Search Results (988)

The rising incidence of chronic autoimmune and autoinflammatory diseases has been increasingly associated with environmental and lifestyle factors, including Western dietary patterns, intestinal dysbiosis, and reduced production of short-chain fatty acids (SCFAs). Reduced production of acetate, propionate, and butyrate has been associated with impaired epithelial barrier function, altered peripheral immune tolerance, and low-grade systemic inflammation. This article integrates and systematizes current knowledge in the field of immunometabolism, focusing on the role of the microbiota–metabolism–immunity axis. The molecular mechanisms by which these bacterial metabolites modulate immune function—both through the activation of specific surface receptors and direct epigenetic regulation—are analyzed in detail. SCFAs have been shown to actively reprogram the metabolic and transcriptional profiles of effector cells, stimulating anti-inflammatory macrophage polarization, suppressing cellular inflammatory cascades, and inducing the differentiation of protective regulatory T cells. To address the pharmacokinetic limitations of natural fatty acids, this study critically evaluates modern translational strategies. The clinical potential of synthetic receptor agonists, selective epigenetic modulators, and advanced next-generation bacterial consortia is analyzed. The presented data synthesis not only organizes the pathophysiological foundations but, above all, points to promising new directions for personalized non-pharmacological immunomodulation in the treatment of inflammatory diseases. Full article

The field of cosmetic science is rapidly evolving due to advances in skin biology research and increasing demand for evidence-based, personalized skincare solutions. A key aspect of this progress is the targeted modulation of biological macromolecules involved in skin aging, pigmentation, inflammation, and tissue regeneration. This review highlights major molecular targets in modern cosmetic research, focusing on telomerase, histone deacetylases (particularly sirtuins), matrix metalloproteinases, antioxidant enzymes, CD44 receptor, tyrosinase, microphthalmia-associated transcription factor, and melanocortin receptors, all of which regulate processes such as DNA repair, gene expression, extracellular matrix remodeling, and melanogenesis. Recent findings indicate that natural and synthetic compounds can effectively modulate these targets, supporting anti-aging and depigmenting strategies. Telomerase activators and sirtuin modulators show potential in maintaining cellular homeostasis and delaying skin aging. In pigmentation research, the transition from mushroom to human tyrosinase assays has enabled development of more selective inhibitors, including thiamidol. The review also addresses molecular targets relevant to inflammatory skin disorders, scars, and skin atrophy. Advances in molecular and biotechnological methods are expected to improve mechanistic understanding and support the rational design of safer, more effective next-generation cosmetic ingredients and formulations. Full article

Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction. Full article

Colorectal cancer therapy requires drug delivery systems that improve treatment efficacy and minimize systemic toxicity. In this study, chitosan-based nanoparticles were fabricated and functionalized with folic acid (FA), phenylalanine (PA), and butyric acid (BA) to enhance the delivery of curcumin to Caco-2 cancer cells. The nanoparticles were prepared using an ionic gelation method, and their physicochemical properties, cellular uptake efficiency, and cytotoxicity—including safety evaluation against normal HIEC-6 cells—were investigated. Results showed that ligand conjugation significantly influenced the physicochemical properties of the nanoparticles. CRFANP (FA-modified) exhibited the largest particle size (263.5 nm) due to its rigid aromatic structure, while CRPANP (PA-modified) showed an intermediate size (138.0 nm) and the lowest surface charge (15.59 mV). In contrast, CRBANP (BA-modified) presented the smallest particle size (128.2 nm) and the highest positive surface charge (23.27 mV). These distinct physicochemical properties directly influenced their cellular interactions; CRBANP and CRFANP showed higher uptake than CRPANP, with CRBANP yielding the maximum accumulation of curcumin in Caco-2 (21.92 nM/mg protein) and HT-29 cells (22.09 nM/mg protein). Correlating with the uptake data, cytotoxicity assays revealed that CRBANP was the most potent formulation, exhibiting the lowest IC₅₀ of 1.30 µM in Caco-2 cells, which was significantly lower than that of CRFANP (3.49 µM) and CRPANP (7.40 µM), while demonstrating high selectivity against Caco-2 cells with an SI of 46.5 and no apparent toxicity toward normal HIEC-6 cells. This enhanced efficacy is attributed to the synergistic action of butyric acid as a histone deacetylase inhibitor (HDACi), which complements curcumin’s anticancer activity. These findings indicate that integrating butyric acid into chitosan nanoparticles provides an effective and selective strategy for targeted colorectal cancer therapy. Full article

