Search Results (524)

Heart failure with preserved ejection fraction (HFpEF) accounts for more than half of the cases of HF worldwide. Among the different phenotypes, cardiometabolic HFpEF has the highest prevalence. Cumulative insults related to cardiometabolic comorbidities—obesity, hypertension and type 2 diabetes—create a milieu of metabolic derangements, low-grade systemic inflammation (i.e., metainflammation), endothelial dysfunction, and coronary microvascular disease. Emerging data indicate that the gut–heart axis is a potential amplifier of this process. Cardiometabolic comorbidities promote gut dysbiosis, loss of short-chain fatty acid (SCFA)-producing taxa, and disruption of the intestinal barrier, leading to endotoxemia and upregulation of pro-inflammatory pathways such as TLR4- and NLRP3-mediated signaling. Concomitantly, beneficial gut-derived metabolites (acetate, propionate, butyrate) decrease, while detrimental metabolites increase (e.g., TMAO), potentially fostering myocardial fibrosis, diastolic dysfunction, and adverse remodeling. SCFAs—acetate, propionate, and butyrate—may exert pleiotropic actions that directly target HFpEF pathophysiology: they may provide a CPT1-independent energy substrate to the failing myocardium, may improve lipid and glucose homeostasis via G protein-coupled receptors and AMPK activation, and may contribute to lower blood pressure and sympathetic tone, reinforce gut barrier integrity, and act as anti-inflammatory and epigenetic modulators through the inhibition of NF-κB, NLRP3, and histone deacetylases. This review summarizes current evidence linking gut microbiota dysfunction to cardiometabolic HFpEF, elucidates the mechanistic role of SCFAs, and discusses nutritional approaches aimed at enhancing their production and activity. Targeting gut–heart axis and SCFAs pathways may represent a biologically plausible and low-risk approach that could help attenuate inflammation and metabolic dysfunctions in patients with cardiometabolic HFpEF, offering novel potential therapeutic targets for their management. Full article

Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets. We provide a critical overview of PI3K/HDAC multitarget inhibitors reported in recent years that have progressed to preclinical or clinical investigation, discussing the structural frameworks employed, medicinal chemistry strategies adopted, and structure–activity relationships established. Particular attention is given to advantageous molecular features as well as challenges related to toxicity, pharmacokinetic behavior, and pharmacodynamic modulation. From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are characterized by complex pathologies with progressive neurodegeneration, protein misfolding, oxidative stress, and persistent inflammation. Recent findings indicate the pivotal involvement of epigenetic disruption, particularly aberrant histone deacetylase (HDAC) activity, in disease initiation and progression. In the current review, we systematically discuss the mechanistic function of HDACs across all classes (I, IIa, IIb, III, and IV) in neurodegenerative disease mechanisms, such as their involvement in the modulation of gene expression, mitochondrial function, proteostasis, and neuronal survival. We discuss the therapeutic potential, as well as limitations, of HDAC inhibitors (HDACis), such as pan-inhibitors and isoenzyme-selective inhibitors, and new multi-target-directed ligands with HDAC inhibition combined with acetylcholinesterase modulation, PDE modulation, MAO-B inhibition, or NMDAR modulation. Particular emphasis is placed on the development of HDAC6-selective inhibitors with enhanced brain permeability and reduced toxicity, which have shown promising preclinical efficacy in ameliorating hallmark pathologies of AD, PD, and HD. In addition, s-triazine-based scaffolds have recently emerged as promising chemotypes in HDAC inhibitor design, offering favorable pharmacokinetic profiles, metabolic stability, and the potential for dual-target modulation relevant to neurodegeneration. The review also explores the future of HDAC-targeted therapies, including PROTAC degraders, dual-inhibitor scaffolds, and sustainable, BBB-penetrant molecules. Collectively, this review underscores the importance of HDAC modulation as a multifaceted strategy in the treatment of neurodegenerative diseases and highlights the need for continued innovation in epigenetic drug design. Full article

