Search Results (1,746)

Background: Gestation is a period of significant biological plasticity where the intrauterine environment influences fetal development via “fetal programming”. This study systematically reviews and meta-analyzes the association between genetic determinants—specifically the NR3C1, FKBP5, and CRHR1 genes, chosen for their pivotal role in the functional regulation and feedback sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis—and stress reactivity during pregnancy. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, and Web of Science, yielding an initial total of 1430 records. After removing duplicates and screening 669 studies, a total of 34 primary observational studies were included in the systematic review and qualitative synthesis. For the quantitative synthesis, 27 articles provided sufficient data, resulting in k = 39 independent effect sizes analyzed via a mixed-effects model to account for tissue-specific and cohort-specific outcomes. Results: Systematic analysis reveals that maternal psychosocial stress significantly correlates with NR3C1 hypermethylation, acting as a biological mediator for neonatal cortisol dysregulation and hippocampal volume reduction. The FKBP5 rs1360780 polymorphism emerged as a key moderator of structural vulnerability, showing a “double-hit” effect when combined with epigenetic alterations. Furthermore, the study identifies sex-specific susceptibility, with divergent placental trajectories for male and female fetuses. Meta-analytic estimates confirmed the robustness of these associations (Rosenthal Fail-Safe N = 431,000), despite a general trend toward statistical significance (p = 0.079) in heterogeneous cohorts. Conclusions: The findings underscore a stable link between genetic determinants and prenatal stress reactivity. The interaction between molecular predisposition and environmental factors defines the health of the mother–infant dyad. These results advocate for a transition toward Precision Prenatal Medicine, integrating polygenic risk scores and epigenetic monitoring to implement early, targeted preventive interventions. Full article

Lower-grade gliomas (LGGs) often follow a relatively protracted clinical course; however, a substantial proportion eventually undergo malignant transformation to high-grade, treatment-refractory disease. This process has traditionally been interpreted in the context of stepwise histopathologic progression and recurrent genetic alterations. Increasing evidence, however, suggests that malignant transformation is more accurately understood as an evolutionary process shaped by the interplay among epigenetic constraints, cell-state plasticity, and selective pressures. In this review, we examine current evidence supporting a model in which early LGGs, particularly isocitrate dehydrogenase (IDH)-mutant tumors, are initially maintained in relatively restricted cellular states by metabolically imposed epigenetic programs, but progressively escape these constraints under the cumulative influence of therapy, hypoxia, immune remodeling, and genomic instability. We summarize recent advances demonstrating that progression from lower-grade to high-grade disease is accompanied by cell-state transitions characterized by altered lineage identity, acquisition of stem-like features, increased proliferative capacity, and adaptation to cellular stress. We further discuss how these transitions are reinforced by microenvironmental evolution, including vascular remodeling, extracellular matrix reorganization, and changes in immune composition, thereby creating conditions that favor clonal expansion, invasion, and therapeutic resistance. Particular attention is given to longitudinal, single-cell, and spatially resolved studies, which collectively indicate that malignant transformation is not a discrete event but a continuous process of evolutionary selection and phenotypic reprogramming. Finally, we discuss the translational implications of this framework for early risk stratification, biomarker development, and mechanism-based therapeutic intervention. By reframing malignant transformation in LGGs as a process of cell-state escape under persistent selective pressure, this review aims to provide an integrated view of glioma progression and to highlight new opportunities for precision monitoring and treatment. Full article

Background: Chronic stress is a major contributing factor to mood disorders, including depression and anxiety; however, the molecular mechanisms underlying individual differences in susceptibility to such disorders remain poorly understood. DNA methyltransferase 3a (Dnmt3a), a key epigenetic regulator, has been increasingly implicated in stress-related neurobiological adaptations. In this study, we employed a well-established mouse model of chronic social defeat stress (CSDS) to investigate the functional role of Dnmt3a in modulating individual susceptibility to social stress. Methods: Male C57BL/6J mice were exposed to chronic/submaximal social defeat stress (CSDS/SSDS). AAV vectors were used to achieve Dnmt3a overexpression or global and oligodendrocyte-specific knockdown in the nucleus accumbens (NAc). Behavioral tests, including social interaction, open field, and elevated zero maze, were conducted alongside Western blotting and immunofluorescence assays. Results: CSDS selectively increased Dnmt3a expression in NAc oligodendrocytes of stress-susceptible mice. Overexpression of Dnmt3a in the NAc enhanced susceptibility to stress, whereas its knockdown conferred resilience, without affecting baseline behaviors. Dnmt3a negatively regulated myelin basic protein (MBP) and dopamine D1 receptor expression. Stress-susceptible mice exhibited shortened myelinated segments and reduced D1 receptor levels, while D2 receptor expression remained unchanged. Conclusions: Dnmt3a in NAc oligodendrocytes modulates susceptibility to social stress through a Dnmt3a-MBP/D1 receptor-NAc pathway, highlighting a critical glia-neuron interaction. This mechanism extends our understanding of the neurobiological basis of stress-related disorders and positions Dnmt3a as a promising therapeutic target for developing precision interventions or biomarkers. Full article

