Search Results (1,301)

Background/Objectives: Cofilin, a key regulator of actin cytoskeleton dynamics, contributes to neuroinflammation, synaptic damage, and blood–brain barrier disruption in ischemic stroke. Despite its established role in stroke pathology, cofilin remains largely untargeted by existing therapeutics. This study aimed to identify potential cofilin-binding molecules by repurposing LIMK1 inhibitors through an integrated computational strategy. Methods: A cheminformatics pipeline combined QSAR modeling with four molecular fingerprint sets and multiple machine learning algorithms. The best-performing QSAR model (substructure–Random Forest) achieved R²_train = 0.8747 and R²_test = 0.8078, supporting the reliability of compound prioritization. Feature importance was assessed through SHAP analysis. Top candidates were subjected to molecular docking against cofilin, followed by 300 ns molecular dynamics simulations, MM-GBSA binding energy calculations, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analyses. Network pharmacology identified overlapping targets between selected compounds and stroke-related genes. Results: Three compounds, CHEMBL3613624, ZINC000653853876, and Gandotinib, were prioritized based on QSAR performance, binding affinity (−6.68, −6.25, and −5.61 Kcal/mol, respectively), and structural relevance. Docking studies confirmed key interactions with Asp98 and His133 on cofilin. Molecular dynamics simulations supported the stability of these interactions, with Gandotinib showing the highest conformational stability, and ZINC000653853876 exhibiting the most favorable energetic profile. Network pharmacology analysis revealed eight intersecting targets, including MAPK1, PRKCB, HDAC1, and serotonin receptors, associated with neuroinflammatory and vascular pathways in strokes. Conclusions: This study presents a rational, integrative repurposing framework for identifying cofilin-targeting compounds with potential therapeutic relevance in ischemic stroke. The selected candidates warrant further experimental validation. Full article

Neuroblastoma (NB) is an aggressive pediatric cancer, with high-risk patients facing a five-year survival rate of ~50%. Standard therapies, including surgery, chemotherapy, radiation, and immunotherapy, are associated with significant long-term toxicities and frequent relapse. Histone deacetylase (HDAC) inhibitors have emerged as promising agents for cancer therapy, given their role in modulating gene expression and tumor phenotypes. This study evaluated M344 [4-(dimethylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide], an HDAC inhibitor, for its efficacy and mechanisms of action against NB. Analysis of clinical NB Gene Expression Omnibus data revealed advanced-stage tumors exhibit higher HDAC expression relative to early-stage samples. M344 treatment effectively increased histone acetylation, induced G0/G1 cell cycle arrest, and activated caspase-mediated cell death. Relative to vorinostat, an HDAC inhibitor in clinical use for lymphoma and clinical trials for NB, M344 displayed superior cytostatic, cytotoxic, and migration-inhibitory effects. In vivo, metronomic M344 dosing suppressed tumor growth and extended survival. Combination therapy with M344 and topotecan improved topotecan tolerability, while M344 co-administration with cyclophosphamide reduced tumor rebound post-therapy. In total, M344 demonstrated strong therapeutic potential for NB, offering improved tumor suppression, reduced off-target toxicities, and enhanced control of tumor growth post-therapy. These findings support further investigation of HDAC inhibitors, such as M344, for clinical application in NB treatment. Full article

Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-related deaths, with notable sex-specific differences in its incidence, diagnosis, and outcomes. Our previous work identified casein kinase 2 alpha (CK2α) as being capable of impairing DNA mismatch repair (MMR) via phosphorylation of MLH1, thereby increasing the tumor mutational burden. This study aimed to investigate sex-specific differences in CK2α protein expression in CRC. Methods: Immunohistochemical (IHC) analysis was performed on 161 CRC tumors and adjacent normal tissues to quantify the CK2α protein levels. A multi-cohort meta-analysis of proteomic and clinical data was conducted to validate our findings and assess the correlations with age, sex, and relevant signaling pathways. Results: Female CRC patients exhibited significantly higher CK2α expression than male patients, which was confirmed in two independent cohorts. Additionally, CK2α expression was positively correlated with age in female but not male patients. Cross-cohort correlation analyses linked CK2α levels with key proteins involved in estrogen receptor signaling and aging, including DEAD-box helicase 5 (DDX5), histone deacetylase 1 (HDAC1), proliferating cell nuclear antigen (PCNA), prohibitin-2 (PHB2), H/ACA ribonucleoprotein complex subunit 2 (NHP2), and dual-specificity mitogen-activated protein kinase kinase 3 (MAP2K3). Conclusions: CK2α is significantly overexpressed in the tumor tissue of female CRC patients and shows a strong age-related correlation. These findings suggest a sex- and age-specific regulatory mechanism potentially influenced by estrogen signaling or menopause. Such dimorphisms underscore the need for sex-specific strategies in CRC biomarker development and therapy. Full article