Background: Glioblastoma is the most common and malignant primary brain tumor in adults, with current treatment presenting limited effectiveness. Therapeutic resistance stems largely from its marked molecular and cellular heterogeneity. Multitarget small molecules (MSMs) have emerged as a promising strategy for treating complex diseases such as cancer. In the present work, we generated a novel family of indole-based MSMs engineered to inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs) while simultaneously acting as histamine H₃ receptor (H3R) antagonists and sigma-1 receptor (S1R) agonists. Methods: To accomplish this, we combined selected pharmacophoric moieties from the parent compounds Contilisant and the HDAC pan-inhibitor Belinostat. Nine MSMs were synthesized. Results: Most of them showed cytotoxic activity in glioma cells. Among them, three molecules (MTP142, MTP156 and MTP150) were prioritized based on potency; these compounds impaired glioma stem cell (GSC) activity and were predicted to cross the blood–brain barrier. In vivo and multi-omic analyses centered on MTP150 showed significant tumor growth inhibition, both as monotherapy and in combination with temozolomide (TMZ). Transcriptomic and proteomic profiling of patient-derived GSCs revealed MTP150-induced disruption of cell cycle regulation pathways. Conclusions: Our data reveal the efficacy of a novel family of MSMs in the pre-clinical setting of glioblastoma. Full article

Background: Ewing sarcoma (ES) is an aggressive malignancy and there is an unmet need for more effective treatment options for patients. Histone deacetylases (HDACs) have been shown to be involved in ES tumorigenesis and HDAC inhibitors have been investigated in the context of ES. Our objective for this study was to investigate the efficacy and mechanism of action of HDAC inhibition in vitro and in vivo in ES models, alone and in combination with standard of care therapies. Methods/Results: HDAC inhibitors were tested for in vitro efficacy against ES cell lines and romidepsin was found to be most effective. The mechanistic changes induced by romidepsin were investigated by Western blotting and proteins involved in cell cycle progression and DNA damage repair were found to be repressed. In vitro we identified that romidepsin synergizes with doxorubicin and etoposide and that it increases the efficacy of the standard of care combinations VDC/IE. Further, the combination treatments lead to an increase in caspase 3/7 cleavage, a decrease in DNA damage repair proteins, and an accumulation of DNA damage. In vivo, the combination of romidepsin and ifosfamide/etoposide (IE) leads to a significant decrease in tumor volume compared to that of IE alone. Conclusions: Our data indicates that romidepsin improves efficacy of chemotherapeutic agents in vitro and leads to a decreased tumor volume in vivo, suggesting that the addition of romidepsin may improve upfront treatment in ES patients. Full article

Background/Objectives: Glioblastoma is the most common and aggressive primary brain tumor in adults, with patient prognosis remaining poor. Treatment resistance and tumor recurrence are frequent, primarily due to the high intra- and inter-tumoral heterogeneity and the existence of glioma stem cells. Thus, there is an urgent need for novel and more effective therapeutic strategies. Multitarget small molecules (MSMs) are emerging as a novel therapeutic strategy for the treatment of complex diseases such as cancer. Methods: In the present work, we have generated a novel family of indole-based MSMs with pharmacophoric moieties combining the parent compounds Contilisant and the HDAC inhibitor Tubastatin A. Thus, the MSMs were designed to inhibit monoamine oxidases (MAOs), cholinesterases (ChEs) and histone deacetylases (HDACs), while acting as histamine H3 receptor (H3R) antagonists and sigma 1 receptor (S1R) agonists. We generated four different molecules and evaluated in detail the activity of the two most efficient MSM compounds in vitro and in vivo. Results: These molecules induced potent cytotoxic effects in vitro in patient-derived glioma stem cells and glioblastoma cell lines and significantly impaired tumor growth in vivo. OMIC analyses further revealed that the compounds induce dysregulation of the cell cycle in glioma stem cells. Moreover, in silico analyses indicated that these compounds are theoretically capable of crossing the blood–brain barrier, while exhibiting low toxicity in healthy cells. Conclusions: In conclusion, our findings demonstrate the potential antitumor activity of a novel family of MSMs in preclinical models of glioblastoma. Full article