Background: Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. Methods: We report a novel de novo missense mutation p.Ala305Val in GAT-1 encoding SLC6A1, in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. Ala305Val was compared with the residue-matched comparator p.Ala305Thr (Ala305Thr). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. Results: AI-based stability predictors uniformly indicated destabilization of GAT-1 p.Ala305Val and GAT-1 p.Ala305Thr. GAT-1 p.Ala305Val reduced 3H GABA uptake across HEK293Ts, astrocytes, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ~80% in GAT-1 p.Ala305Val; PBA reduced ER retention to approximately ~40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved GABA uptake in the heterozygous condition but combined PBA plus wildtype allele augmentation produced rescue greater than either intervention alone in the available dose-response ranges. Conclusions: GAT-1 p.Ala305Val is a trafficking-impaired, loss-of-function variant whose dysfunction is amenable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter expression. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by genetic approaches. Full article

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on ethanol consumption remain poorly understood. Methods: We collected the nucleus accumbens shell (NAcSh) of HAD1 rats, which has been used to investigate the impact of TSA treatment on ethanol consumption. RNA-seq profiling of NAcSh followed by IPA and GSEA analysis were conducted. Results: Gene profiling identified differentially expressed genes (DEGs) with sex- and dose-specific effects, with some genes demonstrating high fold change (FC). Males showed significantly increased Oxt and decreased Ttr expression following 1 mg/kg TSA treatment. In females, Pmch expression significantly decreased following 1 mg/kg TSA treatment, whereas Tmem179 expression increased following 2 mg/kg TSA treatment. Pathways centered on Hdac and Fkbp5 in males, and Bdnf and estrogen receptor in females were significantly enriched following TSA treatment, with distinct pathways identified at the 1 mg/kg and 2 mg/kg doses. IL1β and β-estradiol are common upstream regulators among all groups. Unexpectedly, some common DEGs between male and female comparisons have opposite responses to the same dose of TSA. GSEA analysis has identified additional gene sets, hallmark genes and microRNAs, and functions including immune response, metabolism, and estrogen response significantly associated with TSA treatment. Conclusions: This study successfully identified gene expression evidence that TSA treatment is sex- and dose-specific, underscoring the importance of considering both variables in the development of HDAC-targeted therapies for alcohol use disorders. Full article

Background: Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy, and LY-11h is a novel acylhydrazide-based histone deacetylase inhibitor with promising therapeutic potential for AML. However, its poor aqueous solubility, limited intestinal dissolution, and narrow therapeutic window hinder oral formulation development and motivate the development of dosage forms with flexible dose-design capabilities. Herein, an integrated hot-melt extrusion (HME)–fused deposition modeling (FDM) strategy was developed to convert LY-11h into printable amorphous solid dispersion (ASD) dosage forms. Methods: HPMC-AS was used as a pH-responsive carrier to enhance intestinal release while restricting premature gastric release, and HPC-EF was incorporated to improve filament processability. Single-factor and DoE studies identified critical formulation and process variables and established formulation–process–property relationships, while machine learning further modeled nonlinear interactions and guided optimization. In-line near-infrared spectroscopy combined with polarized light microscopy enabled real-time monitoring of LY-11h amorphization and melt homogenization during HME. Results: ExtraTrees and Bagging models showed promising predictive performance for key filament properties, and PAT-stage validation confirmed strong agreement with experimental values. The 15 DoE-designed ASD filaments were successfully fabricated into FDM-printed tablets with reproducible geometry. Equilibrium-solubility and in vitro dissolution studies demonstrated enhanced intestinal-pH solubility and reproducible pH-responsive release. Conclusions: Collectively, these findings establish a technological proof of concept for the manufacture of LY-11h dosage forms with adjustable formulation and geometric attributes. Further in vivo pharmacokinetic studies are required to determine whether these manufacturing capabilities translate into predictable dose–exposure relationships and individualized dose control. Full article