Background: Histone deacetylase 6 (HDAC6) is a unique class IIb HDAC isozyme characterized by two catalytic domains and a zinc finger ubiquitin-binding domain. It plays critical roles in various cellular processes, including protein degradation, autophagy, immune regulation, and cytoskeletal dynamics. Due to its multifunctional nature and overexpression in several cancer types, HDAC6 has emerged as a promising therapeutic target. Methods: In this study, we employed a ligand-based pharmacophore modeling approach using a structurally diverse set of known HDAC6 inhibitors. This was followed by the virtual screening of over 140,000 commercially available compounds from both the MolPort and Asinex databases. The screening workflow incorporated pharmacophore filtering, molecular docking, and molecular dynamic (MD) simulations. Binding free energies were estimated using Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis to prioritize top candidates. A fluorometric enzymatic assay was used to measure HDAC6 activity, while cell viability assay by Cell Titer Glo was used to assess the anti-tumor activity against drug-sensitive and -resistant multiple myeloma (MM) cells. Western blotting was used to evaluate the acetylation of tubulin or histone H4 after treatment with selected compounds. Results: Three promising compounds were identified based on stable binding conformations and favorable interactions within the HDAC6 catalytic pocket. Among them, Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis identified Compound 10 (AKOS030273637) as the top theoretical binder, with a ΔG_bind value of −45.41 kcal/mol. In vitro enzymatic assays confirmed its binding to the HDAC6 catalytic domain and inhibitory activity. Functional studies on MM cell lines, including drug-resistant variants, showed that Compound 10 reduced cell viability. Increased acetylation of α-tubulin, a substrate of HDAC6, likely suggested on-target mechanism of action. Conclusions: Compound 10, featuring a benzyl 4-[4-(hydroxyamino)-4-oxobutylidene] piperidine-1-carboxylate scaffold, demonstrates potential drug-like properties and a predicted bidentate zinc ion coordination, supporting its potential as an HDAC6 inhibitor for further development in hematologic malignancies. Full article

Hepatocellular carcinoma (HCC) is a leading cause of global cancer-related mortality worldwide. Increasing evidence indicates that epigenetic mechanisms, which are potentially reversible and modifiable by environmental and nutritional factors, play a key role in hepatocarcinogenesis. Histone deacetylases (HDACs) are fundamental epigenetic modulators that regulate chromatin dynamics and ultimately gene transcription with important pathophysiological implications and promising therapeutic perspectives. The role of HDACs is gaining interest for the understanding of HCC development mechanisms and for the potential therapeutic implications of their natural and synthetic inhibitors. This review provides an overview on HDACs classification and their peculiar expression patterns in HCC, with a focus on zinc-dependent histone deacetylases (HDACs). HDAC inhibitors (HDACis), both synthetic and natural-derived compounds, are also discussed for their emerging effects in optimizing the anticancer efficacy of the current therapeutic strategies. Novel dietary-derived and bioactive compounds-based interventions are discussed in the context of HCC management as promising nutri-epigenetic avenues. Targeting HDACs bears a significant therapeutic potential for HCC management while further confirmatory clinical investigation is warranted. Full article

Histone deacetylases (HDACs) are key epigenetic regulators that influence chromatin remodeling, gene expression, and cellular plasticity in the central nervous system (CNS). This review provides a comprehensive overview of the classification and functional diversity of HDACs, with particular emphasis on their roles in neural progenitor cells, mature neurons, and glial populations. In neural stem and progenitor cells, HDACs modulate neurogenesis, fate specification, and lineage commitment. In differentiated neurons, HDACs govern synaptic plasticity, memory formation, and survival. In glial cells, including astrocytes and microglia, HDACs orchestrate inflammatory responses, redox balance, and metabolic adaptations. We further examine the dysregulation of HDAC expression and activity in major neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Evidence from human post-mortem brain studies reveals region- and isoform-specific alterations in HDAC expression, which are closely associated with cognitive decline, mitochondrial dysfunction, and neuroinflammation. Preclinical studies support the use of HDAC inhibitors (HDACi) as neuroprotective agents, capable of restoring acetylation homeostasis, reducing neuroinflammation, and improving neuronal function. Given the relevance of HDACi, we summarize current clinical studies assessing the safety of these compounds in the context of tumor biology, as well as their potential future applications in neurodegenerative diseases. Together, this review underscores the dual significance of HDACs as biomarkers and therapeutic targets in the context of CNS disorders. Full article

