Search Results (85)

The oral cavity contains a diverse group of bacteria in the saliva, as well as structured aggregates of bacterial cells on the mucosal surfaces. Oral microbiota (OM) dysbiosis not only induces local inflammation, it can also trigger systemic inflammation leading to metabolic diseases and neuropsychiatric diseases (NPDs). While primary evidence indicates that oral microbiota dysbiosis induces gut microbiota aberrations, which exacerbate inflammation associated with metabolic diseases (obesity, dyslipidemia, diabetes, nonalcoholic fatty liver disease (NAFLD), and insulin resistance), other studies revealed the contribution of the oral microbiota–brain axis in the pathogenesis of NPDs. GM dysbiosis and inflammation also induce epigenetic alterations in cytokine genes, such as IL-1β, IL-6, TNF-α, NF-kB, BTLA, IL-18R1, TGF-β, P13k/Akt1, Ctnnb1, and Hsp90aa1, as well as DNMTs, HDACs, and DAT1 associated with the development and progression of metabolic disorders and/or NPDs. Therefore, the epigenome could serve as a target for preventive or therapeutic interventions. Here, we (i) review emerging evidence of the potential impact of OM dysbiosis in the pathogenesis of metabolic diseases and NPDs, (ii) highlight the relationship between OM-induced inflammation and epigenetic alterations driving NPDs pathogenesis and interlinked metabolic aberrations, (iii) discuss therapeutic approaches capable of treating metabolic diseases and NPDs through reshaping the microbiota and its epigenetic metabolites, and hence mitigating epigenetic aberrations linked to metabolic diseases and NPDs. Finally, we outline challenges and current research gaps related to investigating the relationship between microbiota, epigenetic aberrations, and metabolic abnormalities associated with NPDs. Full article

Neuronutrition to improve brain resilience to stress and human health has received considerable attention. The use of specific nutrients is effective in preventing and slowing neurodegenerative and neuropsychiatric disorders. Selective neuronutrients, including polyphenols, short-chain fatty acids (SCFAs), tryptophan, tyrosine, and sulfur metabolites, can modulate the dysregulated nuclear factor erythroid 2 (Nrf2) pathway through neuroepigenetic modifications and altered levels of neurotransmitters such as serotonin, melatonin, and dopamine. In particular, abnormal epigenetic alterations in the promoter function of the NFE2L2/Nrf2 gene may contribute to the onset and progression of various diseases by disrupting cellular homeostasis. Recent evidence has documented that polyphenols are capable of modulating Nrf2 signaling; to do this, they must reverse hypermethylation in the CpG islands of the NFE2L2 gene. This process is achieved by modifying the activity of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). Furthermore, a diverse group of polyphenolic metabolites can be identified and quantified using innovative mass spectrometry platforms in both in vitro models and human urine samples to investigate redox metabolic homeostasis under physiological and pathophysiological conditions. This review aims to deepen the current understanding of the role of nutrient-derived secondary metabolites. It highlights innovative strategies to effectively prevent, slow, or potentially reverse neuroinflammation and oxidative stress, key drivers of neuronal damage. The targeted application of these metabolites can be considered a novel, personalized neuronutritional approach to promote brain health and neuronal adaptation. Full article

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. It is characterized by a high degree of heterogeneity, meaning that although these tumors may appear morphologically similar, they often exhibit distinct clinical outcomes. By associating specific molecular fingerprints with different clinical behaviors, high-throughput omics technologies (e.g., genomics, transcriptomics, and epigenomics) have significantly advanced our understanding of GBM, particularly of its extensive heterogeneity, by proposing a molecular classification for the implementation of precision medicine. However, due to the vast volume and complexity of data, the integrative analysis of omics data demands substantial computational power for processing, analyzing and interpreting GBM-related data. Artificial intelligence (AI), which mainly includes machine learning (ML) and deep learning (DL) computational approaches, now presents a unique opportunity to infer valuable biological insights from omics data and enhance the clinical management of GBM. In this review, we explored the potential of integrating multi-omics, imaging radiomics and clinical data with AI to uncover different aspects of GBM (molecular profiling, prognosis, and treatment) and improve its clinical management. Full article