Epigenetic mechanisms play a crucial role in OC drug resistance, and emerging evidence suggests that dysregulated epigenetic modifications are among the key contributors to OC. Epigenetic agents, including DNA methyltransferase inhibitors, histone deacetylase inhibitors, and non-coding RNA-based therapeutics, have important limitations, including poor water solubility, limited tissue distribution, low stability, and systemic toxicity. To overcome this, a novel drug delivery system is needed to manage variability in drug administration and maximize the efficacy of these drugs. In this regard, nanotechnology offers an attractive option for formulating epigenetic drugs with various encapsulation strategies to increase bioavailability and drug efficacy, reduce drug dose, administration frequency, and toxicity, and enhance cellular internalization and tumor-targeted delivery. In this review, we summarize various epigenetic regulators and their roles in OC therapy resistance as well as the development of nanosystems for epigenetic drug delivery, which could lay the foundation for designing nanoformulations encapsulating epigenetic therapeutics, ultimately advancing personalized, targeted therapy for patients with OC. This review also discusses the current clinical status of nanocarrier platforms and translational barriers that limit the clinical development of epigenetic nanomedicine, highlighting the future directions required for successful clinical translation. Full article

Background: Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its pronounced molecular heterogeneity and frequent resistance to conventional therapies. A key driver of therapeutic failure is the overexpression of the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-XL), which collectively maintain mitochondrial integrity and promote tumor cell survival. Methods: In this study, we evaluated a rational combination strategy targeting these complementary survival pathways using the histone deacetylase inhibitor panobinostat and the DNA-damaging agent bleomycin in HepG2 cells, a p53-functional HCC cell model. Results: In HepG2 cells, each agent alone produced only limited cytotoxicity, whereas their combination resulted in a marked and synergistic induction of apoptosis. This was shown by increased Annexin V positivity, mitochondrial outer membrane permeabilization (MOMP), and activation of caspases-8, -9, and -3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Mechanistically, panobinostat reduced Bcl-XL expression and primed mitochondria for apoptosis but simultaneously triggered compensatory upregulation of Mcl-1, representing an adaptive resistance response within this experimental system. Bleomycin effectively counteracted this escape mechanism by suppressing Mcl-1 induction, thereby lowering the apoptotic threshold and enabling mitochondrial permeabilization. In parallel, combined treatment potentiated caspase-8 cleavage, suggesting an additional caspase-8-associated apoptotic signal that amplified caspase-3/PARP execution. Pharmacological inhibition with zVAD-FMK confirmed that the observed cell death was predominantly caspase-dependent, supporting a coordinated engagement of both intrinsic and extrinsic apoptotic pathways. In summary, the combination of panobinostat and bleomycin overcomes anti-apoptotic defenses in HepG2 cells through synergistic and coordinated disruption of mitochondrial survival checkpoints and dual apoptosis pathway activation. Conclusions: By blocking a compensatory Mcl-1 escape response while simultaneously engaging extrinsic apoptosis signaling, this strategy produces potent synergistic cell death in this defined p53-functional HCC model and represents a promising mechanistic proof of concept that warrants further validation in additional molecularly diverse HCC models before broader translational conclusions can be drawn. Full article

