Search Results (1,673)

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

Pediatric asthma is a multifactorial and heterogeneous disease determined by the dynamic interplay of genetic susceptibility, environmental exposures, and immune dysregulation. Recent advances have highlighted the pivotal role of epigenetic mechanisms, in particular, DNA methylation, histone modifications, and non-coding RNAs, in the regulation of inflammatory pathways contributing to asthma phenotypes and endotypes. This review examines the role of respiratory viruses such as respiratory syncytial virus (RSV), rhinovirus (RV), and other bacterial and fungal infections that are mediators of infection-induced epithelial inflammation that drive epithelial homeostatic imbalance and induce persistent epigenetic alterations. These alterations lead to immune dysregulation, remodeling of the airways, and resistance to corticosteroids. A focused analysis of T2-high and T2-low asthma endotypes highlights unique epigenetic landscapes directing cytokines and cellular recruitment and thereby supports phenotype-specific aspects of disease pathogenesis. Additionally, this review also considers the role of miRNAs in the control of post-transcriptional networks that are pivotal in asthma exacerbation and the severity of the disease. We discuss novel and emerging epigenetic therapies, such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, miRNA-based treatments, and immunomodulatory probiotics, that are in preclinical or early clinical development and may support precision medicine in asthma. Collectively, the current findings highlight the translational relevance of including pathogen-related biomarkers and epigenomic data for stratifying pediatric asthma patients and for the personalization of therapeutic regimens. Epigenetic dysregulation has emerged as a novel and potentially transformative approach for mitigating chronic inflammation and long-term morbidity in children with asthma. 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

Psoriasis is a chronic inflammatory skin disease characterized by abnormal proliferation of keratinocytes and infiltration of inflammatory cells. Significant challenges remain in developing effective and safe targeted therapies for psoriasis. Here, we reported the discovery of novel cystamine derivatives for the treatment of psoriasis. These compounds effectively attenuated LPS-induced inflammation in vitro, and the optimal candidate CS1 ameliorated imiquimod-induced psoriasis-like inflammation in mice. Mechanistically, CS1 bound and inhibited the deacetylase HDAC6, subsequently inhibited the AKT, MAPK, and STAT3 pathways, attenuated the hyperproliferation and altered differentiation of keratinocytes and reduced the infiltration of immune cells. These findings suggest that HDAC6 may serve as a potential target for drug development in the treatment of psoriasis. Full article

Background/Objectives: The prolonged M1-like pro-inflammatory polarization of macrophages is a key factor in the delayed healing of diabetic ulcers (DU). SIRT3, a primary mitochondrial deacetylase, has been identified as a regulator of inflammation and represents a promising new therapeutic target for DU treatment. Nonetheless, the efficacy of existing SIRT3 agonists remains suboptimal. Methods: Here, we introduce a novel compound, SZC-6, demonstrating promising activity levels. Results: SZC-6 treatment down-regulated the expression of inflammatory factors in LPS-treated RAW264.7 cells and reduced the proportion of M1 macrophages. Mitosox, IF, and JC-1 staining revealed that SZC-6 preserved cellular mitochondrial homeostasis and reduced the accumulation of reactive oxygen species. In vivo experiments demonstrated that SZC-6 treatment accelerated wound healing in diabetic mice. Furthermore, HE and Masson staining revealed increased neovascularization at the wound site with SZC-6 treatment. Tissue immunofluorescence results indicated that SZC-6 effectively decreased the proportion of M1-like cells and increased the proportion of M2-like cells at the wound site. We also found that SZC-6 significantly reduced MyD88, p-IκBα, and NF-χB p65 protein levels and inhibited the nuclear translocation of P65 in LPS-treated cells. Conclusions: The study concluded that SZC-6 inhibited the activation of the NF-χB pathway, thereby reducing the inflammatory response and promoting skin healing in diabetic ulcers. SZC-6 shows promise as a small-molecule compound for promoting diabetic wound healing. Full article

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems. Full article

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases. Full article

β-hydroxybutyrate (BHB) is the most abundant ketone body produced during ketosis, a process initiated by glucose depletion and the β-oxidation of fatty acids in hepatocytes. Traditionally recognized as an alternative energy substrate during fasting, caloric restriction, and starvation, BHB has gained attention for its diverse signaling roles in various physiological processes. This review explores the emerging therapeutic potential of BHB in the context of sarcopenia, metabolic disorders, and neurodegenerative diseases. BHB influences gene expression, lipid metabolism, and inflammation through its inhibition of Class I Histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs), specifically HCAR2 and FFAR3. These actions lead to enhanced mitochondrial function, reduced oxidative stress, and regulation of inflammatory pathways, with implication for muscle maintenance, neuroprotection, and metabolic regulation. Moreover, BHB’s ability to modulate adipose tissue lipolysis and immune responses highlight its broader potential in managing chronic metabolic conditions and aging. While these findings show BHB as a promising therapeutic agent, further research is required to determine optimal dosing strategies, long-term effects, and its translational potential in clinical settings. Understanding BHB’s mechanisms will facilitate its development as a novel therapeutic strategy for multiple organ systems affected by aging and disease. Full article