Pharmacotherapy in the geriatric population is one of the greatest challenges in modern medicine. Elderly patients, characterized by multimorbidity and the resulting polypharmacy, are significantly more exposed to adverse drug reactions (ADRs), which often lead to hospitalization and a decline in quality of life. Understanding the reasons for this difference requires an analysis of the physiological changes that occur during the aging process at the molecular level. This article presents a perspective on the molecular aspects of geriatric pharmacotherapy, focusing on the fundamental mechanisms that are modified with age. The analysis covers changes in pharmacokinetics, including the role and regulation of cytochrome P450 (CYP) enzymes, whose activity, especially in phase I reactions, is significantly reduced. The age-dependent dysfunction of drug transporters from the ABC (ATP-binding cassette) and SLC (solute carrier) families in key organs such as the intestines, liver and kidneys is discussed, which affects the absorption, distribution and elimination of xenobiotic compounds, including drugs. The article also provides a comprehensive analysis of the blood–brain barrier (BBB), describing changes in neurovascular integrity, including the dysfunction of tight junctions and a decrease in the activity of P-glycoprotein, sometimes referred to as multidrug resistance protein (MDR). This increases the susceptibility of the central nervous system to the penetration and action of drugs. In the realm of pharmacodynamics, changes in the density and sensitivity of key receptors (serotonergic, dopaminergic, adrenergic) are described based on neuroimaging data, explaining the molecular basis for increased sensitivity to certain drug classes, such as anticholinergics. The paper also explores new research perspectives, such as the role of the gut microbiome in modulating pharmacokinetics by influencing gene expression and the importance of pharmacoepigenetics, which dynamically regulates drug response throughout life via changes in DNA methylation and histone modifications. The clinical implications of these molecular changes are also discussed, emphasizing the potential of personalized medicine, including pharmacogenomics, in optimizing therapy and minimizing the risk of adverse reactions. Such an integrated approach, incorporating data from multiple fields (genomics, epigenomics, microbiomics) combined with a comprehensive geriatric assessment, appears to be the future of safe and effective pharmacotherapy in the aging population. Full article

Maternal exposure to polycyclic aromatic hydrocarbons (PAHs) during pregnancy may have effects on the offspring epigenome. And the change in onset epigenome may be associated with children’s neurodevelopment. The current study investigated the relationship between 5-hydroxymethylcytosine (5-hmC) levels in cord blood and PAH metabolites in maternal urine at delivery and children’s neurodevelopment at birth and at age 2. We enrolled 400 pregnant women and their newborns and collected their biological samples after obtaining written informed consent. Enzyme linked immunosorbent assay kits and Chromatin immunoprecipitation kits were used to assess the DNA hydroxymethylation level in cord blood. We observed that 1-hydroxypyrene (1-OHPyr) was inversely associated with gesell developmental scale scores, positively associated with global DNA 5-hmC levels, and associated with decreased 5-hmC levels of the brain-derived neurotrophic factor (BDNF) and methyl CpG binding protein 2 (MeCP2) gene promoter. In addition, the 5-hmC levels of the BDNF and MeCP2 gene promoters were associated with motor scores. The global DNA 5-hmC was inversely associated with motor scores. Mediation analysis showed mediation effects between 1-OHPyr and motor scores by 5-hmC. The global DNA 5-hmC and MeCP2 and BDNF gene promoter 5-hmC contributed 28.51%, 27.29%, and 18.98% of the effect on motor scores changes related to 1-OHPyr. The study results suggested that 5-hmC can be a potential mechanism between prenatal PAH exposure and children’s neurodevelopment at age 2 and provide a better understanding of the role of hydroxymethylation in neurodevelopment. Full article

