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18 pages, 2678 KiB  
Article
Pre-Conception Maternal Obesity Confers Autism Spectrum Disorder-like Behaviors in Mice Offspring Through Neuroepigenetic Dysregulation
by Nina P. Allan, Amada Torres, Michael J. Corley, Brennan Y. Yamamoto, Chantell Balaan, Yasuhiro Yamauchi, Rafael Peres, Yujia Qin, Vedbar S. Khadka, Youping Deng, Monika A. Ward and Alika K. Maunakea
Cells 2025, 14(15), 1201; https://doi.org/10.3390/cells14151201 (registering DOI) - 5 Aug 2025
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we [...] Read more.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with early-life origins. Maternal obesity has been associated with increased ASD risk, yet the mechanisms and timing of susceptibility remain unclear. Using a mouse model combining in vitro fertilization (IVF) and embryo transfer, we separated the effects of pre-conception and gestational obesity. We found that maternal high fat diet (HFD) exposure prior to conception alone was sufficient to induce ASD-like behaviors in male offspring—including altered vocalizations, reduced sociability, and increased repetitive grooming—without anxiety-related changes. These phenotypes were absent in female offspring and those exposed only during gestation. Cortical transcriptome analysis revealed dysregulation and isoform shifts in genes implicated in ASD, including Homer1 and Zswim6. Whole-genome bisulfite sequencing of hippocampal tissue showed hypomethylation of an alternative Homer1 promoter, correlating with increased expression of the short isoform Homer1a, which is known to disrupt synaptic scaffolding. This pattern was specific to mice with ASD-like behaviors. Our findings show that pre-conceptional maternal obesity can lead to lasting, isoform-specific transcriptomic and epigenetic changes in the offspring’s brain. These results underscore the importance of maternal health before pregnancy as a critical and modifiable factor in ASD risk. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Autism Spectrum Disorder)
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28 pages, 3157 KiB  
Review
Deciphering Medulloblastoma: Epigenetic and Metabolic Changes Driving Tumorigenesis and Treatment Outcomes
by Jenny Bonifacio-Mundaca, Sandro Casavilca-Zambrano, Christophe Desterke, Íñigo Casafont and Jorge Mata-Garrido
Biomedicines 2025, 13(8), 1898; https://doi.org/10.3390/biomedicines13081898 - 4 Aug 2025
Abstract
Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving [...] Read more.
Background/Objectives: Medulloblastoma is the most common malignant brain tumor in children and comprises four molecular subtypes—WNT, SHH, Group 3, and Group 4—each with distinct genetic, epigenetic, and metabolic features. Increasing evidence highlights the critical role of metabolic reprogramming and epigenetic alterations in driving tumor progression, therapy resistance, and clinical outcomes. This review aims to explore the interplay between metabolic and epigenetic mechanisms in medulloblastoma, with a focus on their functional roles and therapeutic implications. Methods: A comprehensive literature review was conducted using PubMed and relevant databases, focusing on recent studies examining metabolic pathways and epigenetic regulation in medulloblastoma subtypes. Particular attention was given to experimental findings from in vitro and in vivo models, as well as emerging preclinical therapeutic strategies targeting these pathways. Results: Medulloblastoma exhibits metabolic adaptations such as increased glycolysis, lipid biosynthesis, and altered amino acid metabolism. These changes support rapid cell proliferation and interact with the tumor microenvironment. Concurrently, epigenetic mechanisms—including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation—contribute to tumor aggressiveness and treatment resistance. Notably, metabolic intermediates often serve as cofactors for epigenetic enzymes, creating feedback loops that reinforce oncogenic states. Preclinical studies suggest that targeting metabolic vulnerabilities or epigenetic regulators—and particularly their combination—can suppress tumor growth and overcome resistance mechanisms. Conclusions: The metabolic–epigenetic crosstalk in medulloblastoma represents a promising area for therapeutic innovation. Understanding subtype-specific dependencies and integrating biomarkers for patient stratification could facilitate the development of precision medicine approaches that improve outcomes and reduce long-term treatment-related toxicity in pediatric patients. Full article
(This article belongs to the Special Issue Genomic Insights and Translational Opportunities for Human Cancers)
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19 pages, 2870 KiB  
Review
Etiopathogenesis and Treatment of Colorectal Cancer
by Mayara Bocchi, Eduardo Vignoto Fernandes, Nathália de Sousa Pereira and Marla Karine Amarante
Immuno 2025, 5(3), 31; https://doi.org/10.3390/immuno5030031 - 4 Aug 2025
Abstract
Human colorectal cancer (CRC) encompasses tumors affecting a segment of the large intestine (colon) and rectum. It is the third most commonly diagnosed malignancy and the second leading cause of cancer deaths worldwide. It is a multifactorial disease, whose carcinogenesis process involves genetic [...] Read more.
