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Search Results (10,149)

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15 pages, 3627 KiB  
Article
Epigenetic Treatment Alters Immune-Related Gene Signatures to Increase the Sensitivity of Anti PD-L1 Drugs
by Chonji Fukumoto, Pritam Sadhukhan, Masahiro Shibata, Muhammed T. Ugurlu, Rachel Goldberg, David Sidransky, Luigi Marchionni, Fenna C. M. Sillé and Mohammad Obaidul Hoque
Cancers 2025, 17(15), 2431; https://doi.org/10.3390/cancers17152431 (registering DOI) - 23 Jul 2025
Abstract
Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most prevalent cancer worldwide. Despite intensive treatments, the prognosis is unfavorable. Recently, immunotherapy has emerged as a novel therapeutic strategy, and several immune-checkpoint blockade blockers provide clinical benefits to patients. However, the [...] Read more.
Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is the seventh most prevalent cancer worldwide. Despite intensive treatments, the prognosis is unfavorable. Recently, immunotherapy has emerged as a novel therapeutic strategy, and several immune-checkpoint blockade blockers provide clinical benefits to patients. However, the response rates of these antibodies are limited, and there is a pressing need to increase the efficacy of immunotherapy for HNSCC patients. Epigenetic treatment is emerging as a promising combination approach able to change immune-related gene signatures in tumors and potentially increase the efficacy of immunotherapy. In this study, we sought to elucidate further immune-related gene signatures altered through epigenetic treatment and explored whether epigenetic drugs can increase the efficacy of anti PD-L1 treatment in HNSCC. Methods: At first, we treated six HNSCC cell lines with 5-azacytidine and romidepsin and analyzed gene expression patterns by microarray and TaqMan arrays analysis. We then explored the therapeutic efficacy of epigenetic treatment with an anti PD-L1 antibody in a syngeneic mouse model. Results: Our microarray analysis revealed the differential expression of immune-related genes in cell lines treated with epigenetic drugs, as compared to untreated controls. Most importantly, these array analyses showed a significant change in the transcription of some immune related-and biologically relevant genes, such as HLA-DRA, HMOX1, IFI6, IL12A, IRF7, NFKB2, RPL3L, STAT1, STAT3, CSF1, CSF2, FAS, OASL, and PD-L1, after epigenetic treatment. Furthermore, the combination of epigenetic treatment with an anti PD-L1 antibody significantly suppressed tumor growth in a syngeneic mouse model. In vivo tumors treated with epigenetic drugs expressed higher STAT1, STAT3, and PD-L1 compared to untreated tumors. Increased PD-L1 expression is postulated to increase the efficacy of anti PD-L1 treatment. Conclusions: Our results highlight the importance of a combinational strategy employing both epigenetic and immunotherapy in HNSCC. Full article
(This article belongs to the Special Issue Insights from the Editorial Board Member)
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17 pages, 2774 KiB  
Article
Chronic Morphine Treatment Leads to a Global DNA Hypomethylation via Active and Passive Demethylation Mechanisms in mESCs
by Manu Araolaza, Iraia Muñoa-Hoyos, Itziar Urizar-Arenaza, Irune Calzado and Nerea Subirán
Int. J. Mol. Sci. 2025, 26(15), 7056; https://doi.org/10.3390/ijms26157056 (registering DOI) - 22 Jul 2025
Abstract
Epigenetic regulation, particularly DNA methylation, plays a crucial role in embryonic development by controlling gene expression patterns. The disruption of this regulation by environmental factors can have long-lasting consequences. Opioid drugs, such as morphine, are known to cross the placental barrier and affect [...] Read more.