The bidirectional relationship between epilepsy and depression illustrates shared neurobiological mechanisms of neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and glutamatergic dysfunction. Depression is present in 20–55% of people with epilepsy, far greater than in the general population, while depression doubles epilepsy risk 2.5-fold, indicating shared pathophysiology. Neuroinflammatory mediators (interleukin-6, tumor necrosis factor alpha, high-mobility group box 1) establish a vicious cycle: seizures exacerbate inflammation and mood disruption, and stress lowers seizure thresholds. Hippocampal damage and cortisol toxicity also link these disorders, with early life stress imprinting lifelong risk via epigenetic alteration. Genetic studies identify pleiotropic genes (brain-derived neurotrophic factor) that regulate synaptic plasticity, serotonin activity, and immune responses. New treatments target shared pathways: ketamine and AMPAkines normalize glutamate tone; mGluR5 antagonists attenuate hyperexcitability and inflammation; DNA methyltransferase inhibitors reverse aberrant DNA methylation; and probiotics manipulate the gut–brain axis by boosting neuroprotective metabolites like butyrate. Despite challenges—transient effects, precision dosing, and blood–brain barrier penetration—these advances constitute a paradigm shift toward mechanistic repair rather than symptom management. The way forward includes clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing, biomarker-led therapies, and combination approaches (e.g., ketamine and probiotics). Such comorbidity needs to be managed holistically through integrated neuropsychiatry care, offering hope to patients with treatment-refractory symptoms. Full article

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor with a dismal prognosis despite advances in multimodal treatment. Conventional therapies fail to achieve durable responses due to GBM’s molecular heterogeneity and capacity to evade therapeutic pressures. Epigenetic alterations have emerged as critical contributors to GBM pathobiology, including aberrant DNA methylation, histone modifications, and non-coding RNA (ncRNA) dysregulation. These mechanisms drive oncogenesis, therapy resistance, and immune evasion. This scoping review evaluates the current state of knowledge on epigenetic modifications in GBM, synthesizing findings from original articles and preclinical and clinical trials published over the last decade. Particular attention is given to MGMT promoter hypermethylation status as a biomarker for temozolomide (TMZ) sensitivity, histone deacetylation and methylation as modulators of chromatin structure, and microRNAs as regulators of pathways such as apoptosis and angiogenesis. Therapeutically, epigenetic drugs, like DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis), appear as promising approaches in preclinical models and early trials. Emerging RNA-based therapies targeting dysregulated ncRNAs represent a novel approach to reprogram the tumor epigenome. Combination therapies, pairing epigenetic agents with immune checkpoint inhibitors or chemotherapy, are explored for their potential to enhance treatment response. Despite these advancements, challenges such as tumor heterogeneity, the blood–brain barrier (BBB), and off-target effects remain significant. Future directions emphasize integrative omics approaches to identify patient-specific targets and refine therapies. This article thus highlights the potential of epigenetics in reshaping GBM treatment paradigms. Full article

Recent investigations into the neuroepigenome of the brain are providing unparalleled understanding into the impact of post-translational modifications (PTMs) of histones in regulating dynamic gene expression patterns required for adult brain cognitive function and plasticity. Histone acetylation is one of the most well-characterized PTMs shown to be required for neuronal function and cognition. Histone acetylation initiates neural circuitry plasticity via chromatin control, enabling neurons to respond to external environmental stimuli and adapt their transcriptional responses accordingly. While interplay between histone acetylation and deacetylation is critical for these functions, dysregulation during the aging process can lead to significant alterations in the neuroepigenetic landscape. These alterations contribute to impaired cognitive functions, neuronal cell death, and brain atrophy, all hallmarks of age-related neurodegenerative disease. Significantly, while age-related generation of DNA mutations remains irreversible, most neuroepigenetic PTMs are reversible. Thus, manipulation of the neural epigenome is proving to be an effective therapeutic strategy for neuroprotection in multiple types of age-related neurodegenerative disorders (NDs) that include Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). Here, we highlight recent progress in research focusing on specific HAT-based neuroepigenetic mechanisms that underlie cognition and pathogenesis that is hallmarked in age-related NDs. We further discuss how these findings have potential to be translated into HAT-mediated cognitive-enhancing therapeutics to treat these debilitating disorders. Full article