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. Full article

Ischemic brain and retinal injuries trigger complex molecular cascades involving neuroinflammation, oxidative stress, and neuronal death. Among these mechanisms, epigenetic regulation has emerged as a critical modulator of the injury response. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) dynamically control gene expression by altering chromatin structure. HDACs often promote neuroinflammation and neuronal apoptosis through repression of neuroprotective and anti-inflammatory genes, while HATs generally enhance the transcription of genes involved in cell survival and repair. In ischemia, specific HDAC isoforms (e.g., HDAC1, HDAC2, HDAC3, and HDAC6) have been implicated in microglial activation, glial reactivity, and disruption of immune balance. Conversely, HATs such as CBP/p300 and Tip60 contribute to neuronal resilience and immune regulation. Understanding the dual and context-dependent roles of these epigenetic enzymes offers promising therapeutic avenues. Selective HDAC inhibitors or HAT activators may represent novel strategies to mitigate ischemic damage, support neuroprotection, and facilitate functional recovery. Full article

Domatinostat is an inhibitor of class I histone deacetylases, whose safety and efficacy as a cancer therapeutic has been demonstrated in a recent phase II study in patients with esophagogastric adenocarcinoma. We previously showed that domatinostat exhibited preferential cytotoxic activity against glioma stem cells (GSCs) compared to their differentiated counterparts. However, the underlying mechanism behind the preferential cytotoxicity is yet to be elucidated. In this study, we examined the effects of domatinostat treatment, as well as those of the knockdown of p53 or BAX or of the overexpression of BAX, on the expression of p53, BAX, and cleaved caspase substrates and on cell death in GSCs and their isogenic, differentiated counterparts. The results obtained indicated that domatinostat induced caspase-dependent apoptotic cell death preferentially in GSCs, which was accompanied by increased BAX expression in GSCs, but not in their differentiated counterparts. The increased BAX expression was required for domatinostat-induced GSC death, whereas BAX overexpression was sufficient to induce cell death in both GSCs and their differentiated counterparts. Notably, the expression of BAX after domatinostat treatment showed an early, p53-independent increase followed by a late, p53-dependent one. Together, the results suggest that the unique ability of domatinostat to activate the p53-dependent and -independent programs of BAX expression selectively in GSCs could account for its preferential cytotoxicity against GSCs. Our findings may also help guide the selection of patients with glioblastoma, and possibly those with other types of cancer, who are most likely to benefit from domatinostat treatment and optimize the treatment strategy for such patients. Full article

Background/Objectives: Gliomas are complex and heterogeneous brain tumors characterized by an unfavorable clinical course and a fatal prognosis, which can be improved by an early determination of tumor kind. Here, we developed explainable machine learning (ML) models for classifying three major glioma subtypes (astrocytoma, oligodendroglioma, and glioblastoma) and predicting survival rates based on RNA-seq data. Methods: We analyzed publicly available datasets and applied feature selection techniques to identify key biomarkers. Using various ML models, we performed classification and survival analysis to develop robust predictive models. The best-performing models were then interpreted using Shapley additive explanations (SHAP). Results: Thirteen key genes (TERT, NOX4, MMP9, TRIM67, ZDHHC18, HDAC1, TUBB6, ADM, NOG, CHEK2, KCNJ11, KCNIP2, and VEGFA) proved to be closely associated with glioma subtypes as well as survival. Support Vector Machine (SVM) turned out to be the optimal classification model with the balanced accuracy of 0.816 and the area under the receiver operating characteristic curve (AUC) of 0.896 for the test datasets. The Case-Control Cox regression model (CoxCC) proved best for predicting survival with the Harrell’s C-index of 0.809 and 0.8 for the test datasets. Using SHAP we revealed the gene expression influence on the outputs of both models, thus enhancing the transparency of the prediction generation process. Conclusions: The results indicated that the developed models could serve as a valuable practical tool for clinicians, assisting them in diagnosing and determining optimal treatment strategies for patients with glioma. Full article

