Search Results (573)

This study aimed to investigate the effects of pterostilbene (PTE) on the intestinal barrier function, antioxidant capacity, lipid metabolism, and microbial and metabolite homeostasis of suckling piglets via its action on breast milk. Findings indicate that PTE supplementation enhanced the antioxidant status of mature milk and strengthened intestinal barrier function in piglets. Specifically, PTE enhanced intestinal antioxidant status and fatty acid β-oxidation in piglets by regulating the PI3K-AKT and SIRT1-Nrf2/Keap1 signaling pathways. 16S rDNA sequencing and Liquid Chromatography–Mass Spectroscopy (LC–MS) identified breast milk and gut microbiota and their metabolites, respectively. Results indicate that PTE significantly elevated levels of amino acid derivatives in colostrum (Glutathione Reducedform (GSH) and N-acetyl-L-glutamate (NAG)), whilst concurrently reducing levels of glycerophospholipid-related metabolites in both colostrum and mature milk (p < 0.05). Moreover, PTE supplementation markedly altered the composition of the colonic mucosal microbiota in piglets, with Faecalibacterium, Mucispirillum and Ruminococcus identified as key beneficial microbial markers of the colonic mucosa. Combined multi-omics revealed strong correlations in microbial community composition between mature milk and the colon, identifying glycerophospholipid metabolism as a key metabolic pathway that may be associated with the regulatory effects of PTE on milk and the piglet colon. In conclusion, the PTE supplement can improve the quality of breast milk and have a positive impact on the intestinal homeostasis of the offspring. Full article

Hydralazine is widely used to treat hypertension during pregnancy and has epigenetic effects in cancer therapy. Cryoplatable human hepatocytes showed concentration-dependent increase in DNA damage response (linear trend p = 0.0069) following 24 h hydralazine treatment. DNA repair-deficient UV5 Chinese hamster ovary (CHO) cell lines expressing human CYP1A2 and either NAT2*4 (reference allele) or NAT2*5 (variant allele) were treated with hydralazine for 24 h. CHO cells expressing NAT2*4 showed a higher acetylation rate than those with NAT2*5 (p < 0.001), whereas CHO cell viability did not differ significantly following hydralazine treatment (p > 0.05). Hydralazine caused a concentration-dependent increase in DNA damage response in the un-transfected UV5 CHO cell line, as well as in each of the UV5 CHO cell lines transfected with human CYP1A2 and/or NAT2 alleles. CHO cells with CYP1A2 only showed higher DNA damage response from hydralazine compared to cells with CYP1A2/NAT2*4 or CYP1A2/NAT2*5 (p < 0.05 and p < 0.0001, respectively), and higher in CYP1A2/NAT2*4 versus CYP1A2/NAT2*5 cells (p = 0.0011). Apurinic/apyrimidinic (AP) sites in CHO cells expressing only CYP1A2 were significantly higher than in the un-transfected UV5 CHO cell line (p < 0.01) and higher in CHO cells expressing CYP1A2/NAT2*4 compared to CYP1A2/NAT2*5, but the difference was not significant (p > 0.05). In contrast, ROS levels were reduced following hydralazine treatment in CHO cells with CYP1A2/NAT2*4 and CYP1A2/NAT2*5 (p < 0.001 and p < 0.05, respectively). The results of the current study document DNA damage responses associated with hydralazine in human hepatocytes and CHO cells. The DNA damage response was increased following N-hydroxylation by CYP1A2, which competes with N-acetylation by NAT2. Full article

In the context of research aimed at identifying the causes of the progressive decline in cellular and tissue functions characteristic of aging, in recent decades, increasing attention has been devoted to the sirtuin family. Sirtuins are named after the Sir2 protein of Saccharomyces cerevisiae, a product of the SIR gene family, known as “silent information regulator 2”. Sirtuins are NAD⁺-dependent protein deacetylases and deacylases characterized by a conserved catalytic domain of approximately 275 amino acids. The removal of acetyl groups from acetyl-lysine residues on proteins is critical in regulating a wide range of biological functions, including gene silencing, genome stability, longevity, metabolism, and cellular physiology. In humans, the sirtuin family comprises seven isoforms (SIRT1–SIRT7), each with specific substrate preferences and primarily, but not exclusively, localized in the nucleus (SIRT1, SIRT6, and SIRT7), cytoplasm (SIRT2), and mitochondria (SIRT3, SIRT4, and SIRT5). Sirtuins may regulate numerous cellular processes associated with survival and longevity, including transcription and DNA repair, inflammation, glucose and lipid metabolism, oxidative stress, mitochondrial function, apoptosis, autophagy, and stress resistance. Sirtuins’ dependence on NAD⁺ allows them to function as cellular energy sensors, linking metabolic demands to selective lysine deacylation in various subcellular organelles. The aim of this review is to provide an update on this family of molecules, describing their molecular structures, physiological functions, roles in aging processes, and potential to be modulated to serve as a strategy for promoting healthy aging. Full article

Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC₅₀-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting. Full article

Minute virus of canines (MVC) is an autonomous canine parvovirus that causes severe pathological outcomes, including embryo mortality, spontaneous abortion, and congenital malformations in neonatal puppies. Although MVC infection has been shown to induce host cell cycle arrest and apoptosis, the underlying regulatory mechanisms that coordinate cell proliferation and control apoptotic responses during viral replication remain poorly understood. Sirtuin 1 (SIRT1) is an NAD⁺-dependent deacetylase that plays a critical role in regulating cell cycle progression, DNA damage responses, and apoptosis. However, its involvement in MVC infection has not been fully elucidated. Herein, we show that MVC infection markedly upregulates the mRNA and protein expression levels of SIRT1 in a time-dependent manner. MVC infection activates the SIRT1-p53 signaling axis and modulates the acetylation status of p53. In addition, MVC alters the subcellular distribution of SIRT1, promoting its nuclear translocation and colocalization with the viral protein VP2. Functional analyses demonstrated that pharmacological activation of SIRT1 enhanced the viability of MVC-infected WRD cells (virus-tropic cell), promoting viral replication, prolonging S-phase arrest, and reducing apoptosis. Conversely, inhibition of SIRT1 produced the opposite effects, which were closely associated with regulation of the SIRT1-p53 signaling axis. Moreover, SIRT1 knockdown accelerated apoptosis and attenuated S-phase arrest, whereas SIRT1 overexpression further strengthened S-phase retention. Collectively, our findings identify the SIRT1-p53 signaling axis as an important regulator of cell cycle progression and apoptosis during MVC infection, highlighting SIRT1 as a key host factor that supports viral replication and persistence and a potential target for antiviral intervention. Full article

Adolescence represents a critical window of metabolic plasticity, during which profound hormonal, neurobiological, and physiological remodelling increases susceptibility to nutritional exposures. In parallel with the rising prevalence of obesity, insulin resistance, metabolic syndrome, and non-alcoholic fatty liver disease among young people, there is growing interest in the potential for functional food components to modulate epigenetic pathways that govern metabolic programming. This narrative review synthesises current evidence (2015–2025) from PubMed, Scopus, Web of Science, and Embase to elucidate how diet-derived bioactive compounds influence epigenetic regulation relevant to adipogenesis, appetite control, insulin signalling, and lipid homeostasis during adolescence. Particular emphasis is placed on molecular mechanisms, including DNA methylation changes in genes regulating adipocyte differentiation, hypothalamic neuropeptide expression, and pancreatic β-cell function; histone modifications, such as acetylation and methylation events that remodel chromatin accessibility in metabolic tissues; and modulation of microRNA networks implicated in lipid metabolism, inflammatory signalling, and insulin secretion. Furthermore, the review examines the interplay between diet, the gut microbiota, and the epigenome, highlighting the role of microbially derived short-chain fatty acids (SCFAs) as endogenous histone deacetylase inhibitors and mediators of epigenetic remodelling in adipose tissue. By linking these mechanisms to specific functional food components, including polyphenols, long-chain omega-3 fatty acids, fermentable dietary fibre, and other bioactive molecules, we demonstrate how nutritional signals can counteract maladaptive metabolic trajectories and potentially reduce the intergenerational transmission of metabolic risk. A deeper understanding of these epigenetic effects provides the foundation for developing personalised nutrition strategies aimed at preventing metabolic disorders from emerging during adolescence and beyond. Full article

