionate supplementation and HDAC inhibitor (trichostatin A) interventions were applied to validate mechanistic pathways. Results: The group GP exhibited exacerbated lung inflammation, increased NETs release, and reduced neutrophil apoptosis compared to the group P. Propionate levels in feces, serum, and lung tissues decreased sharply in GP rats, correlating with elevated HDAC1/2/3/6 activity and reduced histone acetylation. Propionate supplementation or HDAC inhibition significantly attenuated lung injury, suppressed NETs, and restored neutrophil apoptosis. Conclusions: High-calorie diets exacerbate pneumonia by depleting gut-derived propionate, which drives HDAC-mediated NETs overproduction and impairs neutrophil apoptosis. Restoring propionate levels or targeting HDACs may offer therapeutic strategies for diet-aggravated respiratory diseases. Mechanistically, propionate-mediated HDAC inhibition demonstrates proof-of-concept efficacy in modulating H4 acetylation, warranting further investigation in disease-specific pneumonia models. Full article

This study explored the causal and molecular overlap among Crohn’s disease (CD), celiac disease (CeD), and ankylosing spondylitis (AS). Bidirectional Mendelian randomization revealed significant causal associations between each disease pair. Transcriptomic analyses identified three consistently upregulated hub genes—P2RY8, ITGAL, and GPR65—across all conditions, which were validated in independent datasets and inflammatory cell models. Functional enrichment suggested these genes are involved in immune signaling and mucosal inflammation. Regulatory network and molecular docking analyses further highlighted Trichostatin A as a potential therapeutic agent. These findings reveal shared genetic and immune-related mechanisms, offering novel targets for cross-disease treatment strategies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types due to its late diagnosis, low survival rates, and high frequency of metastasis. Considering the molecular mechanism of PDAC development has not been fully elucidated, this study aimed to shed more light on the molecular regulatory signatures of circular RNAs (circRNAs) in PDAC progression and provide a different perspective to identify potential biomarkers as well as discover candidate repositioned drug molecules for the prevention or treatment of PDAC with network-based integrative analysis. The mRNA, miRNA, and circRNA expression profiles of PDAC were obtained from nine microarray datasets. Differentially expressed genes (DEGs), microRNAs (DEmiRNAs), and circular RNAs (DEcircRNAs) were identified. The competing endogenous RNA (ceRNA; DEG–DEmiRNA–DEcircRNA) regulatory network was constructed, which included 12 DEcircRNAs, 64 DEGs, and 6 miRNAs specific to PDAC. The ADAM12, MET, QKI, SEC23A, and ZEB2 were identified as hub genes and demonstrated significant survival probability for PDAC. In addition to providing novel biomarkers for diagnosis that can be detected non-invasively, the secretion levels of hub genes-associated proteins were found in plasma, serum, and oral epithelium. The drug repositioning analysis revealed vorinostat, meclocycline sulfosalicylate, and trichostatin A, which exhibited significant binding affinities to the hub genes compared to their inhibitors via molecular docking analysis. Full article

Background: The epigenetic regulation of adipogenic differentiation in dental stem cells (DSCs) remains poorly understood, as research has prioritized osteogenic differentiation for dental applications. However, elucidating these mechanisms could enable novel regenerative strategies for soft tissue engineering. Periodontal ligament stem cells (PDLSCs) exhibit notable adipogenic potential, possibly linked to histone 3 acetylation at lysine 9 (H3K9ac); however, the mechanistic role of this modification remains unclear. Methods: To address this gap, we investigated how histone deacetylase inhibitors (HDACis)—valproic acid (VPA, 8 mM) and trichostatin A (TSA, 100 nM)—modulate H3K9ac dynamics, adipogenic gene expression (C/EBPβ and PPARγ-2), and chromatin remodeling during PDLSCs differentiation. Techniques used included quantitative PCR (qPCR), lipid droplet analysis, and chromatin immunoprecipitation followed by qPCR (ChIP-qPCR). Results: TSA-treated cells exhibited increased lipid deposition with smaller lipid droplets compared to VPA-treated cells. Global H3K9ac levels correlated positively with adipogenic progression. VPA induced early upregulation of C/EBPβ and PPARγ-2 (day 7), whereas TSA triggered a delayed but stronger PPARγ-2 expression. ChIP-qPCR analysis revealed significant H3K9ac enrichment at the PPARγ-2 promoter in TSA-treated cells, indicating enhanced chromatin accessibility. Conclusions: These findings demonstrate that H3K9ac-mediated epigenetic remodeling plays a critical role in the adipogenic differentiation of PDLSCs and identifies TSA as a potential tool for modulating this process. Full article

Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic malignancies. Despite the remarkable improvement concerning treatment, late detection and resistance to clinically used chemotherapeutic agents remain major challenges. Trichostatin A (TSA), a histone deacetylase inhibitor, has been recognized as an effective therapeutic agent against PDAC by inhibiting proliferation, inducing apoptosis, and sensitizing PDAC cells to chemotherapeutic agents such as gemcitabine. Microgravity has become a useful tool in cancer research due to its effects on various cellular processes. This paper presents a deep molecular and proteomic analysis investigating cell growth, the modulation of cytokeratins, and proteins related to apoptosis, cellular metabolism, and protein synthesis after TSA treatment in simulated microgravity (SMG)-exposed PaCa44 3D cells. Our analysis concerns the effects of TSA treatment on cell proliferation: the impairment of the cell cycle with the downregulation of proteins involved in Cdc42 signaling and G1/G2- and G2/M-phase transitions. Thus, we observed modification of survival pathways and proteins related to autophagy and apoptosis. We also observed changes in proteins involved in the regulation of transcription and the repair of damaged DNA. TSA treatment promotes the downregulation of some markers involved in the maintenance of the potency of stem cells, while it upregulates proteins involved in the induction and modulation of the differentiation process. Our data suggest that TSA treatment restores the cell phenotype prior to simulated microgravity exposure, and exerts an intriguing activity on PDAC cells by reducing proliferation and inducing cell death via multiple pathways. Full article

Background: Dynamic changes in histone acetylation play crucial roles during cellular differentiation and disease development, but their detection in living cells is still a challenging task. Objectives: Here, we developed a Bimolecular Anchor Detector (BiAD) sensor for the detection of locus-specific changes in histone acetylation in living cells by fluorescence microscopy. Methods: We used the BRD9 bromodomain cloned as tandem double domain (2xBRD9-BD) as a reader of histone acetylation. It was integrated into a dual-color BiAD chassis that was previously described by us. Results: We identified the gene body of TTC34 as a potential target for our sensor, because it contains dense histone acetylation and 392 local sequence repeats. Using a binding-deficient mutant of 2xBRD9-BD as a negative control, we established a successful readout of histone acetylation at the TTC34 locus. A single-domain reader did not function, indicating the requirement for the double reader to enhance the affinity and specificity of the chromatin interaction via avidity effects. With this sensor, we could detect dynamic increases in histone acetylation at the TTC34 locus after the treatment of cells with the histone deacetylase inhibitor Trichostatin A for 6 h indicating the applicability of the sensor for single-cell epigenome studies. Conclusions: Our data demonstrate that active chromatin modifications can be detected by BiAD sensors using 2xBRD9-BD as a reader. This complements the toolkit of the available BiAD sensors and documents the modularity of BiAD sensors. Full article

The melanoma-associated antigen gene (MAGE) is a key target in cancer immunotherapy. Given the potential of MAGE-B genes in veterinary immunotherapy for canine mammary tumors (CMTs), this study investigated the mRNA expression of MAGE-B1, -B4, -B5, and -B10 in CMT tissues and cells from dogs. Quantitative real-time PCR was used to analyze 28 CMT tissue samples, including 4 benign and 24 malignant tumors (13 simple carcinomas, 6 complex carcinomas, 3 carcinosarcomas, and 2 fibrosarcomas). Benign mixed tumor and complex carcinoma-type CMT cells were cultured and treated with a DNA methylase inhibitor (5-aza-2′-deoxycytidine; 5-aza-CdR) and a histone deacetylase inhibitor (Trichostatin A; TSA) under the following four conditions: (1) 5-aza-CdR for 72 h; (2) TSA for 24 h; (3) 5-aza-CdR for 48 h followed by TSA for 24 h; and (4) control. MAGE-B1 and -B4 showed the highest expression in the CMT samples (100% and 89.29%, respectively), followed by MAGE-B10 (82.14%). Carcinosarcomas and simple anaplastic carcinomas had significantly higher MAGE-B expression levels than simple tubulopapillary carcinomas (p < 0.05). 5-aza-CdR treatment increased MAGE-B expression, whereas TSA had a mild effect. Further research involving larger cohorts is needed to confirm these findings. Full article