Uterine leiomyomas (ULM) and uterine leiomyosarcomas (ULMS) represent smooth muscle tumors with similar initial presentations but drastically different outcomes. This literature review analyzes the similarities and differences in their epigenetic profiles to identify diagnostic biomarkers and potential therapeutic targets that could improve clinical management. Both tumor types exhibit mostly distinct epigenetic signatures while sharing key pathway dysregulations. ULMS demonstrates global DNA hypomethylation, increased histone acetyltransferase activity, elevated Histone Deacetylase (HDAC) class I expression, and characteristic microRNA profiles. ULM displays focal methylation patterns and specific microRNA alterations that promote extracellular matrix accumulation. Despite these differences in epigenetic mechanisms, both tumors converge on dysregulation of signaling pathways including PI3K/AKT/mTOR, Wnt/β-catenin, and Transforming Growth Factor beta (TGF-β) signaling, suggesting common downstream effects from distinct epigenetic origins. Understanding the shared and distinct epigenetic landscape between ULM and ULMS will enhance our insights into tumor pathogenesis and may offer promising biomarkers and therapeutic targets. Full article

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer’s and Parkinson’s. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood–brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets—including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites—that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody–drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases. Full article

Background. Studies of comorbid (syntropic) and inversely comorbid (rarely occurring together, i.e., dystropic) diseases have focused on the search for molecular causes of this phenomenon. Materials. We investigated DNA methylation levels in regulatory regions of 23 apoptosis-associated genes as candidate loci associated with the “cancer–neurodegeneration” dystropy in patients with Huntington’s disease (HD) and patients with non–small cell lung cancer (LC). Results. Statistically significant differences in methylation levels between the HD and LC groups were found for 41 CpG sites in 16 genes. The results show that five genes (SETDB1, TWIST1, HDAC1, SP1, and GRIA2) are probably involved in the phenomenon of inverse comorbidity of these diseases. For these genes, the methylation levels of the studied CpG sites were altered in opposite directions in the two groups of patients, compared to the control group. Conclusions. For the SP1 gene, the above hypothesis is supported by our analysis of open-access data on gene expression in patients with the aforementioned diagnoses and fits a probable mechanism of the “HD–LC” dystropy. Full article

Saffron (Crocus sativus L.) contains bioactive compounds with potential health benefits, including modulation of protein function and gene expression. However, their ability to tune the epigenetic machine remains poorly understood. This study employs molecular docking (AutoDock Vina 1.4), dynamics simulations, and MM/PBSA calculations to investigate the interactions between four saffron-derived molecules—crocetin, beta-D-glucosyl trans-crocetin, picrocrocin and safranal—and four epigenetic enzymes—DNMT1, DNMT3a, HDAC2, and SIRT1. Our in silico screening identifies beta-D-glucosyl trans-crocetin, one of the saffron’s crocins, as a potential DNMT1 inhibitor. Along with crocetin, it also shows the ability to inhibit HDAC2 and activate SIRT1. Picrocrocin displays a resveratrol-like ability to activate SIRT1. None of the saffron-derived compounds effectively bind or inhibit DNMT3a. Among the tested molecules, safranal shows no interaction with the selected epigenetic targets. These findings highlight saffron’s nutriepigenomic potential and emphasize the need for functional validation within relevant in vitro and in vivo experimental methodologies. Full article

Background/Objectives: Cancer suffers from unresolved therapeutic challenges owing to the lack of targeted therapies and heightened recurrence risk. This study aimed to investigate the new series of hydroxamate by structurally modifying the pharmacophore of vorinostat. Methods: The present work involves the synthesis of 15 differently substituted 2H-1,2,3-triazole-based hydroxamide analogs by employing triazole ring as a cap with varied linker fragments. The compounds were evaluated for their anticancer effect, especially their anti-breast cancer response. Molecular docking and molecular dynamics simulations were conducted to examine binding interactions. Results: Results indicated that among all synthesized hybrids, the molecule VI(i) inhibits the growth of MCF-7 and A-549 cells (GI₅₀ < 10 μg/mL) in an antiproliferative assay. Compound VI(i) was also tested for cytotoxic activity by employing an MTT assay against A549, MCF-7, and MDA-MB-231 cell lines, and the findings indicate its potent anticancer response, especially against MCF-7 cells with IC₅₀ of 60 µg/mL. However, it experiences minimal toxicity towards the normal cell line (HEK-293). Mechanistic studies revealed a dual-pathway activation: first, apoptosis (17.18% of early and 10.22% of late apoptotic cells by annexin V/PI analysis); second, cell cycle arrest at the S and G2/M phases. It also promotes ROS generation in a concentration-dependent manner. The HDAC–inhibitory assay, extended in silico molecular docking, and MD simulation experiments further validated its significant binding affinity towards HDAC 1 and 6 isoforms. DFT and ADMET screening further support the biological proclivity of the title compounds. The notable biological contribution of VI(i) highlights it as a potential candidate, especially against breast cancer cells. Full article