Rett syndrome (RTT) is a multisystem neurological disorder. Pathogenic changes in the MECP2 gene that codes for methyl-CpG-binding protein 2 (MeCP2) in RTT lead to a loss of previously established motor and cognitive skills. Unravelling the mechanisms of neurological regression in RTT is complex, due to multiple components of the neural epigenome being affected. Most evidence has primarily focused on deciphering the complexity of transcriptional machinery at the molecular level. Little attention has been paid to how epigenetic changes across the neural epigenome in RTT lead to neurological regression. In this narrative review, we examine how pathogenic changes in MECP2 can disrupt the balance of the RTT neural epigenome and lead to neurological regression. Environmental and genetic factors can disturb the balance of the neural epigenome in RTT, modifying the onset of neurological regression. Methylation changes across the RTT neural epigenome and the consequent genotoxic stress cause neurons to regress into a senescent state. These changes influence the brain as it matures and lead to the emergence of specific symptoms at different developmental periods. Future work could focus on epidrugs or epi-editing approaches that may theoretically help to restore the epigenetic imbalance and thereby minimise the impact of genotoxic stress on the RTT neural epigenome. Full article

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD. Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis. Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation. Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons. Full article

Background. Single-cell RNA sequencing (scRNA-seq) has transformed genomics by enabling the study of cellular heterogeneity. However, its high dimensionality, noise, and sparsity pose significant challenges for data analysis. Methods. We investigate the use of Hyperdimensional Computing (HDC), a brain-inspired computational framework recognized for its noise robustness and hardware efficiency, to tackle the challenges in scRNA-seq data analysis. We apply HDC to both supervised classification and unsupervised clustering tasks. Results. Our experiments demonstrate that HDC consistently outperforms established methods such as XGBoost, Seurat reference mapping, and scANVI in terms of noise tolerance and scalability. HDC achieves superior accuracy in classification tasks and maintains robust clustering performance across varying noise levels. Conclusions. These results highlight HDC as a promising framework for accurate and efficient single-cell data analysis. Its potential extends to other high-dimensional biological datasets including proteomics, epigenomics, and transcriptomics, with implications for advancing bioinformatics and personalized medicine. Full article

Recent studies show that patients with Alzheimer’s disease (AD) harbor specific methylation marks in the brain that, if accessible, could be used as epigenetic biomarkers. Liquid biopsy enables the study of circulating cell-free DNA (cfDNA) fragments originated from dead cells, including neurons affected by neurodegenerative processes. Here, we isolated and epigenetically characterized plasma cfDNA from 35 patients with AD and 35 cognitively healthy controls by using the Infinium^® MethylationEPIC BeadChip array. Bioinformatics analysis was performed to identify differential methylation positions (DMPs) and regions (DMRs), including APOE ε4 genotype stratified analysis. Plasma pTau181 (Simoa) and cerebrospinal fluid (CSF) core biomarkers (Fujirebio) were also measured and correlated with differential methylation marks. Validation was performed with bisulfite pyrosequencing and bisulfite cloning sequencing. Epigenome-wide cfDNA analysis identified 102 DMPs associated with AD status. Most DMPs correlated with clinical cognitive and functional tests including 60% for Mini-Mental State Examination (MMSE) and 80% for Global Deterioration Scale (GDS), and with AD blood and CSF biomarkers. In silico functional analysis connected 30 DMPs to neurological processes, identifying key regulators such as SPTBN4 and APOE genes. Several DMRs were annotated to genes previously reported to harbor epigenetic brain changes in AD (HKR1, ZNF154, HOXA5, TRIM40, ATG16L2, ADAMST2) and were linked to APOE ε4 genotypes. Notably, a DMR in the HKR1 gene, previously shown to be hypermethylated in the AD hippocampus, was validated in cfDNA from an orthogonal perspective. These results support the feasibility of studying cfDNA to identify potential epigenetic biomarkers in AD. Thus, liquid biopsy could improve non-invasive AD diagnosis and aid personalized medicine by detecting epigenetic brain markers in blood. Full article