Epigenetic regulation, particularly DNA methylation, plays a crucial role in embryonic development by controlling gene expression patterns. The disruption of this regulation by environmental factors can have long-lasting consequences. Opioid drugs, such as morphine, are known to cross the placental barrier and affect the developing central nervous system, yet their precise epigenetic effects during early development remain unclear. This study aimed to elucidate the impact of chronic morphine exposure on the DNA methylation landscape and gene expression in mouse embryonic stem cells (mESCs). mESCs were chronically exposed to morphine (10 μM for 24 h). Genome-wide bisulfite sequencing was performed to identify DNA methylation changes, while RNA sequencing (RNA-Seq) assessed corresponding gene expression alterations. Global levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were quantified using mass spectrometry. Morphine exposure induced global DNA hypomethylation and identified 16,808 differentially methylated genes (DMGs) related to development, cell signalling, metabolism, and transcriptional regulation. Integrative transcriptomic analysis with RNA-Seq data revealed 651 overlapping genes, including alterations in key epigenetic regulators involved on DNA methylation machinery. Specifically, Tet1 was upregulated with promoter hypomethylation, while Dnmt1 was downregulated, without changes in promoter methylation after morphine exposiure. Mass spectrometry results confirmed a global decrease in 5mC levels alongside increased 5hmC, indicating the involvement of both passive and active demethylation pathways. These findings demonstrate for the first time that morphine disrupts the epigenetic homeostasis of mESCs by promoting global and gene-specific DNA demethylation, which might be key to the phenotypic changes that occur in adulthood. This work provides novel mechanistic insights into how opioid exposure during early development may lead to persistent epigenetic alterations, with potential long-term implications for neurodevelopment and disease susceptibility. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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20 pages, 7332 KiB  
Article
Chromatin Accessibility Dynamics Reveal Conserved Transcriptional Regulatory Networks During Insect Metamorphosis in Harmonia axyridis and Drosophila melanogaster
by Jiejing Tang, Hang Zhou, Ziqi Cheng, Yang Mei, Yueqi Lu and Xi Chen
Biology 2025, 14(8), 912; https://doi.org/10.3390/biology14080912 - 22 Jul 2025
Abstract
Insect metamorphosis is a complex developmental process regulated by hormonal signaling and gene transcription. To elucidate its transcriptional regulatory mechanisms, we examined chromatin accessibility dynamics during metamorphosis in two holometabolous insects, Harmonia axyridis and Drosophila melanogaster, using ATAC-seq. Our analysis revealed distinct [...] Read more.
Insect metamorphosis is a complex developmental process regulated by hormonal signaling and gene transcription. To elucidate its transcriptional regulatory mechanisms, we examined chromatin accessibility dynamics during metamorphosis in two holometabolous insects, Harmonia axyridis and Drosophila melanogaster, using ATAC-seq. Our analysis revealed distinct stage-specific chromatin accessibility patterns, with peak accessibility during the prepupal stage in H. axyridis and the wandering larval to prepupal transition in D. melanogaster. Through analysis of differential accessibility regions (DARs), we identified enrichment of metamorphosis-related processes including cell morphogenesis, tissue remodeling, and hormone signaling pathways via Gene Ontology and KEGG pathway analyses. Integration of chromatin accessibility with gene expression data revealed 608 conserved genes exhibiting coordinated accessibility and expression changes across both species. Additionally, we constructed a regulatory network centered around four key transcription factors (dsx, E93, REPTOR, and Sox14) that form core regulatory modules controlling metamorphosis. This study provides novel insights into the epigenetic landscape of insect metamorphosis and establishes a foundation for understanding the transcriptional regulatory mechanisms governing this critical developmental process. Full article
(This article belongs to the Section Biochemistry and Molecular Biology)
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34 pages, 3024 KiB  
Article
A Novel Quantum Epigenetic Algorithm for Adaptive Cybersecurity Threat Detection
by Salam Al-E’mari, Yousef Sanjalawe and Salam Fraihat
AI 2025, 6(8), 165; https://doi.org/10.3390/ai6080165 - 22 Jul 2025
Abstract
The escalating sophistication of cyber threats underscores the critical need for intelligent and adaptive intrusion detection systems (IDSs) to identify known and novel attack vectors in real time. Feature selection is a key enabler of performance in machine learning-based IDSs, as it reduces [...] Read more.
