Epigenetic Mechanisms Research Articles

Epigenetic changes in patients with post-acute COVID-19 symptoms (PACS) and long-COVID: A systematic review.

Up to 30% of people infected with SARS-CoV-2 report disabling symptoms 2 years after the infection. Over 100 persistent symptoms have been associated with Post-Acute COVID-19 Symptoms (PACS) and/or long-COVID, showing a significant clinical heterogeneity. To develop effective, patient-targeted treatment, a better understanding of underlying mechanisms is needed. Epigenetics has helped elucidating the pathophysiology of several health conditions and it might help unravelling inter-individual differences in patients with PACS and long-COVID. As accumulating research is exploring epigenetic mechanisms in PACS and long-COVID, we systematically summarized the available literature on the topic. We interrogated five databases (Medline, Embase, Web of Science, Scopus and medXriv/bioXriv) and followed PRISMA and SWiM guidelines to report our results. Eight studies were included in our review. Six studies explored DNA methylation in PACS and/or long-COVID, while two studies explored miRNA expression in long-COVID associated with lung complications. Sample sizes were mostly small and study quality was low or fair. The main limitation of the included studies was a poor characterization of the patient population that made a homogeneous synthesis of the literature challenging. However, studies on DNA methylation showed that mechanisms related to the immune and the autonomic nervous system, and cell metabolism might be implicated in the pathophysiology of PACS and long-COVID. Epigenetic changes might help elucidating PACS and long-COVID underlying mechanisms, aid subgrouping, and point towards tailored treatments. Preliminary evidence is promising but scarce. Biological and epigenetic research on long-COVID will benefit millions of people suffering from long-COVID and has the potential to be transferable and benefit other conditions as well, such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We urge future research to employ longitudinal designs and provide a better characterization of included patients.

Identification and Validation of the Hsa_circ_0001726/miR-140-3p/KRAS Axis in Hepatocellular Carcinoma Based on Microarray Analyses and Experiments.

Hepatocellular carcinoma (HCC) is one of the most fatal malignancies. Epigenetic mechanisms have revealed that noncoding RNAs, such as microRNAs (miRNAs) and circular RNAs (circRNAs), are involved in HCC progression. This study aimed to construct a circRNA-miRNA-mRNA network in HCC and validate one axis within the network. HCC-related transcriptome data were obtained from the Gene Expression Omnibus, and HCC-related genes were sourced from GeneCards to identify differentially expressed circRNAs and miRNAs. The targeting relationships between circRNA-miRNA and miRNA-mRNA interactions were predicted. The involvement of the hsa_circ_0001726/miR-140-3p/KRAS axis in HCC was evaluated through cellular experiments and survival analyses. We identified six differentially expressed circRNAs in HCC, which were linked to 13 miRNAs and 88 mRNAs. A network containing 34 circRNA-miRNA pairs and 194 miRNA-mRNA pairs was constructed. Cell proliferation and migration assays confirmed the role of hsa_circ_0001726 in promoting HCC progression, possibly through the miR-140-3p/KRAS axis. Survival analysis verified that hsa_circ_0001726 was a prognostic factor for overall survival in patients with HCC. The hsa_circ_0001726/miR-140-3p/KRAS axis also mediates lenvatinib resistance in HCC cells. The HCC circRNA/miRNA/mRNA network provides new insights into the post-transcriptional regulatory mechanism of HCC. The hsa_circ_0001726/miR-140-3p/KRAS axis is involved in HCC progression and lenvatinib resistance.

Epigenetic regulation of FOXP3 gene expression in relation to impaired function of regulatory T cells in systemic lupus erythematosus

The impaired function of regulatory T (Treg) cells and the imbalance of Treg/Th17 cells play a central role in developing autoimmune diseases such as systemic lupus erythematosus (SLE). Treg cells are crucial for maintaining immune homeostasis and tolerance to self-antigens. One of the most important transcription factors that regulate the differentiation and function of Treg cells is the FOXP3 protein. Aberrant epigenetic modifications affecting FOXP3 gene expression and consequently dysregulated function of Treg cells have been implicated in the pathogenesis of SLE. Therefore, understanding the intricate interplay between FOXP3 expression pattern in Treg cells and epigenetic regulatory mechanisms (e.g., DNA methylation, histone modifications and non-coding RNAs such as microRNAs and long non-coding RNAs) is crucial for unravelling the underlying mechanisms of SLE. Moreover, targeting these epigenetic pathways may offer novel therapeutic strategies for restoring immune balance and ameliorating autoimmune pathology. This review report aimed to provide an update on the epigenetic controlling of FOXP3 gene expression in SLE disease.