Human colorectal cancer (CRC) encompasses tumors affecting a segment of the large intestine (colon) and rectum. It is the third most commonly diagnosed malignancy and the second leading cause of cancer deaths worldwide. It is a multifactorial disease, whose carcinogenesis process involves genetic and epigenetic alterations in oncogenes and tumor suppressor genes, including genes related to DNA repair. The pathogenic mechanisms are described based on the pathways of chromosomal instability, microsatellite instability, and CpG island methylator phenotype. When detected early, CRC is potentially curable, and its treatment is based on the pathological characteristics of the tumor and factors related to the patient, as well as on drug efficacy and toxicity studies. Therefore, the aim of this study was to review the pathogenesis and molecular subtypes of CRC and to describe the main targets of disease-directed therapy used in patients refractory to current treatments. Full article
(This article belongs to the Section Cancer Immunology and Immunotherapy)
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24 pages, 10561 KiB  
Article
Investigating the Potential of Propranolol as an Anti-Tumor Agent in Colorectal Cancer Cell Lines
by Shiekhah Mohammad Alzahrani, Huda Abdulaziz Al Doghaither, Hind Ali Alkhatabi, Mohammad Abdullah Basabrain and Peter Natesan Pushparaj
Int. J. Mol. Sci. 2025, 26(15), 7513; https://doi.org/10.3390/ijms26157513 (registering DOI) - 4 Aug 2025
Abstract
The incidence and mortality of colorectal cancer (CRC) have increased globally. Several therapeutic approaches have been suggested to address this health issue, in addition to classical methods. Propranolol (PRO) is a beta-blocker that was repurposed to treat infantile hemangiomas, and its anti-tumor activity [...] Read more.
The incidence and mortality of colorectal cancer (CRC) have increased globally. Several therapeutic approaches have been suggested to address this health issue, in addition to classical methods. Propranolol (PRO) is a beta-blocker that was repurposed to treat infantile hemangiomas, and its anti-tumor activity has been reported. This study aimed to investigate the effects of PRO in a panel of CRC cell lines and its potential impact when combined with chemotherapy. The effects of PRO on cell cytotoxicity, cell morphology, colony formation, cell death induction, cell cycle, mitochondrial and intracellular reactive oxygen species (ROS), and migration were measured in all cells. CompuSyn software was utilized to assess the possible synergistic or additive interaction in the combined treatment. The results showed that PRO suppressed cell proliferation, altered cell morphology, inhibited colony formation, induced apoptosis, altered cell cycle and ROS generation, and inhibited the migration of treated cells in a cell-type-specific, time-dependent, and dose-dependent manner compared with the control. HT-29 was the most sensitive cell line to PRO in terms of cytotoxicity, apoptosis, cell cycle arrest, and ROS generation, while SW-480 was the most sensitive in terms of migration inhibition. Moreover, the PRO and capecitabine combination exhibited a synergistic effect and induced mitochondrial apoptosis in metastatic CRC cells. The data suggest that PRO could be a promising adjuvant therapy for primary and advanced CRC. This study identified variations between CRC cell lines in response to PRO, which may be related to their genetic and epigenetic differences. In addition, the findings highlight the potential of combination strategies to improve therapeutic outcomes in metastatic CRC. Full article
(This article belongs to the Special Issue Programmed Cell Death and Oxidative Stress: 3rd Edition)
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26 pages, 1034 KiB  
Review
Metabolic Interactions in the Tumor Microenvironment of Classical Hodgkin Lymphoma: Implications for Targeted Therapy
by Michał Kurlapski, Alicja Braczko, Paweł Dubiela, Iga Walczak, Barbara Kutryb-Zając and Jan Maciej Zaucha
Int. J. Mol. Sci. 2025, 26(15), 7508; https://doi.org/10.3390/ijms26157508 (registering DOI) - 4 Aug 2025
Abstract
Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. [...] Read more.
Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed–Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies—such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies—which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL. Full article
(This article belongs to the Special Issue Lymphoma: Molecular Pathologies and Therapeutic Strategies)
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21 pages, 632 KiB  
Review
DNA Methylation in Bladder Cancer: Diagnostic and Therapeutic Perspectives—A Narrative Review
by Dragoş Puia, Marius Ivănuță and Cătălin Pricop
Int. J. Mol. Sci. 2025, 26(15), 7507; https://doi.org/10.3390/ijms26157507 (registering DOI) - 3 Aug 2025
Viewed by 60
Abstract
Bladder cancer pathogenesis is closely linked to epigenetic alterations, particularly DNA methylation and demethylation processes. Environmental carcinogens and persistent inflammatory stimuli—such as recurrent urinary tract infections—can induce aberrant DNA methylation, altering gene expression profiles and contributing to malignant transformation. This review synthesizes current [...] Read more.
Bladder cancer pathogenesis is closely linked to epigenetic alterations, particularly DNA methylation and demethylation processes. Environmental carcinogens and persistent inflammatory stimuli—such as recurrent urinary tract infections—can induce aberrant DNA methylation, altering gene expression profiles and contributing to malignant transformation. This review synthesizes current evidence on the role of DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and the hypermethylation of key tumour suppressor genes, including A2BP1, NPTX2, SOX11, PENK, NKX6-2, DBC1, MYO3A, and CA10, in bladder cancer. It also evaluates the therapeutic application of DNA-demethylating agents such as 5-azacytidine and highlights the impact of chronic inflammation on epigenetic regulation. Promoter hypermethylation of tumour suppressor genes leads to transcriptional silencing and unchecked cell proliferation. Urine-based DNA methylation assays provide a sensitive and specific method for non-invasive early detection, with single-target approaches offering high diagnostic precision. Animal models are increasingly employed to validate these findings, allowing the study of methylation dynamics and gene–environment interactions in vivo. DNA methylation represents a key epigenetic mechanism in bladder cancer, with significant diagnostic, prognostic, and therapeutic implications. Integration of human and experimental data supports the use of methylation-based biomarkers for early detection and targeted treatment, paving the way for personalized approaches in bladder cancer management. Full article
(This article belongs to the Section Molecular Oncology)
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26 pages, 1112 KiB  
Review
The Invisible Influence: Can Endocrine Disruptors Reshape Behaviors Across Generations?
by Antonella Damiano, Giulia Caioni, Claudio D’Addario, Carmine Merola, Antonio Francioso and Michele Amorena
Stresses 2025, 5(3), 46; https://doi.org/10.3390/stresses5030046 - 1 Aug 2025
Viewed by 109
Abstract
Among the numerous compounds released as a result of human activities, endocrine-disrupting chemicals (EDCs) have attracted particular attention due to their widespread detection in human biological samples and their accumulation across various ecosystems. While early research primarily focused on their effects on reproductive [...] Read more.
Among the numerous compounds released as a result of human activities, endocrine-disrupting chemicals (EDCs) have attracted particular attention due to their widespread detection in human biological samples and their accumulation across various ecosystems. While early research primarily focused on their effects on reproductive health, it is now evident that EDCs may impact neurodevelopment, altering the integrity of neural circuits essential for cognitive abilities, emotional regulation, and social behaviors. These compounds may elicit epigenetic modifications, such as DNA methylation and histone acetylation, that result in altered expression patterns, potentially affecting multiple generations and contribute to long-term behavioral phenotypes. The effects of EDCs may occur though both direct and indirect mechanisms, ultimately converging on neurodevelopmental vulnerability. In particular, the gut–brain axis has emerged as a critical interface targeted by EDCs. This bidirectional communication network integrates the nervous, immune, and endocrine systems. By altering the microbiota composition, modulating immune responses, and triggering epigenetic mechanisms, EDCs can act on multiple and interconnected pathways. In this context, elucidating the impact of EDCs on neurodevelopmental processes is crucial for advancing our understanding of their contribution to neurological and behavioral health risks. Full article
(This article belongs to the Collection Feature Papers in Human and Animal Stresses)
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38 pages, 2158 KiB  
Review
Epigenetic Modulation and Bone Metastasis: Evolving Therapeutic Strategies
by Mahmoud Zhra, Jasmine Hanafy Holail and Khalid S. Mohammad
Pharmaceuticals 2025, 18(8), 1140; https://doi.org/10.3390/ph18081140 - 31 Jul 2025
Viewed by 437
Abstract
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 [...] Read more.