The escalating sophistication of cyber threats underscores the critical need for intelligent and adaptive intrusion detection systems (IDSs) to identify known and novel attack vectors in real time. Feature selection is a key enabler of performance in machine learning-based IDSs, as it reduces the input dimensionality, enhances the detection accuracy, and lowers the computational latency. This paper introduces a novel optimization framework called Quantum Epigenetic Algorithm (QEA), which synergistically combines quantum-inspired probabilistic representation with biologically motivated epigenetic gene regulation to perform efficient and adaptive feature selection. The algorithm balances global exploration and local exploitation by leveraging quantum superposition for diverse candidate generation while dynamically adjusting gene expression through an epigenetic activation mechanism. A multi-objective fitness function guides the search process by optimizing the detection accuracy, false positive rate, inference latency, and model compactness. The QEA was evaluated across four benchmark datasets—UNSW-NB15, CIC-IDS2017, CSE-CIC-IDS2018, and TON_IoT—and consistently outperformed baseline methods, including Genetic Algorithm (GA), Particle Swarm Optimization (PSO), and Quantum Genetic Algorithm (QGA). Notably, QEA achieved the highest classification accuracy (up to 97.12%), the lowest false positive rates (as low as 1.68%), and selected significantly fewer features (e.g., 18 on TON_IoT) while maintaining near real-time latency. These results demonstrate the robustness, efficiency, and scalability of QEA for real-time intrusion detection in dynamic and resource-constrained cybersecurity environments. Full article
30 pages, 775 KiB  
Review
Epigenetic Therapies in Endocrine-Related Cancers: Past Insights and Clinical Progress
by Dhruvika Varun, Maria Haque, Jorja Jackson-Oxley, Rachel Thompson, Amber A. Kumari, Corinne L. Woodcock, Anna E. Harris, Srinivasan Madhusudan, Emad Rakha, Catrin S. Rutland, Nigel P. Mongan and Jennie N. Jeyapalan
Cancers 2025, 17(15), 2418; https://doi.org/10.3390/cancers17152418 - 22 Jul 2025
Abstract
In hormone-dependent cancers, front-line treatment options include surgery and therapies that target hormone dependance. These therapies are effective initially but fail in tumors that recur, develop resistance or present at an advanced stage. Consequently, new therapeutic avenues are urgently needed. Increasing evidence implicates [...] Read more.
In hormone-dependent cancers, front-line treatment options include surgery and therapies that target hormone dependance. These therapies are effective initially but fail in tumors that recur, develop resistance or present at an advanced stage. Consequently, new therapeutic avenues are urgently needed. Increasing evidence implicates epigenetic modulators in tumor initiation, progression and therapeutic response, making them attractive biomarkers for patient stratification and targets for intervention. Over the past two decades, the discovery and development of small-molecule inhibitors directed against key epigenetic regulators have accelerated. This review provides a comprehensive overview of the major epigenetic targets, the inhibitors developed against them and the clinical trials currently underway in endocrine-related cancers. While epigenetic agents have shown limited benefits as monotherapies, their use in combination regimens is emerging as a strategy to overcome resistance and enhance the efficacy of existing treatments. We summarize the current landscape of combination trials, highlight early signs of clinical activity and discuss the opportunities and challenges inherent in integrating epigenetic drugs into the management of advanced endocrine-related cancers. Full article
(This article belongs to the Special Issue Epigenetics in Endocrine-Related Cancer)
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14 pages, 3307 KiB  
Article
Expanding the Spectrum of CSF3R-Mutated Myeloid Neoplasm Beyond Chronic Neutrophilic Leukemia and Atypical Chronic Myeloid Leukemia: A Comprehensive Analysis of 13 Cases
by Neha Seth, Judith Brody, Peihong Hsu, Jonathan Kolitz, Pratik Q. Deb and Xinmin Zhang
J. Clin. Med. 2025, 14(15), 5174; https://doi.org/10.3390/jcm14155174 - 22 Jul 2025
Abstract
Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid [...] Read more.
Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with CSF3R alterations. Patients (median age, 77 years) were categorized into groups with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (n = 5), acute leukemia (n = 4), and other myeloid neoplasms (n = 4) based on the WHO 2022 and ICC criteria. Results: The CSF3R p.Thr618Ile mutation was most frequent (11/13), with additional pathogenic variants including p.Gln743Ter and frameshift mutations affecting the cytoplasmic tail. Variant allele frequencies (VAFs) ranged from 2% to 49%, with the highest median VAF in the MDS/MPN group. Co-mutations varied by subtype; MDS/MPN, NOS, and CMML cases frequently harbored mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SF3B1, SRSF2, ZRSR2), while acute leukemia cases showed alterations in JAK3, STAT3, and NRAS. Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. Conclusion: This study expands the recognized spectrum of CSF3R-related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and the potential for targeted therapies. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies for Acute Myeloid Leukemia)
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16 pages, 2682 KiB  
Article
Modulatory Effect of Curcumin on Expression of Methyltransferase/Demethylase in Colon Cancer Cells: Impact on wt p53, mutp53 and c-Myc
by Roberta Santarelli, Claudia Di Dio, Michele Di Crosta, Paola Currà, Roberta Gonnella and Mara Cirone
Molecules 2025, 30(15), 3054; https://doi.org/10.3390/molecules30153054 - 22 Jul 2025
Abstract
Curcumin-mediated anti-cancer properties have been correlated with the inhibition of oncogenic molecules such as mutp53 and c-Myc. Their targeting is therapeutically significant, as p53, following point mutations, can acquire oncogenic functions, and c-Myc overexpression, due to translocations, point mutations, protein/protein interactions, or epigenetic [...] Read more.
Curcumin-mediated anti-cancer properties have been correlated with the inhibition of oncogenic molecules such as mutp53 and c-Myc. Their targeting is therapeutically significant, as p53, following point mutations, can acquire oncogenic functions, and c-Myc overexpression, due to translocations, point mutations, protein/protein interactions, or epigenetic modifications, plays a central role in cancer cell proliferation and metabolic reprogramming, particularly in colorectal cancer. In a previous study, we showed that curcumin strongly downregulated mutp53 while activating wtp53 and reduced the expression of methyltransferases such as EZH2, G9a, and MLL-1 in colon cancer cells. Based on this background, here we investigated whether the dysregulation of such methyltransferases could correlate with the effect observed on p53. We also explored whether these epigenetic changes could affect c-Myc expression in these cells. By Western blot analysis and RT-qPCR, we found that the downregulation of EZH2; G9a; and, to a lesser extent, KDM1, which was also reduced by curcumin, correlated with the decrease in mutp53 and that the reduction of EZH2 and KDM1 correlated with the activation of wtp53. Regarding c-Myc, we unveiled the occurrence of a positive feedback loop between it and MLL-1, which was inhibited by curcumin, independently of the p53 status. In conclusion, this study provides new insights into the therapeutic potential of curcumin, which involves its properties to act as an epigenetic modulator and target key molecules in colon cancer cells. Full article
(This article belongs to the Special Issue Natural Compounds in Modern Therapies, 2nd Edition)
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29 pages, 1528 KiB  
Review
Is Human Chorionic Gonadotropin a Reliable Marker for Testicular Germ Cell Tumor? New Perspectives for a More Accurate Diagnosis
by Nunzio Marroncelli, Giulia Ambrosini, Andrea Errico, Sara Vinco, Elisa Dalla Pozza, Giulia Cogo, Ilaria Cristanini, Filippo Migliorini, Nicola Zampieri and Ilaria Dando
Cancers 2025, 17(14), 2409; https://doi.org/10.3390/cancers17142409 - 21 Jul 2025
Abstract
Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high [...] Read more.
Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high worldwide variability), TGCTs’ incidence is increasing, particularly in industrialized countries. The initial phase of TGCT diagnosis is performed by detecting in the blood the presence of three proteins, i.e., alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG). Despite these proteins being defined as markers of TGCTs, they present limitations in specificity. Indeed, AFP is not elevated in pure seminomas; LDH serum levels can be elevated in other conditions, such as liver disease or tissue damage, and hCG can be elevated in both seminomas and non-seminomas, reducing its ability to differentiate between tumor types. However, the existence of hCG variants, characterized by distinct glycosylation profiles that are differentially expressed in TGCT types and subtypes, may increase the diagnostic and prognostic potential of this hormone. Furthermore, emerging molecular biomarkers, including miRNAs and tumor cells-related epigenetic status, may offer new promising alternatives to improve diagnostic accuracy. Nonetheless, standardized diagnostic protocols still need to be implemented. Finally, understanding the biological roles of hCG isoforms and their “canonical” (e.g., LHCGR) and “non-canonical” (e.g., TGF-βR) receptor interactions may help in understanding tumor biology and therapeutic targeting. Full article
(This article belongs to the Special Issue Insights from the Editorial Board Member)
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28 pages, 1358 KiB  
Review
Understanding the Borderline Brain: A Review of Neurobiological Findings in Borderline Personality Disorder (BPD)
by Eleni Giannoulis, Christos Nousis, Ioanna-Jonida Sula, Maria-Evangelia Georgitsi and Ioannis Malogiannis
Biomedicines 2025, 13(7), 1783; https://doi.org/10.3390/biomedicines13071783 - 21 Jul 2025
Abstract
Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence [...] Read more.
Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence from 112 studies published up to 2025 is synthesized, encompassing structural MRI, resting-state and task-based functional MRI, EEG, PET, and emerging machine learning applications. Consistent disruptions are observed across the prefrontal–amygdala circuitry, the default mode network (DMN), and mentalization-related regions. BPD shows a dominant and stable pattern of hyperconnectivity in the precuneus. Transdiagnostic comparisons with PTSD and cocaine use disorder (CUD) suggest partial overlap in DMN dysregulation, though BPD-specific traits emerge in network topology. Machine learning models achieve a classification accuracy of 70–88% and may support the tracking of early treatment responses. Longitudinal fMRI studies indicate that psychodynamic therapy facilitates the progressive normalization of dorsal anterior cingulate cortex (dACC) activity and reductions in alexithymia. We discuss the role of phenotypic heterogeneity (internalizing versus externalizing profiles), the potential of neuromodulation guided by biomarkers, and the need for standardized imaging protocols. Limitations include small sample sizes, a lack of effective connectivity analyses, and minimal multicenter cohort representation. Future research should focus on constructing multimodal biomarker panels that integrate functional connectivity, epigenetics, and computational phenotyping. This review supports the use of a precision psychiatry approach for BPD by aligning neuroscience with scalable clinical tools. Full article
(This article belongs to the Section Neurobiology and Clinical Neuroscience)
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23 pages, 1372 KiB  
Article
Immunization with Complete Freund’s Adjuvant Reveals Trained Immunity-like Features in A/J Mice
by Kiruthiga Mone, Shraddha Singh, Fatema Abdullatif, Meghna Sur, Mahima T. Rasquinha, Javier Seravalli, Denise K. Zinniel, Indranil Mukhopadhyay, Raul G. Barletta, Teklab Gebregiworgis and Jay Reddy
Vaccines 2025, 13(7), 768; https://doi.org/10.3390/vaccines13070768 - 21 Jul 2025
Abstract
Background/Objectives: Freund’s adjuvants induce different immunomodulatory effects, but their underlying molecular mechanisms are unclear. In this study, we investigated whether the immune-stimulating effects of the complete Freund’s adjuvant (CFA) involve the mechanisms of trained immunity (TI). Methods: We examined bone marrow cells (BMCs) [...] Read more.