Exercise adaptation depends on a dynamic alternation between catabolic and anabolic states coordinated primarily by AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR). While transient activation of these pathways underpins beneficial molecular remodeling, the system-level consequences of sustained anabolic drive remain insufficiently conceptualized in exercise biology. This article presents a conceptual mechanistic narrative review integrating evidence from molecular nutrition, exercise physiology, redox biology, and epigenetic regulation to define limits of adaptive signaling. We propose the Metabolic Overdrive Model, a systems-level framework describing the transition from adaptive AMPK–mTOR oscillation to a high-anabolic lock-in state characterized by persistent mTORC1 activation, suppressed AMPK signaling, altered NAD⁺ economy (SIRT1–PARP imbalance), redox dysregulation, and progressive epigenetic drift. Using exercise and training as models of sustained metabolic stress, we synthesize mechanistic parallels across energy sensing, oxidative signaling, and chromatin regulation without implying pathological causality. The framework generates testable predictions linking prolonged post-exercise anabolic signaling (>24 h) to specific molecular signatures, including AMPK phosphorylation status, NAD⁺ availability, PARylation, histone acetylation, and DNA methylation dynamics. By reframing exercise adaptation as a loss-of-oscillation phenomenon rather than a linear continuum, this model provides a mechanistic language for hypothesis generation, biomarker-guided periodization, and future experimental validation. Full article

Inflammatory and immune-mediated skin diseases are increasingly recognized as disorders in which genetic susceptibility is shaped and sustained by environmentally responsive regulatory programs. Psoriasis, atopic dermatitis (AD), vitiligo, systemic sclerosis (SSc), lupus erythematosus (LE), and lichen planus (LP) are clinically distinct, yet they share chronic or relapsing inflammation, tissue remodeling, and limited durability of many current therapies. Because genetic variation alone cannot fully explain disease onset, flare dynamics, heterogeneity in severity, or lesion recurrence, epigenetic mechanisms have emerged as a plausible link between environmental exposures and stable disease phenotypes in skin. Epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA networks, controls cell-type-specific transcription without altering the DNA sequence and may contribute to persistent inflammatory states and disease memory despite clinical improvement. The current review synthesizes primary preclinical and translational evidence on epigenetic-targeted therapeutic strategies across these conditions, focusing on interventions that modulate DNA methylation, histone acetylation and deacetylation, histone methylation, chromatin-associated regulatory proteins, and RNA-based approaches. We compare the maturity of therapeutic development across diseases, noting that research and intervention studies are concentrated in psoriasis and AD, whereas evidence for vitiligo, SSc, LE, and LP remains more limited and often derived from systemic or non-cutaneous models. Finally, we outline key gaps that currently restrict clinical translation and discuss why bridging them is essential for determining whether epigenetic modulation can move beyond proof-of-concept toward durable and clinically actionable interventions in inflammatory skin disease. Full article

The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We demonstrated that stress responses, including serum deprivation, oxidative stress, and anticancer drug treatment, increase WWOX expression in human SCC-15 cells and wild-type mouse embryonic fibroblasts (MEFs) through transcriptional activation. Serum deprivation induces higher levels of reactive oxygen species and cell death in Wwox^+/+ than Wwox^−/− MEFs. Anti-apoptotic Bcl-2 family proteins regulate mitochondrial homeostasis and prevent serum deprivation-induced oxidative stress and cell death. Our results showed that serum starvation decreases protein expression levels of Bcl-X_L and Mcl-1 in Wwox^+/+ but not in Wwox^−/− MEFs. Serum starvation also fails to downregulate Bcl-X_L and Mcl-1 protein expression in WWOX-knockdown SCC-15 cells. Replenishment of ectopic WWOX induces downregulation of Bcl-X_L and Mcl-1 protein levels in Wwox^−/− MEFs after serum starvation. We determined that WWOX-mediated downregulation of Bcl-XL and Mcl-1 is accomplished through a lysosome-dependent protein degradation pathway. Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox^+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death. Full article