Redox imbalance and epigenetic dysregulation, which both contribute to tumor initiation, survival, and resistance to therapy, are intimately linked to the progression of cancer. Reactive oxygen species (ROS) have two contrasting effects: at moderate concentrations, they promote angiogenesis and oncogenic signaling, whereas at high concentrations, they trigger apoptosis. Oxidative stress alters histone modifications, DNA methylation, and non-coding RNA (ncRNA) expression, reshaping the epigenetic landscape and supporting malignant phenotypes. Plant-derived antioxidants, including flavonoids, polyphenols, alkaloids, and terpenoids, act as dual modulators of cancer biology. They scavenge or regulate reactive oxygen species (ROS), restore redox balance, activate tumor suppressor pathways, inhibit oncogenic mechanisms, and reverse abnormal epigenetic marks. Compounds such as resveratrol, curcumin, epigallocatechin gallate (EGCG), quercetin, and sulforaphane modulate DNA methyltransferases (DNMTs), histone deacetylases (HDACs), and non-coding RNA networks, and can enhance chemotherapy and radiation therapy. Despite promising mechanisms, challenges remain in translational efficacy, optimal dosing, and bioavailability. This review emphasizes the potential of plant-derived antioxidants as precision oncology adjuncts and highlights the need for biomarker-guided strategies, nano-delivery systems, and clinical validation to fully realize their therapeutic benefits. Plant-derived antioxidants mitigate ROS-induced oncogenic signaling, as evidenced by in vitro and clinical models. Full article

Corneal problems, such as delayed and incomplete wound repair, are frequent in diabetes, affecting up to 70% of diabetic patients. In skin, histone deacetylases (HDACs) have been previously found to repress expression of the glycerol channel aquaporin-3 (AQP3), the deficiency of which delays corneal wound healing. We hypothesized that the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would improve corneal healing in diabetic mice. Diabetic and normoglycemic C57BL/6J male and female mice were subjected to corneal debridement. Wounds were treated topically with vehicle or SAHA every four hours until they healed. Treatment with SAHA improved wound healing in both normoglycemic and hyperglycemic male mice but, unexpectedly, no changes were detected in female mice. In male mice interleukin-1beta (IL-1β) and tumor necrosis factor (TNF) were significantly increased in diabetic corneas, and SAHA reduced their expression, returning IL-1β and TNF to levels comparable to those in normoglycemic mice regardless of treatment. In normoglycemic male mice, AQP3 levels were not changed in the cornea with SAHA treatment but the expression of AQP3 was increased in the wound’s edge relative to the rest of the cornea. In vitro SAHA treatment of human corneal epithelial cells (HCECs) significantly increased protein expression of AQP3, important for corneal wound healing, but had no effect on ROS production. In conclusion, treatment with SAHA improved corneal wound healing, not only in male mice with diabetes and delayed wound healing but also in normoglycemic male mice; therefore, SAHA could potentially be repurposed as a topical treatment clinically to improve corneal wound healing. Full article

Histone acetylation and deacetylation are key regulators of gene expression and are frequently dysregulated in cancer, contributing to tumorigenesis and drug resistance. Overexpression of histone deacetylases (HDACs) in many cancer types leads to silencing of tumor suppressor genes and uncontrolled proliferation. Tumors often rely on epigenetic mechanisms to escape therapy and develop resistance. This study aimed to identify novel compounds that selectively target cancer cells while minimizing toxicity to non-cancerous cell lines. A series of novel HDAC inhibitors was evaluated using the Differential Nuclear Staining (DNS) assay, flow cytometry, and HDAC inhibition assays. These assays assessed cytotoxicity, selectivity, and mechanisms of cell death. Among seven compounds tested, VS-186B exhibited the highest cytotoxicity and Selective Cytotoxicity Index (SCI), particularly against the human Jurkat T-cell leukemia cell line. Flow cytometry experiments (Annexin V-FITC, ROS, JC-1, and Caspase-3/7 assays) revealed that VS-186B induced apoptosis. VS-186B was more cytotoxic than Curcumin and Vorinostat across most of the cell lines tested and was more specific to hematological cells. Connectivity Map (CMap) analysis showed strong similarity to genes affected by known HDAC inhibitors. Subsequently, HDAC enzymatic assays confirmed that VS-186B inhibits Class I and II HDACs in a dose-dependent manner. VS-186B exhibits promising anticancer potential as a selective HDAC inhibitor since it induces apoptosis in cancer cells without significant cytotoxicity to non-cancerous lines with a similar gene expression profile to known HDAC inhibitors. These findings support further development of VS-186B as an epigenetic treatment for leukemia/lymphoma. Full article