Background/Objectives: Glioblastoma (GBM) is an aggressive brain tumor known for its profound heterogeneity and treatment resistance. Dysregulated complement signaling and epigenetic alterations have been implicated in GBM progression. This study identifies kynureninase (KYNU), a key enzyme in the kynurenine pathway, as a novel regulator of complement components and investigates its interaction with histone deacetylase 6 (HDAC6) in the context of therapeutic targeting. Methods: KYNU expression, and its association with complement signaling in GBM, were analyzed using publicly available datasets (TCGA, GTEx, HPA). Pathway enrichment was performed via LinkedOmics. In vitro studies in GBM cell lines (U87, U251, T98G) assessed the effects of KYNU silencing and treatment with an HDAC6 inhibitor (tubastatin) and a BET inhibitor (apabetalone) on gene expression and cell viability. Results: Bioinformatic analyses revealed significant overexpression of KYNU in GBM tissues compared to normal brain tissue. KYNU expression was positively associated with genes involved in complement and coagulation cascades. In vitro experiments demonstrated that KYNU silencing reduced the expression of C3, C3AR1, and C5AR1 and suppressed GBM cell viability. Treatment with tubastatin, while reducing viability, paradoxically upregulated complement genes, suggesting potential limitations in therapeutic efficacy. However, this effect was mitigated by KYNU knockdown. Combined treatment with apabetalone and tubastatin effectively suppressed KYNU expression and enhanced cytotoxicity, particularly in cells with high complement expression. Conclusions: Our findings establish the KYNU–HDAC6–complement axis as a critical regulatory pathway in GBM. Targeting KYNU-mediated complement activation through combined epigenetic approaches—such as HDAC6 and BET inhibition—represents a promising strategy to overcome complement-driven resistance in GBM therapy. Full article

Background/Objectives: SIRT1 is a NAD⁺-dependent protein deacetylase regulating metabolic and stress response pathways. Genetic variations in the SIRT1 gene may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This case–control study investigates the associations of two SIRT1 promoter polymorphisms, rs12778366 and rs3758391, in patients with type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM), preeclampsia, and healthy controls. Methods: This case–control study compared the genotypes between T2DM and pregnant and non-pregnant controls. We also compared genotypes between pregnant women with T2DM, GDM, preeclampsia, and healthy pregnant controls. Genomic DNA was extracted and analyzed using PCR-RFLP for the detection of rs12778366 and rs3758391 polymorphisms. Genotype frequencies were compared using chi-square tests, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The study included 66 patients with T2DM, 36 with GDM, 12 with preeclampsia, and 81 pregnant and non-pregnant controls (33 pregnant controls). Although rs3758391 was more frequent in T2DM, the difference was not statistically significant between SIRT1 polymorphisms and T2DM. The CT genotype was more prevalent in T2DM (54.5%) compared to controls (33.4%); however, this difference was not significant. We finally found no significant association of the investigated SIRT1 polymorphisms with any of the conditions studied. In addition, the small sample size, especially for preeclampsia cases, limits the statistical power to detect significant associations. Conclusions: Although no significant association was observed between SIRT1 polymorphisms and diabetes, the findings of our study underscore the need for further studies examining SIRT1 polymorphisms in various ethnic groups, with a focus on leveraging these genetic variations in diabetes pathophysiology. Larger studies in the Greek population could also provide additional meaningful findings. Full article

Class IIa histone deacetylases (HDACs) are pleiotropic regulators of various differentiation pathways and adaptive responses. They form complexes with other co-repressors and can bind to DNA by interacting with selected transcription factors, with members of the Myocyte Enhancer Factor-2 (MEF2) family being the best characterized. A notable feature of class IIa HDACs is the substitution of tyrosine for histidine in the catalytic site, which has occurred over the course of evolution and has a profound effect on the efficiency of catalysis against acetyl-lysine. Another distinctive feature of this family of “pseudoenzymes” is the regulated nucleus–cytoplasm shuttling associated with several non-histone proteins that have been identified as potential substrates, including proteins localized in the cytosol. Within the complexity of class IIa HDACs, several aspects deserve further investigation. In the following, I will discuss some of the recent advances in our knowledge of class IIa HDACs. Full article