Background/Objectives: Although clinically distinct, bipolar disorder (BP), schizophrenia (SZ), major depressive disorder (MDD), and social anxiety disorder (SAD) share fundamental biology. We mapped these transdiagnostic systemic mechanisms. Methods: Weighted Gene Co-Expression Network Analysis (WGCNA) of peripheral blood RNA-Seq datasets evaluated module preservation, hub gene disruption, and microRNA (miRNA) networks. Results: Seven modules showed robust cross-disease preservation. Overall, 56 of 105 candidate hub genes exhibited altered expression, with 22 passing the false discovery rate (FDR) correction. Hubs like IL1B, TLR2, and MMP9 dominated networks linked to altered inflammatory signaling and structural remodeling. Downregulated ribosomal hubs characterized systemic metabolic stress. Discussion: These signatures capture extensive systemic dysregulation. Inflammation and metabolic shifts correlate strongly with pathways regulating chronic neuroinflammation, epigenetic control, and dendritic pruning. Computational models suggest these cascades evade miRNA controls, potentially compromising structural neural plasticity. Conclusions: This shared transcriptomic architecture challenges rigid diagnostic boundaries. Identifying systemic immune dysregulation and translational alterations as core pathogenic denominators provides a rationale for transdiagnostic therapies targeting upstream systemic networks to mitigate neural vulnerabilities. Full article

The endocannabinoid system (ECS) is a fundamental regulator of brain and body homeostasis, integrating neural, immune, and stress-related signaling pathways. Dysregulation of ECS components, including cannabinoid receptors (CB1 and CB2), endocannabinoids such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes (FAAH and MAGL), has been increasingly implicated in the pathophysiology of neuropsychiatric disorders, including mood, anxiety, psychotic, stress-related, and eating disorders. Altered endocannabinoid signaling contributes to maladaptive stress responses, emotional dysregulation, and impaired synaptic plasticity, highlighting the role of the ECS as a core integrative mechanism. Therapeutic strategies targeting ECS, particularly through FAAH inhibition and the use of plant-derived cannabinoids, such as cannabidiol (CBD), show promise in restoring endogenous homeostasis while minimizing the adverse cognitive and affective effects associated with direct CB1 activation. ECS function and treatment response are further influenced by genetic polymorphisms in CNR1, CNR2, FAAH, and MGLL, as well as epigenetic mechanisms, including DNA methylation, histone modifications, and microRNA regulation. Despite these advances, clinical translation remains limited by interindividual variability, the complexity of ECS interactions, and the relatively small size of existing clinical studies. Future research integrating longitudinal clinical trials with multi-omics approaches is essential to support the development of evidence-based, personalized interventions. Overall, understanding ECS mechanisms and dysregulation provides a valuable framework for the development of targeted therapies in neuropsychiatric disorders. Full article