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
(This article belongs to the Section Biopharmaceuticals)
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41 pages, 1640 KiB  
Review
Early Roots of Childhood Obesity: Risk Factors, Mechanisms, and Prevention Strategies
by Giuseppina Rosaria Umano, Simonetta Bellone, Raffaele Buganza, Valeria Calcaterra, Domenico Corica, Luisa De Sanctis, Anna Di Sessa, Maria Felicia Faienza, Nicola Improda, Maria Rosaria Licenziati, Melania Manco, Carla Ungaro, Flavia Urbano, Giuliana Valerio, Malgorzata Wasniewska and Maria Elisabeth Street
Int. J. Mol. Sci. 2025, 26(15), 7388; https://doi.org/10.3390/ijms26157388 - 30 Jul 2025
Viewed by 620
Abstract
Childhood obesity is a growing global health concern, with established links to physical activity, nutrition, and, increasingly, to prenatal and perinatal factors. Emerging evidence highlights the significant role of maternal conditions such as obesity, comorbidities, nutrition, and environmental exposures in predisposing offspring to [...] Read more.
Childhood obesity is a growing global health concern, with established links to physical activity, nutrition, and, increasingly, to prenatal and perinatal factors. Emerging evidence highlights the significant role of maternal conditions such as obesity, comorbidities, nutrition, and environmental exposures in predisposing offspring to long-term metabolic and cardiovascular diseases. The “Developmental Origins of Health and Disease” (DOHaD) paradigm provides a framework for understanding how early life environmental exposures, particularly during the periconceptional, fetal, and neonatal periods, can program future health outcomes through epigenetic mechanisms. Epigenetic modifications alter gene expression without changing the DNA sequence and are increasingly recognized as key mediators in the development of obesity. This narrative review summarizes current findings on the early determinants of childhood obesity, emphasizing the molecular and epigenetic pathways involved. A comprehensive literature search was conducted across multiple databases and international sources, focusing on recent studies from the past decade. Both human and animal research were included to provide a broad perspective. This review aims to consolidate recent insights into early life influences on obesity, underscoring the need for preventive strategies starting as early as the preconception period. Full article
(This article belongs to the Special Issue Genetic and Molecular Mechanisms of Obesity)
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16 pages, 6361 KiB  
Article
The Study of Chromobox Protein Homolog 4 in 3D Organoid Models of Colon Cancer as a Potential Predictive Marker
by Vincenza Ciaramella, Valentina Belli, Francesco Izzo, Andrea Belli, Antonio Avallone, Alfonso De Stefano, Andrea Soricelli and Anna Maria Grimaldi
Int. J. Mol. Sci. 2025, 26(15), 7385; https://doi.org/10.3390/ijms26157385 - 30 Jul 2025
Viewed by 129
Abstract
The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal [...] Read more.
The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal cancer (CC) remain unclear. In this study, we show that CBX genes are significantly dysregulated in CC tissues and cell models compared to normal colorectal tissue. Among them, CBX4 and CBX8 emerged as the most upregulated isoforms in tumors. Functional analyses revealed that CBX4 overexpression enhances CC cell proliferation, while its silencing reduces tumor growth. Similarly, pharmacological inhibition of CBX4 in patient-derived tumor organoids led to decreased proliferation, supporting its pro-tumorigenic role. Immunofluorescence analysis further revealed alterations in NF-κB signaling upon CBX4 inhibition, along with reduced mRNA levels of pathway components including NF-κB, TNF, IL-1, and c-Myc. These findings point to a potential interplay between CBX4 and inflammation-related pathways in CC. Overall, our study highlights the oncogenic role of CBX4 in colorectal cancer and supports its potential as a novel therapeutic target and early biomarker for disease progression. Full article
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13 pages, 2697 KiB  
Article
Integrating Molecular Alterations with Immunophenotype and Clinical Characteristics in Myelodysplastic Syndromes: A Single-Center Study
by Maciej Majcherek, Krzysztof Przeorski, Aleksandra Mroczkowska-Bękarciak, Natalia Nogaj, Donata Szymczak, Anna Kopszak, Krzysztof Kujawa, Paula Jabłonowska-Babij, Maciej Tomasiewicz, Agnieszka Szeremet, Tomasz Wróbel and Anna Czyż
Int. J. Mol. Sci. 2025, 26(15), 7382; https://doi.org/10.3390/ijms26157382 - 30 Jul 2025
Viewed by 259
Abstract
Continuous development of molecular and immunophenotypic techniques enables more precise diagnoses and more accurate assessment of prognosis in myelodysplastic syndromes (MDS). However, the relationship between genetic alterations and immunophenotype remains very poorly understood. The analysis included 30 patients diagnosed at a tertiary center [...] Read more.