Sirtuin 1 (SIRT1), an NAD⁺-dependent histone deacetylase, exerts complex and context-dependent effects in breast and gynecological cancers. By deacetylating histone and non-histone proteins such as p53, FOXO, and NF-κB, SIRT1 regulates essential processes including DNA repair, apoptosis, metabolism, and stress response. In breast cancer, SIRT1 may act as a tumor suppressor in early stages by maintaining genomic stability but promotes epithelial–mesenchymal transition, metastasis, and chemoresistance in aggressive subtypes such as triple-negative breast cancer. Similarly, in gynecological cancers, SIRT1 displays dual roles: promoting proliferation via estrogen signaling and p53/FOXO1 inhibition in Type I endometrial cancer yet potentially supporting DNA repair in high-grade Type II tumors. Its overexpression in ovarian and cervical cancers is linked to enhanced survival and drug resistance. Preclinical studies show that pharmacological inhibition of SIRT1 (e.g., with EX-527 or cambinol) restores chemosensitivity and reduces tumor cell viability, suggesting potential for SIRT1 inhibitors as adjuncts in cancer therapy. However, clinical trials specifically targeting SIRT1 in these cancers remain limited. Further investigation is needed to define therapeutic windows, molecular contexts, and combination strategies that could optimize SIRT1-targeted therapies. This review summarizes the current understanding of SIRT1’s roles in breast and gynecologic malignancies. Full article

Background/Objectives: Dilated cardiomyopathy (DCM) is a prevalent and life-threatening heart muscle disease often caused by titin (TTN) truncating variants (TTNtv). While TTNtvs are the most common genetic cause of heritable DCM, the precise downstream regulatory mechanisms linking TTN deficiency to cardiac dysfunction and maladaptive fibrotic remodeling remain incompletely understood. This study aimed to identify key epigenetic regulators of TTN-mediated gene expression and explore their potential as therapeutic targets, utilizing human patient data and in vitro models. Methods: We analyzed RNA sequencing (RNA-seq) data from left ventricles of non-failing donors and cardiomyopathy patients (DCM, HCM, PPCM) (GSE141910). To model TTN deficiency, we silenced TTN in human iPSC-derived cardiomyocytes (iPSC-CMs) and evaluated changes in cardiac function genes (MYH6, NPPA) and fibrosis-associated genes (COL1A1, COL3A1, COL14A1). We further tested the effects of TMP-195, a class IIa histone deacetylase (HDAC) inhibitor, and individual knockdowns of HDAC4/5/7/9. Results: In both human patient data and the TTN knockdown iPSC-CM model, TTN deficiency suppressed MYH6 and NPPA while upregulating fibrosis-associated genes. Treatment with TMP-195 restored NPPA and MYH6 expression and suppressed collagen genes, without altering TTN expression. Among the HDACs tested, HDAC5 knockdown was most consistently associated with improved cardiac markers and reduced fibrotic gene expression. Co-silencing TTN and HDAC5 replicated these beneficial effects. Furthermore, the administration of TMP-195 enhanced the modulation of NPPA and COL1A1, though its impact on COL3A1 and COL14A1 was not similarly enhanced. Conclusions: Our findings identify HDAC5 as a key epigenetic regulator of maladaptive gene expression in TTN deficiency. Although the precise mechanisms remain to be clarified, the ability of pharmacological HDAC5 inhibition with TMP-195 to reverse TTN-deficiency-induced gene dysregulation highlights its promising translational potential for TTN-related cardiomyopathies. Full article