Pregnancy is characterized by progressive maternal hyperlipidemia, including increased triglycerides, total cholesterol, and low-density lipoprotein, with dynamic fluctuations in high-density lipoprotein. Excess maternal free fatty acids induce oxidative stress through reactive oxygen species, causing mitochondrial dysfunction, lipid peroxidation, activation of inflammatory pathways, and epigenetic remodeling in the placenta and fetal tissues. These molecular alterations impair placental lipid transport and nutrient sensing, leading to hypertrophy of fetal liver, myocardium, and adipose tissue, while disrupting neonatal glucose and lipid homeostasis and increasing susceptibility to perinatal complications and long-term metabolic disorders. This review aims to evaluate mechanistic pathways linking maternal lipid metabolism, oxidative stress, placental function, and fetal organ remodeling. Mechanistic and translational studies were identified through searches of PubMed, Scopus, the Cochrane Library, and Web of Science (2000–2025) using predefined keywords including lipid metabolism, free fatty acids, oxidative stress, placental lipid transport, epigenetics, DNA methylation, fetal programming, and perinatal outcomes. Evidence indicates that maternal lipid imbalance drives placental oxidative and epigenetic modifications, directly contributing to fetal organ hypertrophy and neonatal metabolic dysregulation. In conclusion, maternal dyslipidemia represents a modifiable determinant of fetal organ hypertrophy and long-term metabolic risk, supporting the clinical relevance of maternal lipid monitoring and targeted metabolic interventions during pregnancy. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide and arises from systemic metabolic dysregulation and insulin resistance. Despite its increasing prevalence, effective pharmacological interventions remain limited. Recent evidence has identified sirtuin 6 (SIRT6), an NAD⁺-dependent epigenetic regulator, as an important modulator of hepatic metabolic and stress-responsive pathways. This review summarizes current knowledge regarding the role of SIRT6 in liver physiology and MASLD pathogenesis. Accumulating evidence indicates that SIRT6 suppresses lipogenic transcriptional programs while enhancing mitochondrial oxidative capacity and fatty acid oxidation, thereby maintaining metabolic homeostasis. Beyond lipid metabolism, SIRT6 is implicated in the regulation of endoplasmic reticulum stress responses, inflammatory signaling, and chromatin accessibility, which are the processes that collectively influence hepatocellular injury and disease progression. In addition, emerging data suggest that SIRT6 modulates hepatic stellate cell activation and fibrogenic signaling pathways, thereby linking epigenetic regulation to the development of liver fibrosis. A reduction in hepatic SIRT6 expression and activity has been reported in metabolic disorders, including MASLD. We further discuss the therapeutic potential of targeting SIRT6, including the development of selective small-molecule activators and naturally derived compounds aimed at restoring SIRT6 activity. Together, the available evidence positions SIRT6 as an important regulatory node in MASLD and a promising candidate for future therapeutic intervention. Full article

This is a narrative conceptual paper, not a systematic review. Ultrasound-guided fascial hydrorelease (FHR) has been reported to provide sustained pain relief in patients with chronic musculoskeletal pain; however, its underlying biological mechanisms remain incompletely understood. In this paper, we propose the “Fascial Memory Reset Hypothesis” as an integrative framework linking mechanobiology, extracellular matrix (ECM) remodeling, peripheral nociception, microcirculatory dynamics, and ultrasound imaging findings. Mechanobiological research has demonstrated that increased tissue stiffness activates YAP/TAZ signaling, promoting fibroblast activation, ECM deposition, and mechano-epigenetic regulation. These mechanically driven processes can stabilize pathological tissue phenotypes without DNA sequence alterations. The “Fascial Memory Reset Hypothesis” proposes that targeted mechanical interventions such as FHR may partially reverse these mechanically maintained states by restoring tissue mobility and modifying stiffness-dependent mechanotransduction. We propose that “stacking fascia” (observed as layered hyperechoic bands on ultrasound) represents the macroscopic structural phenotype of mechano-epigenetic memory formed through sustained mechanical stress. Integrating molecular mechanotransduction pathways, mechano-epigenetic mechanisms, neural sensitization, and vascular factors, we propose that FHR may hypothetically partially normalize pathological fascial states by mechanically restoring tissue mobility and modifying stiffness-dependent signaling. Although direct molecular evidence of the effect of FHR in human fascia remains limited, this hypothesis provides a biologically plausible link between mechanical stress, ultrasound-visible structural alterations, and sustained clinical improvement. Full article

Plant-derived exosomes (PDEs) are gaining attention owing to their key implications in cross-kingdom communication, facilitating bioactive entities among plants and animals. PDEs are tiny nanoscale vesicles generally comprised of RNAs, proteins, and secondary metabolites and are involved in the regulation of physiological processes (immune modulation, cell regeneration, and stress response). An important feature of PDEs is to enable cross-kingdom regulation in skin wound repair. This is because PDEs can modulate several signaling pathways (PI3K-Akt, TGF-β, and mitogen-activated protein kinase) that further direct inflammatory, cell migratory, angiogenic, and extracellular matrix remodeling. Key features of PDEs, including modest immunogenicity, easy crossing of biological barriers, and natural biocompatibility, make them novel alternatives to synthetic wound-healing agents. Therefore, this review disparagingly examines the biogenesis, molecular composition, and diversified biological functions of PDEs, particularly with reference to potential implications in wound healing and overall skin health. The current challenges pertaining to PDE isolation, scalability, and bioavailability and regulatory hurdles for their clinical translation were also explored. In addition, the epigenetic effects of PDEs on human skin cells and wound healing are explained in detail. Finally, this review presents a comprehensive investigation of PDEs in skin wound repair, identifies research gaps, and outlines future directions for dermatological applications. Full article