Brain injuries can result from accidents, warfare, sports injuries, or brain diseases. Identifying regeneration-associated genes (RAGs) during epigenome remodeling upon brain injury could have a significant impact on reducing neuronal death and subsequent neurodegeneration for patients with brain injury. We previously identified several WNT genes as RAGs involved in the neurite regrowth of injured cortical neurons. Among them, the expression of the Wnt8a gene increased most significantly during neurite regrowth, indicating its potential to promote neuronal regeneration. In this study, we investigated the regulatory mechanism of Wnt8a transcription. An algorithm was developed to predict the novel enhancer regions of candidate genes. By combining active enhancer marks, histone H3 lysine 27 acetylation (H3K27ac), and histone H3 lysine 4 mono-methylation (H3K4me1), we identified a candidate enhancer region for Wnt8a located 1.7 Mb upstream and 0.1 Mb downstream of the Wnt8a gene. This region was organized into enhancers (Ens) 1–15. Enhancer RNA expression from the predicted En1–15 regions, DNA topological dynamics, and the activity of predicted enhancers were analyzed to validate the candidate active enhancers. Our findings showed that the En8, 9, 10, 14, and 15 regions expressed higher eRNAs during neurite regrowth. Notably, the En8-2 and En14-2 subregions showed significantly up-regulated H3K4me1 modification during neurite regrowth. Using chromatin conformation capture assays and enhancer–reporter assays, we delineated that the molecular regulation of Wnt8a transcription during neurite regrowth occurs through looped En8-promoter interplay. Full article

Cognitive impairment in various mental illnesses, particularly neuropsychiatric disorders, has adverse functional and clinical consequences. While genetic mutations and epigenetic dysregulations of several genes during embryonic and adult periods are linked to cognitive impairment in mental disorders, the composition and diversity of resident bacteria in the gastrointestinal tract—shaped by environmental factors—also influence the brain epigenome, affecting behavior and cognitive functions. Accordingly, many recent studies have provided evidence that human gut microbiota may offer a potential avenue for improving cognitive deficits. In this review, we provide an overview of the relationship between cognitive impairment, alterations in the gut microbiome, and epigenetic alterations during embryonic and adult periods. We examine how various factors beyond genetics—such as lifestyle, age, and maternal diet—impact the composition, diversity, and epigenetic functionality of the gut microbiome, consequently influencing cognitive performance. Additionally, we explore the potential of maternal gut microbiome signatures and epigenetic biomarkers for predicting cognitive impairment risk in older adults. This article also explores the potential roles of nutritional deficiencies in programming cognitive disorders during the perinatal period in offspring, as well as the promise of gut microbiome-targeted therapeutics with epigenetic effects to prevent or alleviate cognitive dysfunctions in infants, middle-aged adults, and older adults. Unsolved challenges of gut microbiome-targeted therapeutics in mitigating cognitive dysfunctions for translation into clinical practice are discussed, lastly. Full article

Background/Objectives: Aging is a natural physiological process involving biological and genetic pathways. Growing evidence suggests that alterations in the epigenome during aging result in transcriptional changes, which play a significant role in the onset of age-related diseases, including cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. For this reason, the epigenetic alterations in aging and age-related diseases have been reviewed, and the major extrinsic factors influencing these epigenetic alterations have been identified. In addition, the role of the gut microbiome and its metabolites as epigenetic modifiers has been addressed. Results: Long-term exposure to extrinsic factors such as air pollution, diet, drug use, environmental chemicals, microbial infections, physical activity, radiation, and stress provoke epigenetic changes in the host through several endocrine and immune pathways, potentially accelerating the aging process. Diverse studies have reported that the gut microbiome plays a critical role in regulating brain cell functions through DNA methylation and histone modifications. The interaction between genes and the gut microbiome serves as a source of adaptive variation, contributing to phenotypic plasticity. However, the molecular mechanisms and signaling pathways driving this process are still not fully understood. Conclusions: Extrinsic factors are potential inducers of epigenetic alterations, which may have important implications for longevity. The gut microbiome serves as an epigenetic effector influencing host gene expression through histone and DNA modifications, while bidirectional interactions with the host and the underexplored roles of microbial metabolites and non-bacterial microorganisms such as fungi and viruses highlight the need for further research. Full article