Cancer is one of the leading causes of mortality worldwide, with breast and colon cancers being among the most common neoplasms in men and women, respectively. Despite significant advancements in treatment, there is a pressing need to enhance specificity and reduce systemic side effects. Importantly, a distinctive feature of cancer cells is their acidic extracellular environment, which profoundly influences cancer progression. In this study, we evaluated the anticancer activity of a pH-sensitive nanocomposite based on silver nanoparticles and pegylated carboxymethyl chitosan (AgNPs-CMC-PEG) in breast cancer (MCF-7) and colon cancer (HCT 116) cell lines. To achieve this, we synthesized and characterized the nanocomposite using UV-Vis spectroscopy, Dynamic Light Scattering (DLS), Fourier-Transform Infrared Spectroscopy (FT-IR), and Scanning Electron Microscopy (STEM-in-SEM). Furthermore, we assessed cytotoxic effects, apoptosis, and reactive oxygen species (ROS) generation using MTT, DAPI, and H2DCFDA assays. Additionally, we analyzed the expression of DNA methyltransferases (DNMT3a) and histone acetyltransferases (MYST4, GCN5) at the mRNA level using RT-qPCR, along with the acetylation and methylation of H3K9ac and H3K9me2 through Western blot analysis. The synthesized nanocomposite demonstrated an average hydrodynamic diameter of approximately 175.4 nm. In contrast, STEM-in-SEM analyses revealed well-dispersed nanoparticles with an average core size of about 14 nm. Additionally, Fourier-transform infrared (FTIR) spectroscopy verified the successful surface functionalization of the nanocomposite with polyethylene glycol (PEG), indicating effective conjugation and structural stability. The nanocomposite exhibited a pH and concentration dependent cytotoxic effect, with enhanced activity observed at an acidic pH 6.5 and at concentrations of 150 µg/ml, 75 µg/ml, and 37.5 µg/ml for both cell lines. Notably, the nanocomposite preferentially induced apoptosis accompanied by ROS generation. Moreover, expression analysis revealed a decrease in H3K9me2 and H3K9ac in both cell lines, with a more pronounced effect in MCF-7 at an acidic pH. Furthermore, the expression of DNMT3a at the mRNA level significantly decreased, particularly at acidic pH. Regarding histone acetyltransferases, GCN5 expression decreased in the HCT 116 line, while MYST4 expression increased in the MCF-7 line. These findings demonstrate that the AgNPs-CMC-PEG nanocomposite has therapeutic potential as a pH-responsive nanocomposite, capable of inducing significant cytotoxic effects and altering epigenetic markers, particularly under the acidic conditions of the tumor microenvironment. Overall, this study highlights the advantages of utilizing pH-sensitive materials in cancer therapy, paving the way for more effective and targeted treatment strategies. Full article

Regulatory B cells (Bregs) are integral to the tumor microenvironment (TME) and influence immune responses through the secretion of immunosuppressive cytokines such as IL-10, IL-35, and TGF-β. This review highlights recent findings on the phenotype and mechanisms of Bregs, emphasizing their dual role in regulating immune responses within the TME. Importantly, we further explored the latest advances in Breg regulatory mechanisms from the novel perspectives of epigenetics and metabolic remodeling, including the effects of DNA methylation, histone acetylation, glycolysis, and oxidative phosphorylation on Bregs. We also investigate the therapeutic targeting of Bregs, with a focus on STAT3 inhibitors such as lipoxin A4, cucurbitacins, and resveratrol, which show promising potential in mitigating the suppressive function of Bregs. Furthermore, this review provides a detailed analysis of the impact of Bregs on tumorigenesis and metastasis, emphasizing the importance of inhibiting specific immune pathways to prevent tumor escape. Finally, this review offers a prospective outlook on immunotherapy strategies based on Bregs, foreseeing a more nuanced understanding of their TME function and the evolution of targeted treatments with enhanced therapeutic efficacy. Full article

Training adaptation involves muscular–metabolic remodeling and personality-linked traits such as motivation, self-regulation, and resilience. This narrative review examines how training load oscillation (TLO)—the deliberate variation in exercise intensity, volume, and substrate availability—may function as a systemic epigenetic stimulus capable of shaping both physiological and psychological adaptation. Fluctuating energetic states reconfigure key energy-sensing pathways (AMPK, mTOR, CaMKII, and SIRT1), thereby potentially influencing DNA methylation, histone acetylation, and microRNA programs linked to PGC-1α and BDNF. This review synthesizes converging evidence suggesting links between these molecular responses and behavioral consistency, cognitive control, and stress tolerance. Building on this literature, a systems model of molecular–behavioral coupling is proposed, in which TLO is hypothesized to entrain phase-shifted AMPK/SIRT1 and mTOR windows, alongside CaMKII intensity pulses and a delayed BDNF crest. The model generates testable predictions—such as amplitude-dependent PGC-1α demethylation, BDNF promoter acetylation, and NR3C1 recalibration under recovery-weighted cycles—and highlights practical implications for timing nutritional, cognitive, and recovery inputs to molecular windows. Understanding TLO as an entrainment signal may help integrate physiology and psychology within a coherent, durable performance strategy. This framework is conceptual in scope and intended to generate testable hypotheses rather than assert definitive mechanisms, providing a structured basis for future empirical investigations integrating molecular, physiological, and behavioral outcomes. Full article