Background/Objectives: Freund’s adjuvants induce different immunomodulatory effects, but their underlying molecular mechanisms are unclear. In this study, we investigated whether the immune-stimulating effects of the complete Freund’s adjuvant (CFA) involve the mechanisms of trained immunity (TI). Methods: We examined bone marrow cells (BMCs) isolated from CFA-immunized A/J mice to address this question. Incomplete Freund’s adjuvant (IFA) and Mycobacterium tuberculosis var. bovis Bacillus Calmette-Guérin (BCG) served as negative and positive controls, respectively. We evaluated cytokine profiles, metabolic, and epigenetic changes. Results: First, BMCs from all groups except saline showed varied levels of IL-1β, IL-6, and TNF-α. But expression of CCL5 and CXCL10 was significantly elevated only in the CFA and BCG groups. Transcriptionally, significant elevations were noted for TNF-α and IL-1β in the CFA and BCG groups, whereas CXCL10, IL-6, and IL-10 were upregulated in the CFA and BCG groups, respectively. Second, while BMCs from the BCG group expressed the markers of both the M1 and M2 macrophages, no clear trends were noted in the CFA and IFA groups. Third, cell lysates from the CFA group revealed metabolic reprogramming in the BMCs. Specifically, we observed an increased level of lactate, indicative of aerobic glycolysis, which is implicated in TI, and this was also detected in the IFA group. Fourth, epigenetic analysis revealed histone enrichment in the promoter region of TNF-α, in the CFA group, but to a lesser degree than the BCG group. However, no epigenetic changes were observed in the IFA group. Conclusions: Our data provide new insights into the mechanisms of Freund’s adjuvants and the immunomodulatory effects of CFA could involve the features of TI. Full article
(This article belongs to the Special Issue Recent Advances in Vaccine Adjuvants and Formulation)
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24 pages, 327 KiB  
Review
Genetic Landscape of Kawasaki Disease: An Update
by Taru Goyal, Saniya Sharma, Rakesh Kumar Pilania, Kajol Jawallia, Sanchi Chawla, Madhubala Sharma, Monica Rawat, Vaishali Thakur, Urvi Arya, Anoop Kumar, Manpreet Dhaliwal, Vignesh Pandiarajan, Amit Rawat and Surjit Singh
Lymphatics 2025, 3(3), 21; https://doi.org/10.3390/lymphatics3030021 - 20 Jul 2025
Viewed by 48
Abstract
Kawasaki disease (KD), first identified in 1967 by Dr. Tomisaku Kawasaki, is an acute, self-limited vasculitis and remains the leading cause of acquired heart disease in children worldwide, particularly affecting those under the age of five. Clinically, it presents with persistent fever, mucocutaneous [...] Read more.
Kawasaki disease (KD), first identified in 1967 by Dr. Tomisaku Kawasaki, is an acute, self-limited vasculitis and remains the leading cause of acquired heart disease in children worldwide, particularly affecting those under the age of five. Clinically, it presents with persistent fever, mucocutaneous inflammation, skin rashes, and lymphadenopathy, with a marked tendency to involve the coronary arteries, potentially leading to serious complications such as coronary artery aneurysms. Despite extensive research spanning more than five decades, the precise etiology of KD remains unclear. However, accumulating evidence supports the significant role of genetic predisposition, highlighting the contribution of inherited factors in modulating immune responses and influencing disease susceptibility and severity. Emerging evidence highlights genetic susceptibility as pivotal, with genome-wide studies identifying polymorphisms in immune-related genes, such as ITPKC, CASP3, BLK, CD40, and ORAI1, which modulate disease risk and coronary complications. Epigenetic mechanisms, including DNA methylation and non-coding RNAs, bridge the gap between genetic and environmental factors, regulating immune responses and endothelial activation. Furthermore, emerging insights into autophagy-related processes provide a deeper understanding of the molecular mechanisms underlying the disease. This review aims to explore the current knowledge on the genetic landscape of KD, examine how these findings contribute to our understanding of its pathophysiology, and investigate the potential for genetically targeted therapeutic strategies in the future. Full article
30 pages, 2320 KiB  
Review
HDACs and Their Inhibitors on Post-Translational Modifications: The Regulation of Cardiovascular Disease
by Siyi Yang, Yidong Sun and Wei Yu
Cells 2025, 14(14), 1116; https://doi.org/10.3390/cells14141116 - 20 Jul 2025
Viewed by 199
Abstract
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 [...] Read more.
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
(This article belongs to the Section Cellular Metabolism)
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41 pages, 2822 KiB  
Review
Sirtuins in Central Nervous System Tumors—Molecular Mechanisms and Therapeutic Targeting
by Agnieszka Nowacka, Martyna Śniegocka, Maciej Śniegocki and Ewa Aleksandra Ziółkowska
Cells 2025, 14(14), 1113; https://doi.org/10.3390/cells14141113 - 19 Jul 2025
Viewed by 270
Abstract
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 [...] Read more.