Osteosarcoma primarily occurs in children and adolescents, and is a highly aggressive bone tumor, particularly presenting challenges in metastatic or recurrent cases due to chemoresistance. Emerging evidences suggest that histone deacetylase inhibitors (HDACis) may exert anti-tumor effects by enhancing the efficacy of various therapeutic modalities. However, the combination of traditional chemotherapy with HDACi-based treatment for osteosarcoma intervention has not been thoroughly explored. This study investigates the anticancer properties of HDACis and/or etoposide (VP16) on the osteosarcoma cell lines U2OS and SJSA-1. Cell viability, morphology, growth and apoptosis were evaluated after treatments, in addition to their influence on the expression levels of proteins associated with apoptotic processes. To elucidate the underlying mechanisms, we employed RNA sequencing, RT-qPCR, and Western blot analyses. Treatment with either HDACis or VP16 alone resulted in an antiproliferative effects in U2OS and SJSA-1 cell lines. Notably, HDACis significantly increased the sensitivity of osteosarcoma cells to VP16, as evidenced by marked differences in cell viability, growth, morphology and apoptosis. Furthermore, when compared to doxorubicin treatment, this VP16/TSA/NAM combinatory regimen demonstrated a comparable ability to suppress cell viability while exhibiting a more pronounced inhibition of cell proliferation. Mechanistically, the combination of HDACis and VP16 specifically resulted in inhibition of the Hippo/YAP signaling cascade, accompanied by a reduction in total YAP1 protein expression. Collectively, our findings suggest that HDACis potentiate the capacity of VP16 to hinder cellular proliferation and trigger apoptosis via the downregulation of the Hippo/YAP pathway, thereby providing a prospective approach to overcome chemoresistance in osteosarcoma. Full article

Background/Objectives: The effects of PD-L1 are mediated via its binding to the PD-1 receptor, which mediates the signals intracellularly to suppress T-cell responses. The expression levels of PD-L1 on cancer cells are an important indicator of immunosuppression and cause poor prognosis in several types of cancers. Therefore, the identification and characterization of mechanisms that regulate the expression of PD-L1 in cancer patients is very critical. Method: Our experiment was designed to determine the impact of histone deacetylase (HDAC) inhibitor on PD-L1 expression to reverse tumor-induced immunosuppression using H460 and HCC827 lung cancer cell lines. These cells were treated with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). PD-L1 expression levels were assessed along with key regulatory proteins, including p53, p21, acetyl-histones, DNMT3B, MGMT, and trimethyl histones. Results: In our experiments, suberoylanilide hydroxamic acid (SAHA) was able to reduce the expression of PD-L1 by 60% in a dose-dependent manner. While the level of PD-L1 was significantly reduced, a concurrent increase in levels of p53, p21, and acetyl histone levels were observed in H460 and HCC827 cells following SAHA treatment. Furthermore, SAHA treatment was able to decrease the levels of DNMT3B, MGMT, and tri-methyl histones. It appears that the decrease in PD-L1 expression observed is solely because of p53 or p21WAF1/CIP1-mediated negative control on the transcription process. Conclusion: Our results suggest that SAHA can be used along with immune checkpoint inhibitors to potentiate the therapeutic outcomes in patients with excessive immunosuppression due to PD-L1 expression. Full article

Vorinostat, an FDA-approved histone deacetylase inhibitor, was evaluated for its potential anti-inflammatory activity through modulation of TACE (ADAM17)-mediated TNF-α signaling. The study was conducted using LPS-stimulated RAW264.7 macrophages. TACE enzymatic activity was assessed by a fluorogenic assay, TNF-α release was measured by ELISA, and phosphorylation of MAPKs and NFκB signaling proteins was examined by a western blot. Molecular docking was performed using GNINA to evaluate binding affinity to ERK. Vorinostat was found to modestly inhibit TACE enzymatic activity in vitro, while significantly suppressing TNF-α secretion in cells, comparable to the selective TACE inhibitor BMS-561392. A concentration-dependent reduction in phosphorylated IκB and NFκB was observed, along with selective inhibition of ERK phosphorylation. Docking studies indicated a stable, albeit weaker, binding of vorinostat to ERK compared to reference ERK inhibitors. These findings suggest that vorinostat suppresses TNF-α production primarily through indirect mechanisms involving ERK and NF-κB signaling pathways, rather than by direct TACE inhibition. The repositioning of vorinostat as a modulator of inflammatory signaling is supported, offering potential therapeutic value in inflammatory disorders. 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