Colorectal cancer (CRC) is associated with factors such as an unhealthy diet, physical inactivity, obesity, diabetes, and chronic inflammatory conditions like inflammatory bowel disease (IBD), as well as TP53 mutations, which are observed in a broad spectrum of CRC. Additionally, alteration in the composition of the gut microbiome community and metabolism plays a significant role in the development of colorectal cancer and its therapeutic effects. It is well known that treatment with sodium butyrate (NaB), an intestinal microbial metabolite, can induce apoptosis by activating histone deacetylase (HDAC) in cancer cells. Therefore, this study examined the relationship between NaB-induced apoptosis and p53 protein level in colorectal cancer cells. Treatment with NaB triggered cell death in the HCT116 cell line. Furthermore, a notable elevation in p53 protein level was detected following treatment with a high concentration of NaB, compared to both the control group and the low concentration NaB. Furthermore, apoptotic cell death was diminished in a p53-deficient cell line (HCT 116 p53^−/−) and p53 protein expression was more stabilized. Although p53 mRNA expression was not affected, acetylation of p53 protein was clearly observed by high concentration NaB treatment. To demonstrate the relationship between p53 acetylation and cell death, HT29 cells were treated with a high concentration of NaB. In HT29 cells with a mutation in the p53 gene, increased cell viability, overproduction p53 protein, and hyperacetylation of p53 were observed compared to the control. The results of this study suggest that p53 protein expression plays an important role in the effectiveness of therapy utilizing gut microbiota metabolites. Full article

Cardiovascular diseases (CVD), such as myocardial hypertrophy, heart failure, atherosclerosis, and myocardial ischemia/reperfusion (I/R) injury, are among the major threats to human health worldwide. Post-translational modifications alter the function of proteins through dynamic chemical modification after synthesis. This mechanism not only plays an important role in maintaining homeostasis and plays a crucial role in maintaining normal cardiovascular function, but is also closely related to the pathological state of various diseases. Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression, and play important roles in post-translational modification by catalyzing the deacetylation of key lysine residues in nucleosomal histones, which are closely associated with the occurrence and development of cardiovascular diseases. Recent studies indicate that HDAC inhibitors (HDACis) may represent a new class of drugs for the treatment of cardiovascular diseases by influencing post-translational modifications. In this review, we systematically summarize the mechanism of action of HDACs and HDACis in post-translational modifications related to common cardiovascular diseases, providing new ideas for the treatment of CVD, and explore possible future research directions on the relationship between HDAC and HDACi in post-translational modifications and cardiovascular diseases. Full article

Background/Objectives: Gestational diabetes mellitus (GDM) is a common metabolic disorder in pregnant women. It can lead to several complications, such as preterm delivery, macrosomia, or metabolic disorders in newborns. Studies have revealed morphological and transcriptional differences between the placentas of patients with GDM and women with normal glucose tolerance. Sirtuins (SIRTs) are nicotinamide adenine dinucleotide-dependent deacetylases that interact with and regulate the activity of numerous proteins. However, little is known about their role in the pathogenesis of GDM. This study was performed to analyze the placental expression of SIRTs and investigate their correlations with clinical parameters. Methods: GDM was diagnosed based on the 75 g oral glucose tolerance test in accordance with the criteria developed by the International Association of Diabetes and Pregnancy Study Groups. Placental tissues were collected, and the expression of SIRT1,-3,-4 and a reference gene (β-2 microglobulin) was analyzed. Results: The placental expression of SIRT1 and SIRT3 was elevated in women with GDM. However, there was no significant difference in SIRT4 expression between women with GDM and those with normal glucose tolerance. Furthermore, we found no significant correlations between SIRT1, SIRT3, and SIRT4 expression and clinical parameters. Conclusions: The findings of this study demonstrate elevated expression of SIRT1 and SIRT3 in the placentas of women with GDM. Further studies are required to confirm our observations and demonstrate the precise role of these enzymes in GDM. Full article

Sirtuins (SIRTs), a family of NAD+-dependent enzymes, play crucial roles in epigenetic regulation, metabolism, DNA repair, and stress response, making them relevant to glioma biology. This review systematically summarizes the molecular mechanisms and context-specific functions of SIRT1–SIRT7 in central nervous system tumors, with particular focus on gliomas. SIRT1, SIRT3, SIRT5, and SIRT7 are often overexpressed and promote glioma cell proliferation, stemness, therapy resistance, and metabolic adaptation. Conversely, SIRT2, SIRT4, and SIRT6 generally exhibit tumor-suppressive functions by inducing apoptosis, inhibiting invasion, and counteracting oncogenic signaling. Preclinical studies have identified several sirtuin modulators—both inhibitors and activators—that alter tumor growth, sensitize cells to temozolomide, and regulate pathways such as JAK2/STAT3, NF-κB, and mitochondrial metabolism. Emerging evidence positions sirtuins as promising targets for glioma therapy. Future studies should evaluate sirtuin modulators in clinical trials and explore their potential for patient stratification and combined treatment strategies. Full article