Background: Cognitive and psychiatric disorders are caused by a complex interplay between genetic predisposition, environmental exposures, and dynamic molecular regulation in the brain. Animal models provide a controlled environment for examining these mechanisms, and advances in transcriptome and epigenomic technologies have greatly expanded our knowledge of disease-relevant pathways. Objective: This scoping review systematically maps and synthesizes the epigenetic and transcriptomic findings from the established animal models of four neuropsychiatric conditions—autism spectrum disorder (ASD), schizophrenia, depression, and Rett syndrome—drawing on a PRISMA-ScR-guided literature search. The review characterizes the breadth of evidence, identifies convergent and divergent molecular pathways, and highlights the translational gaps and therapeutic implications. Methods: Research employing chromatin accessibility testing, genome-wide DNA methylation mapping, single-cell and bulk RNA sequencing, histone modification profiling, and multi-omics integration in mouse and other validated animal models was thoroughly reviewed. A quality appraisal of the primary experimental studies (n = 63) was performed using a modified CAMARADES checklist. Results: Beyond generalized cellular stress responses, multi-omics analysis emphasizes the cell-type- and context-dependent nature of epigenetic changes in animal models, including isoform-specific histone modifications and model-dependent binding of HDAC/MeCP2 complexes to genes involved in synaptic plasticity. Single-cell RNA sequencing analyses have uniformly shown transcriptional changes in parvalbumin-positive (PV+) interneurons. Conclusions: The specific convergence of epigenetic disruptions in neural circuits involved in synaptic structure and inhibitory function could play a role in the generation of neuropsychiatric phenotypes in animal models, highlighting the importance of circuit- and cell-type-specific epigenetics while pointing to potential therapeutic avenues. Full article

Male reproductive aging is increasingly recognized as a systemic process in which inflammaging drives progressive dysfunction of urogenital tissues. Key mechanisms include immune–metabolic alterations, activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, as well as epigenetic remodeling. Evidence from experimental and clinical studies suggests that these processes are often investigated independently, and integrative models in humans remain limited. Here, we propose a conceptual framework linking the prostate, testis, and skeletal muscle, in which oxidative stress may act as a mediator amplifying systemic dysregulation at different levels during the aging process. Lifestyle and metabolic interventions, including caloric restriction, resistance exercise, and selected nutraceuticals, may act as key modulators of inflammaging pathways, thus highlighting new potential targets for precision medicine approaches. Full article

Trained immunity is a concept that is currently in development and refers to the long-term functional reprogramming of innate immune cells in response to microbial or inflammatory stimuli. This process serves a dual purpose in the gastrointestinal tract, contributing to chronic inflammatory conditions like inflammatory bowel disease and maintaining host defense. The production of pro-inflammatory mediators is augmented by epigenetic and metabolic changes that are induced by the persistent activation of innate immune cells, which is triggered by microbial components and damage-associated signals. Although this increased responsiveness may initially be protective, sustained activation leads to tissue damage, epithelial barrier dysfunction, and chronic inflammation. These mechanisms are significant contributors to colorectal carcinogenesis, particularly in colitis-associated cancer. Through the activation of oncogenic signaling pathways, the establishment of a pro-tumorigenic microenvironment, and an increase in oxidative stress, trained immunity also influences tumor development. Additionally, the systemic reprogramming of hematopoietic progenitor cells has the potential to exacerbate inflammation and facilitate the progression of tumors. The identification of epigenetic and metabolic biomarkers associated with trained immunity can lead to novel diagnostic opportunities. Targeting metabolic and epigenetic pathways, as well as regulating the intestinal microbiota, is a promising therapeutic approach that could enhance the effectiveness of treatments for colorectal cancer while minimizing adverse effects on the immune system. Nevertheless, it is necessary to maintain a delicate equilibrium to suppress pathological inflammation without compromising protective immune responses. In general, trained immunity may represent a potentially relevant mechanistic link between chronic inflammation and colorectal cancer; however, its role remains context-dependent and not yet fully defined. Full article