Cancer metastasis is the leading cause of cancer-related mortality, accounting for more than 90% of cancer deaths worldwide. However, the epigenetic mechanisms governing the metastatic cascade remain incompletely understood. Epigenetic reprogramming, including reversible changes in histone modifications, DNA methylation, chromatin remodeling, and non-coding RNA (ncRNA)-mediated regulation, enables tumor cells to acquire invasive, migratory, stem-like, and immune-evasive characteristics. During epithelial-to-mesenchymal transition (EMT), key epigenetic regulators such as histone deacetylases (HDACs), the Polycomb repressive complex 2 (PRC2) subunit EZH2, lysine-specific demethylase 1 (LSD1/KDM1A), and bromodomain and extraterminal (BET) proteins repress epithelial gene expression while activating mesenchymal transcriptional programs, promoting invasion and dissemination. At distant sites, epigenetic plasticity facilitates metastatic colonization through mesenchymal-to-epithelial transition (MET) and adaptive chromatin remodeling. Because these changes are reversible, they represent attractive therapeutic targets. HDAC, EZH2, LSD1/KDM1A, BET, and DNA methyltransferase (DNMT) inhibitors have shown promise in preclinical models of metastasis, with several advancing through clinical trials. Long non-coding RNAs, particularly HOTAIR, function as epigenetic scaffolds that reinforce metastatic programs, while reciprocal interactions between tumor cells and the tumor microenvironment (TME) drive epigenetic adaptations that promote immune evasion and metastatic progression. In addition, circulating tumor DNA (ctDNA) methylation signatures are emerging as minimally invasive biomarkers for assessing metastatic risk and monitoring treatment. This review summarizes current insights into the epigenetic regulation of cancer metastasis, evaluates emerging epigenetic therapies, and highlights translational opportunities to advance precision anti-metastatic strategies and improve patient outcomes. Full article

Diabetic painful neuropathy (DPN) is a common complication of diabetes. Despite ongoing efforts, the underlying biological mechanisms of DPN remain poorly understood. Hyperglycemia-mediated oxidative stress can affect cell barrier properties, triggering low-grade inflammation. Previous studies have reported increased histone deacetylase (HDAC) activity and altered expression of tight junction proteins in diabetes, which may link to nerve damage. This study examined the effects of the HDAC inhibitor FK228 on cell barrier-mediated changes in the spinal cord and dorsal root ganglia (DRG) of type 2 diabetic mice. Diabetic mice were treated with FK228 (1 mg/kg, twice a week for 3 weeks). Behavioral assessment of cold hypersensitivity was assessed at the end of the treatment regimen. In vitro studies were conducted using ND7/23 immortalized DRG cells. The expression of tight junction proteins (occludin, claudin-1, and zona occludens-1 or ZO-1) and a number of stress-related cellular markers, including HDAC2, growth-associated protein (GAP) 43, epidermal growth factor receptor (EGFR), and nuclear factor erythroid 2-related factor (Nrf2), were evaluated in DRG, spinal cord tissue, and cultured ND7/23 DRG cells following treatment. FK228 treatment demonstrated changes in cold pain sensitivity as well as the expression of tight junction proteins and stress related markers in both in vivo and in vitro models of diabetic neuropathy. These findings indicate that HDAC inhibition by FK228 may support the maintenance of tight junction protein expression and alter cellular stress responses in the spinal cord and DRG, suggesting a possible role of FK228 in mitigating DPN. Full article