Continuous development of molecular and immunophenotypic techniques enables more precise diagnoses and more accurate assessment of prognosis in myelodysplastic syndromes (MDS). However, the relationship between genetic alterations and immunophenotype remains very poorly understood. The analysis included 30 patients diagnosed at a tertiary center who were eligible for azacitidine treatment. Next-generation sequencing (NGS) was performed at the start of the study to assess the mutation status of 40 genes associated with MDS pathogenesis. In addition, multiparametric flow cytometry (MFC) was performed to assess the ELN score (Ogata score) and, additionally, to detect an abnormal CD11b/HLA-DR and CD11b/CD13 expression pattern. In the studied patient population, higher ELN score results were found in patients with mutations in epigenetic modifiers and pathogenic mutations of the tumor suppressor genes. Signal pathway mutations were associated with lower platelet counts at diagnosis. The results of this study indicate a correlation between molecular abnormalities and deviations in cell immunophenotype. Investigating this correlation may, in the future, allow the development of new scales that allow a more sensitive and specific diagnosis of MDS and a more precise prediction of its course. Full article
(This article belongs to the Special Issue Immunophenotyping in Autoimmune Diseases and Cancer, 4th Edition)
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22 pages, 1013 KiB  
Review
Genomic Alterations and Microbiota Crosstalk in Hepatic Cancers: The Gut–Liver Axis in Tumorigenesis and Therapy
by Yuanji Fu, Jenny Bonifacio-Mundaca, Christophe Desterke, Íñigo Casafont and Jorge Mata-Garrido
Genes 2025, 16(8), 920; https://doi.org/10.3390/genes16080920 - 30 Jul 2025
Viewed by 198
Abstract
Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and [...] Read more.
Background/Objectives: Hepatic cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), are major global health concerns due to rising incidence and limited therapeutic success. While traditional risk factors include chronic liver disease and environmental exposures, recent evidence underscores the significance of genetic alterations and gut microbiota in liver cancer development and progression. This review aims to integrate emerging knowledge on the interplay between host genomic changes and gut microbial dynamics in the pathogenesis and treatment of hepatic cancers. Methods: We conducted a comprehensive review of current literature on genetic and epigenetic drivers of HCC and CCA, focusing on commonly mutated genes such as TP53, CTNNB1, TERT, IDH1/2, and FGFR2. In parallel, we evaluated studies addressing the gut–liver axis, including the roles of dysbiosis, microbial metabolites, and immune modulation. Key clinical and preclinical findings were synthesized to explore how host–microbe interactions influence tumorigenesis and therapeutic response. Results: HCC and CCA exhibit distinct but overlapping genomic landscapes marked by recurrent mutations and epigenetic reprogramming. Alterations in the gut microbiota contribute to hepatic inflammation, genomic instability, and immune evasion, potentially enhancing oncogenic signaling pathways. Furthermore, microbiota composition appears to affect responses to immune checkpoint inhibitors. Emerging therapeutic strategies such as probiotics, fecal microbiota transplantation, and precision oncology based on mutational profiling demonstrate potential for personalized interventions. Conclusions: The integration of host genomics with microbial ecology provides a promising paradigm for advancing diagnostics and therapies in liver cancer. Targeting the gut–liver axis may complement genome-informed strategies to improve outcomes for patients with HCC and CCA. Full article
(This article belongs to the Special Issue Feature Papers in Microbial Genetics and Genomics)
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20 pages, 887 KiB  
Review
Epigenetics of Endometrial Cancer: The Role of Chromatin Modifications and Medicolegal Implications
by Roberto Piergentili, Enrico Marinelli, Lina De Paola, Gaspare Cucinella, Valentina Billone, Simona Zaami and Giuseppe Gullo
Int. J. Mol. Sci. 2025, 26(15), 7306; https://doi.org/10.3390/ijms26157306 - 29 Jul 2025
Viewed by 241
Abstract
Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several [...] Read more.
Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. Risk factors for EC include metabolic alterations (obesity, metabolic syndrome, insulin resistance), hormonal imbalance, age at menopause, reproductive factors, and inherited conditions, such as Lynch syndrome. For the inherited forms, several genes had been implicated in EC occurrence and development, such as POLE, MLH1, TP53, PTEN, PIK3CA, PIK3R1, CTNNB1, ARID1A, PPP2R1A, and FBXW7, all mutated at high frequency in EC patients. However, gene function impairment is not necessarily caused by mutations in the coding sequence of these and other genes. Gene function alteration may also occur through post-transcriptional control of messenger RNA translation, frequently caused by microRNA action, but transcriptional impairment also has a profound impact. Here, we review how chromatin modifications change the expression of genes whose impaired function is directly related to EC etiopathogenesis. Chromatin modification plays a central role in EC. The modification of chromatin structure alters the accessibility of genes to transcription factors and other regulatory proteins, thus altering the intracellular protein amount. Thus, DNA structural alterations may impair gene function as profoundly as mutations in the coding sequences. Hence, its central importance is in the diagnostic and prognostic evaluation of EC patients, with the caveat that chromatin alteration is often difficult to identify and needs investigations that are specific and not broadly used in common clinical practice. The different phases of the healthy endometrium menstrual cycle are characterized by differential gene expression, which, in turn, is also regulated through epigenetic mechanisms involving DNA methylation, histone post-translational modifications, and non-coding RNA action. From a medicolegal and policy-making perspective, the implications of using epigenetics in cancer care are briefly explored as well. Epigenetics in endometrial cancer is not only a topic of biomedical interest but also a crossroads between science, ethics, law, and public health, requiring integrated approaches and careful regulation. Full article
(This article belongs to the Section Molecular Oncology)
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21 pages, 3446 KiB  
Article
Targeting the Kynureninase–HDAC6–Complement Axis as a Novel Therapeutic Strategy in Glioblastoma
by Arif Ul Hasan, Sachiko Sato, Mami Obara, Yukiko Kondo and Eiichi Taira
Epigenomes 2025, 9(3), 27; https://doi.org/10.3390/epigenomes9030027 - 28 Jul 2025
Viewed by 321
Abstract
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 [...] Read more.
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
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25 pages, 1258 KiB  
Review
Seed Priming Beyond Stress Adaptation: Broadening the Agronomic Horizon
by Mujo Hasanović, Adaleta Durmić-Pašić and Erna Karalija
Agronomy 2025, 15(8), 1829; https://doi.org/10.3390/agronomy15081829 - 28 Jul 2025
Viewed by 211
Abstract
Seed priming, traditionally viewed as a method for enhancing crop resilience to abiotic stress, has evolved into a multifaceted agronomic strategy. This review synthesizes the current findings demonstrating that priming influences plant development, metabolic regulation, and yield enhancement even under optimal conditions. By [...] Read more.
Seed priming, traditionally viewed as a method for enhancing crop resilience to abiotic stress, has evolved into a multifaceted agronomic strategy. This review synthesizes the current findings demonstrating that priming influences plant development, metabolic regulation, and yield enhancement even under optimal conditions. By covering a wide range of crops, including cereals (e.g., wheat, maize, rice, and barley) as well as vegetables and horticultural species (e.g., tomato, carrot, spinach, and lettuce), we highlight the broad applicability of priming across agricultural systems. The underlying mechanisms include hormonal modulation, altered source–sink dynamics, accelerated phenology, and epigenetic memory. Various priming techniques are discussed, including hydropriming, osmopriming, biopriming, chemopriming, and nanopriming, with attention to their physiological and molecular effects. Special focus is given to the role of seed priming in advancing climate-smart and precision agriculture. By shifting the narrative from stress mitigation to holistic crop performance optimization, seed priming emerges as a key tool for sustainable agriculture in the face of global challenges. Full article
(This article belongs to the Section Plant-Crop Biology and Biochemistry)
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