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
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16 pages, 2408 KiB  
Article
Female Mice Lacking LSD1 in Myeloid Cells Are Resistant to Inflammatory Bone Loss
by Kristina Astleford-Hopper, Flavia Saavedra, Peter Bittner-Eddy, Clara Stein, Jennifer Auger, Rachel Clark, Juan E. Abrahante Llorens, Bryce A. Binstadt, Vivek Thumbigere-Math and Kim C. Mansky
Cells 2025, 14(14), 1111; https://doi.org/10.3390/cells14141111 - 19 Jul 2025
Viewed by 88
Abstract
Osteoclasts, which are derived from myeloid precursors, are essential for physiologic bone remodeling but also mediate pathological bone loss in inflammatory diseases such as periodontitis and rheumatoid arthritis. Lysine-specific demethylase (LSD1/KDM1A) is a histone demethylase that modulates the chromatin landscape via demethylation of [...] Read more.
Osteoclasts, which are derived from myeloid precursors, are essential for physiologic bone remodeling but also mediate pathological bone loss in inflammatory diseases such as periodontitis and rheumatoid arthritis. Lysine-specific demethylase (LSD1/KDM1A) is a histone demethylase that modulates the chromatin landscape via demethylation of H3K4me1/2 and H3K9me1/2, thereby regulating the expression of genes essential for deciding cell fate. We previously demonstrated that myeloid-specific deletion of LSD1 (LSD1LysM-Cre) disrupts osteoclast differentiation, leading to enhanced BV/TV under physiological conditions. In this study, we show that LSD1LysM-Cre female mice are similarly resistant to inflammatory bone loss in both ligature-induced periodontitis and K/BxN serum-transfer arthritis models. Bulk RNA-seq of mandibular-derived preosteoclasts from LSD1LysM-Cre mice with ligature-induced periodontitis revealed the upregulation of genes involved in inflammation, lipid metabolism, and immune response. Notably, LSD1 deletion blocked osteoclastogenesis even under TGF-β and TNF co-stimulation, which is an alternative RANKL-independent differentiation pathway. Upregulation of Nlrp3, Hif1α, and Acod1 in LSD1LysM-Cre preosteoclasts suggests that LSD1 is essential for repressing inflammatory and metabolic programs that otherwise hinder osteoclast commitment. These findings establish LSD1 as a critical epigenetic gatekeeper integrating inflammatory and metabolic signals to regulate osteoclast differentiation and bone resorption. Therapeutic inhibition of LSD1 may selectively mitigate inflammatory bone loss while preserving physiological bone remodeling. Full article
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17 pages, 3159 KiB  
Article
Csn5 Depletion Reverses Mitochondrial Defects in GCN5-Null Saccharomyces cerevisiae
by Angela Cirigliano, Emily Schifano, Alessandra Ricelli, Michele M. Bianchi, Elah Pick, Teresa Rinaldi and Arianna Montanari
Int. J. Mol. Sci. 2025, 26(14), 6916; https://doi.org/10.3390/ijms26146916 - 18 Jul 2025
Viewed by 102
Abstract
In this study, we investigated the mitochondrial defects resulting from the deletion of GCN5, a lysine-acetyltransferase, in the yeast Saccharomyces cerevisiae. Gcn5 serves as the catalytic subunit of the SAGA acetylation complex and functions as an epigenetic regulator, primarily acetylating N-terminal [...] Read more.
In this study, we investigated the mitochondrial defects resulting from the deletion of GCN5, a lysine-acetyltransferase, in the yeast Saccharomyces cerevisiae. Gcn5 serves as the catalytic subunit of the SAGA acetylation complex and functions as an epigenetic regulator, primarily acetylating N-terminal lysine residues on histones H2B and H3 to modulate gene expression. The loss of GCN5 leads to mitochondrial abnormalities, including defects in mitochondrial morphology, a reduced mitochondrial DNA copy number, and defective mitochondrial inheritance due to the depolarization of actin filaments. These defects collectively trigger the activation of the mitophagy pathway. Interestingly, deleting CSN5, which encodes to Csn5/Rri1 (Csn5), the catalytic subunit of the COP9 signalosome complex, rescues the mitochondrial phenotypes observed in the gcn5Δ strain. Furthermore, these defects are suppressed by exogenous ergosterol supplementation, suggesting a link between the rescue effect mediated by CSN5 deletion and the regulatory role of Csn5 in the ergosterol biosynthetic pathway. Full article
(This article belongs to the Special Issue Research on Mitochondrial Genetics and Epigenetics)
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