Purpose: The reversible deviant in epigenomic modulations is the highlight of developing new anti-cancer drugs, necessitating the use of fisetin as an epigenetic modifier in the study. Methods: In silico and molecular studies were performed to analyze the modulatory effect of fisetin on various writers and erasers. Further, whole genome DNA methylation sequencing and expression studies were performed. Global DNA methylation-LINE 1 kit was used to check global DNA methylation. Additionally, the effect of fisetin on migration was evaluated by colony, scratch, and invasion assays and qPCR and protein expression studies of migration-related genes were carried out on HeLa cells. Results: In silico studies have supported that fisetin interacts with writers and erasers in their catalytic site and the simulation studies showed minimum fluctuations in energy and temperature over a 10 ns timescale indicating that these complexes are likely to remain stable. Fisetin (20–50 µM) dose-dependently inhibited DNA methyltransferases (DNMT), histone deacetyl transferases (HDAC), histone acetyl transferases (HAT), and histone methyltransferases (HMT) activities at 48 h, with inhibition ranging from 24 to 72% compared to the control. The expression and enzymatic activity of these proteins, along with various H4 and H3 modification marks, were observed to be altered following fisetin treatment at 48 h. Fisetin treatment reduced promoter methylation in various tumor suppressor genes ranging from 15.29% to 76.23% and leading to the corresponding reactivation of important tumor suppressor genes; however, it did not lead to any alteration in the global DNA methylation compared to untreated controls linked with the anti-migratory properties of fisetin as the percentage of migrated cells dropped from ~40% to ~8%. Conclusions: This study gives a mechanistic insight of fisetin as a potential epigenetic modifier in HeLa cells. Full article

Mastitis remains a prevalent and economically detrimental disease within the dairy industry, profoundly affecting animal welfare, milk quality, and overall production output. Nowadays, Somatic Cell Count (SCC) is widely recognized as the gold-standard indicator for the detection of mastitis; however, its limitations in pathogens discrimination and the lack of early-stage characterization of mastitis highlight the need for complementary diagnostic approaches. This review synthesizes recent research into the development and validation of novel biomarkers for the early and accurate identification of mastitis in dairy cows. The investigation encompasses a range of biological molecules for improving mastitis diagnosis. Biomarkers such as lactoferrin (LTF), β-defensin 4 (DEFB4), vitronectin, paraoxonase 1 (PON1), and N-acetyl-β-D-glucosaminidase (NAGase) show promise in distinguishing between cows not susceptible and cows susceptible to mastitis. Concurrently, nucleic acid-based biomarkers are emerging as a particularly promising frontier. While mitochondrial DNA (mtDNA) has demonstrated insufficient specificity, microRNAs (miRNAs) are gaining attention as highly stable and sensitive indicators of intramammary inflammation, potentially enabling the detection of subclinical infections before they become clinically apparent. Despite these advances, significant challenges related to specificity, reliability, and cost-effectiveness currently hinder the widespread practical application of any single biomarker. Therefore, future research should be directed towards the validation of a synergistic panel of multiple biomarkers to improve mastitis management in dairy cow farms. Full article

This review article attempts to provide a unifying hypothesis to explain the myriad of symptoms and predispositions underlying the development of PASC (Postacute Sequelae of COVID), often referred to as Long COVID. The hypothesis described here proposes that Long COVID is best understood as a disorder of persistent immune dysregulation, with chronic macrophage activation representing the fundamental underlying pathophysiology. Unlike transient post-viral syndromes, Long COVID involves a sustained innate immune response, particularly within monocyte-derived macrophages, driven by persistent spike protein (peripherally in MAIT cells and centrally in Microglial cells), epigenetic imprinting, and gut-related viral reservoirs. These macrophages are not merely activated temporarily but also become epigenetically “trained” into a prolonged inflammatory state, as demonstrated by enduring histone acetylation markers such as H3K27acDNA Reprogramming. It is proposed that recognizing macrophage activation as the central axis of Long COVID pathology offers a framework for personalized risk assessment, targeted intervention, and therapeutic recalibration. Full article