Generally, forest trees with medicinal value present diverse chemotypes considered key determinants of efficacy, safety, and commercial valuation. Such heterogeneity varies among tissues, genotypes, and seasons, and stress exposure. This review summarizes how regulatory controls and genome architecture affect the stability and synthesis of secondary metabolites in woody medicinally important taxa. Detailed haplotypic and chromosomal analyses have recently identified diverse and repeatable architectural drivers. Among these, LTR/transposon-mediated revamping, neofunctionalization, biosynthetic gene clusters, and tandem duplication play a special role in reshaping pathway capacity. The enzymatic regulation of these drivers translates this “capacity” into harvest-pertinent chemistry by employing conserved TF modules, hormone crosstalk, and emergent chromatin/epigenetic layers. Nevertheless, major parameters pertaining to the tissue-specific storage, transport, and compartmentalization of these chemotypes are contextualized with certain limitations. In this review, the integration of GWAS/eQTL/TWAS with multi-tissue is explained in addition to the replacement of a single reference with pangenome/haplotype frameworks, and explicit modeling of G × E further strengthen genotype-to-chemotype mapping. Therefore, in this review we summarize practical workflows for chemotype discovery utilizing staged validation models of heterologous reconstitution, isotope/spatial evidence, and chemistry. These findings were supported by data on saponins, alkaloids, iridoids, and defense response. Such an integration links mechanistic understanding to authentication, standardization, and sustainable utilization strategies in woody medicinal trees. Full article

Background/Objectives: Physical activity is one of the most powerful lifestyle factors influencing brain health, with growing evidence supporting its role in promoting neuroplasticity, cognitive function, and resilience to age-related neurological decline. Recent studies indicate that these effects are mediated by coordinated molecular responses involving epigenetics, activity-dependent gene expression, metabolic adaptation, and inter-organ communication pathways. This narrative review synthesizes current knowledge from experimental and clinical studies on the neurogenomic and epigenetic mechanisms underlying exercise-induced brain plasticity. Methods: Literature searches were conducted in PubMed, Scopus, Web of Science, and Google Scholar to identify studies examining neurogenomic and epigenetic mechanisms underlying neuroplasticity and cognitive adaptations in response to exercise, with an emphasis on mechanistic and translational evidence. Results: Available evidence, derived predominantly from animal studies and supported by more limited, often indirect human data, indicates that physical activity induces epigenetic modifications, including changes in DNA methylation, histone modifications, and microRNA expression, which contribute to lasting changes in exercise-responsive genes involved in brain plasticity. These adaptations include the upregulation of key neuroplasticity-related mediators that support neurogenesis, synaptic plasticity, angiogenesis, and metabolic adaptation, alongside the downregulation of pathways linked to neuroinflammation, oxidative stress, and apoptotic signalling. Conclusions: Integrating neurogenomics with systems biology approaches offers promising opportunities to better understand how physical activity influences brain plasticity throughout life. These insights may support the development of personalized exercise medicine to improve cognitive health and reduce the risk of neurodegenerative disorders. Full article

Colorectal cancer (CRC) remains one of the most prevalent malignancies worldwide and is the second largest contributor to both incidence and mortality, underscoring the urgent need for effective prevention strategies. This comprehensive review provides the most up-to-date evidence on the protective role of plant-based dietary patterns against CRC carcinogenesis, with particular emphasis on underlying cellular and molecular level mechanisms. Accumulating research demonstrates that plant-based foods, rich in dietary fibre, polyphenols, and multiple other bioactive compounds, promote gut microbial eubiosis, support immune regulation, and modulate adipose tissue homeostasis. These effects are accompanied by intestinal barrier integrity, enhanced production of short-chain fatty acids, and the induction of apoptosis in malignant cells. Moreover, plant-derived nutrients reduce the abundance of pro-inflammatory microbial taxa, decrease oxidative, nitrosative and carbonyl stress, and downregulate pro-inflammatory cytokines and signalling pathways, implicated in tumourigenesis. As a result, plant-based dietary patterns have high potential to reduce CRC risk through modulating the intricate interplay between epigenetics, inflammation, immune dysregulation, metabolic and hormonal disruptions, and gut microbiota, suggesting a highly promising, cost-effective and equitable strategy for CRC prevention. Full article