H3K9me3 demethylation by JMJD2B is regulated by pirfenidone resulting in improved NASH

NASH is characterized by hepatic lipid accumulation and inflammation; and JMJD2B—a histone demethylase—upregulation has been linked to its progression. Pirfenidone (PFD) is an antifibrotic agent with anti-inflammatory and antioxidant effects recognized to decrease NASH symptoms. Herein, our aim was to investigate PFD-induced epigenetics mechanisms involving JMJD2B and histone modifications in experimental NASH. Male C57BL/6J mice were fed with normo-diet, or high fat/carbohydrate diet (HF) for 16 weeks. A HF-subgroup was treated with PFD 300 mg/kg/d from week 8th to the end of protocol. Insulin tolerance test and liver and fat histological and biochemical analyses were carried out. Hepatic transcriptome was examined. Liver proteins were studied by western blot (WB) and Chromatin immunoprecipitation. In vitro, lipotoxicity was induced in HepG2 cells and proteins were evaluated using WB. Molecular docking was used to explore binding of PFD to JMJD2B. Mice treated with PFD reduced weight gain, epididymal fat and inflammatory nodules, and steatosis in liver tissue, as well as, improved biochemical test. PFD modified the expression of Jmjd2b, Pparg, Fasn and Srebp1, and restored JMJD2B protein and H3K9me3 repressive mark, both in animal and cell models. PFD increased hepatic enrichment of H3K9me2 and H3K9me3 at the promoter region of Fasn and Srebp1, and Pparg. In HepG2 cells, PFD reduced lipid vacuole accumulation. In silico, PFD interacted with JMJD2B catalytic site. PFD is an epigenetic regulator modifying JMJD2B activity, resulting in reduced NASH traits.

The deficiency of ALKBH5 contributes to hepatic lipid deposition by impairing VPS11-dependent autophagic flux.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Hepatic lipid deposition is a key factor in the development of NAFLD. N6-methyladenosine (m6A) modification, the most prevalent mRNA modification in eukaryotic cells, plays an important role in regulating hepatic lipid metabolism. However, its potential role in hepatic lipid deposition remains poorly understood. Histological and immunohistochemistry studies were used to investigate lipid deposition in free fatty acids (FFAs)-incubated LO2 cells, high-fat diet-fed mice models and clinical samples. Stable overexpression and knockdown of AlkB homolog 5 (ALKBH5) was manipulated to investigate the effects of ALKBH5 on m6A methylation and lipid metabolism in hepatocytes. RNA-sequencing transcriptome analysis and methylated RNA immunoprecipitation-quantitative-PCR analysis were used to reveal the potential downstream molecular targets of ALKBH5. ALKBH5 was down-regulated in fatty liver compared to normal liver in both humans and mice. Overexpression of ALKBH5 significantly improved FFA-induced lipid accumulation and promoted autophagosome-lysosome fusion in hepatocytes. Meanwhile, knockdown of ALKBH5 significantly increased the expression of microtubule-associated protein 1A/1B-light chain 3B and Sequestosome 1, leading to impaired autophagic flux and further lipid deposition in hepatocytes under FFA incubation. Overexpression of vacuolar protein sorting 11 (VPS11) reversed FFA-induced lipid accumulation in ALKBH5-silenced hepatocytes. Mechanistically, ALKBH5 alleviated hepatic lipid deposition and impaired autophagic flux by removing the m6A modification on VPS11 mRNA to promote its translation. Collectively, our findings revealed an epigenetic mechanism by which ALKBH5 alleviates hepatic lipid deposition by restoring VPS11-dependent autophagic flux, providing a potential target to counteract NAFLD.

Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer.