The review covers research on dual-target antitumor agents over the past five years. One of the targets is histone deacetylases (HDACs), while the second potential target is a protein group located both on the membrane surface (phosphatidylinositol 3-kinase (PI3K), anaplastic lymphoma kinase (ALK), receptor tyrosine kinase (AXL), tyrosine protein kinase (HER2), FMS-like tyrosine kinase (FLT3), and vascular endothelial growth factor receptor (VEGFR2)) and in the nucleus (serine/threonine protein kinase Wee1, DNA methyltransferase (DNMT), dual-specificity phosphatase (CDC25A), an enzyme from the cyclin-dependent kinase family (CDK9), dual-specificity tyrosine-serine/threonine kinase (DYRK2), and BET family proteins (BRD4, BD1, and BD2)). This review presents the results of studies on the inhibitory activity of various HDAC isoforms and other enzymes, as well as in vitro cytotoxicity studies on both neoplastic and healthy cells. It also includes selectivity studies, in vivo experiments (changes in tumor volume in mice) and oral bioavailability assessments. The review also describes the chemical structures of several dual-target agents and identifies the molecular fragments responsible for inhibiting different targets. Based on the studies reviewed in this paper, it can be concluded that some dual inhibitors have superior in vitro cytotoxicity and exhibit selectivity towards some tumor cells compared to monofunctional reference compounds. These findings may be useful for molecular design in the field of polypharmacology, with the aim of developing new dual-target molecules that exhibit improved antitumor activity and selectivity towards neoplastic cells. Full article

Posterior axis development during mammalian embryogenesis is driven by transient progenitor states that give rise to neural and mesodermal lineages, including neuromesodermal progenitors (NMPs). In vitro derivation of posterior progenitor populations from human pluripotent stem cells (hPSCs) has relied on modulation of Wnt and FGF signaling; however, these approaches frequently generate heterogeneous and unstable cell populations. Here, we investigated whether sodium butyrate (NaB) supplementation could promote a posteriorly biased intermediate state without extensive extracellular signaling control. We show that NaB, a histone deacetylase inhibitor, promotes the induction of posterior pre-neural progenitors (PNPs) characterized by co-expression of CDX2 and SOX2, together with suppression of SOX1. Transcriptomic analyses revealed that NaB-treated cells exhibit a posteriorly enriched PNPs with restrained anterior neural differentiation, transient early TBXT induction, and progressive activation of posterior HOX genes, consistent with an incompletely caudalized intermediate rather than a fully specified NMP population. Importantly, these PNPs remained responsive to canonical neural tube patterning cues, including retinoic acid and smoothened agonists, enabling further differentiation toward ventral spinal cord lineages. Collectively, our findings demonstrate that NaB supplementation supports posterior PNPs from hPSCs, providing a simple and reproducible platform for modeling early posterior neural development in vitro. Full article

Wheat anther culture-mediated embryogenesis is strongly influenced by genotype responsiveness and remains limited by low embryo-like structure (ELS) conversion efficiency, frequent albino formation, and unstable developmental progression. In this study, the effects of DNA methylation inhibitors (5-azacytidine (AZC), 5-aza-2′-deoxycytidine (DEC), and zebularine (ZEB)) and the histone deacetylase inhibitor trichostatin A (TSA) on ELS induction, ELS conversion into green regenerants (GRs), albino frequency, and spontaneous genome doubling were evaluated in wheat anther cultures with contrasting embryogenic responsiveness. The results revealed strong genotype-dependent responses to treatments with epigenetic inhibitors. The spring wheat cultivar AC Abbey showed the highest overall anther culture response, whereas winter wheat genotypes displayed limited and variable ELS conversion competence. ELS formation was observed even in recalcitrant genotypes but was not consistently associated with efficient ELS conversion into GR. Multivariate analyses indicated stronger genotype differentiation at the conversion stage than during ELS induction, suggesting that this stage represents a major bottleneck in wheat anther culture-mediated embryogenesis. Among the tested compounds, AZC and TSA most effectively stimulated ELS induction, while AZC was associated with the lowest albino frequency. DEC showed the highest proportion of spontaneous doubled haploids. Overall, treatment with epigenetic inhibitors may enhance ELS induction but does not overcome genotype-dependent recalcitrance at the conversion stage under the applied anther culture conditions. Full article

Histone deacetylases (HDACs) are important epigenetic regulatory enzymes contributing to cancer proliferation, which could be critical targets in cancer therapy. The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC₅₀ values of 3.44 μM and 3.39 μM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics. Full article