Iron is an essential biomineral in the human body. Here, we describe a subset of iron-loaded cancer-associated fibroblasts, termed as FerroCAFs, that utilize iron to induce immunosuppression in prostate cancer and predict an unfavorable clinical outcome. FerroCAFs secrete myeloid cell-associated proteins, including CCL2, CSF1 and CXCL1, to recruit immunosuppressive myeloid cells. We report the presence of FerroCAFs in prostate cancer from both mice and human, as well as in human lung and ovarian cancers, and identify a conserved cell surface marker, the poliovirus receptor. Mechanistically, the accumulated iron in FerroCAFs is caused by Hmox1-mediated iron release from heme degradation. The intracellular iron activates the Kdm6b, an iron-dependent epigenetic enzyme, to induce an accessible chromatin state and transcription of myeloid cell-associated protein genes. Targeting the FerroCAFs by inhibiting the Hmox1/iron/Kdm6b signaling axis incurs anti-tumor immunity and tumor suppression. Collectively, we report an iron-loaded FerroCAF cluster that drives immunosuppression through an iron-dependent epigenetic reprogramming mechanism and reveal promising therapeutic targets to boost anti-tumor immunity.

A "poly-matter network" conception of biological inheritance.

Here we intend to shift the "DNA- and information-centric" conception of biological inheritance, with the accompanying exclusion of any non-DNA matter, to a "poly-matter network" framework which, in addition to DNA, considers the action of other cellular membranous constituents. These cellular structures, in particular organelles and plasma membranes, express "landscapes" of specific topologies at their surfaces, which may become altered in response to certain environmental factors. These so-called "membranous environmental landscapes" (MELs), which replicate by self-organization / autopoiesis rather than self-assembly, are transferred from donor to acceptor cells by various - vesicular and non-vesicular - mechanisms and exert novel features in the acceptor cells. The "DNA-centric" conception may be certainly explanatorily sufficient for the transfer of heritable phenotype variation to acceptor cells following the copying of DNA in donor cells and thereby for the phenomenon of biological inheritance of traits. However, it is not causally sufficient. With the observation of phenotype variation, as initially manifested during bacterial transformation, the impact of environmental factors, such as nutrition and stress, in the differential regulation of gene expression has been widely accepted and resulted in intense efforts to resolve the underlying epigenetic mechanisms. However, these are explained under a conceptual frame where the DNA (and associated proteins) are the only matter of inheritance. In contrast, it is our argumentation that inheritance can only be adequately understood as the transfer of DNA in concert with non-DNA matter in a "poly-matter network" conception. The adequate inclusion of the transfer of non-DNA matter is still a desideratum of future genetic research, which may pave the way for the experimental elucidation not only of how DNA and membrane matter act in concert to enable the inheritance of innate traits, but also whether they interact for that of acquired biological traits. Moreover, the "poly-matter network" conception may open new perspectives for an understanding of the pathogenesis of "common complex" diseases.

Sodium arsenite-induced DNA methylation alterations exacerbated by p53 knockout in MCF7 cells

Epigenetic alterations are ubiquitous across human malignancies. Thus, functional characterization of epigenetic events deregulated by environmental pollutants should enhance our understanding of the mechanisms of carcinogenesis and inform preventive strategies. Recent reports showing the presence of known cancer-driving mutations in normal tissues have sparked debate on the importance of non-mutational stressors potentially acting as cancer promoters. Here, we aimed to test the hypothesis that the presence of mutations in p53, a commonly mutated gene in human malignancies, may influence cellular response to an environmental non-mutagenic agent, potentially involving epigenetic mechanism. We used the CRISPR-Cas9 system to generate knockouts of p53 in MCF7 and T47D breast cancer cell lines and characterized DNA methylome changes by targeted pyrosequencing and methylome-wide Infinium MethylationEPIC BeadChip arrays after exposure to sodium arsenite, a well-established human carcinogen with documented effects on the epigenome. We found that the knockout of p53 alone was associated with extensive alterations in DNA methylation content, with predominant CpG hypermethylation concurrent with global demethylation, as determined by LINE-1 repetitive element pyrosequencing. While exposure to sodium arsenite induced little to no effects in parental cell lines, mutant cells, upon treatment with sodium arsenite, exhibited a markedly altered response in comparison to their wild-type counterparts. We further performed genome regional analyses and found that differentially methylated regions (DMRs) associated with exposure to sodium arsenite map to genes involved in chromatin remodeling and cancer development. Reconstitution of wild-type p53 only partially restored p53-mutant-specific differential methylation states in response to sodium arsenite exposure, which may be due to the insufficient reconstitution of p53 function, or suggestive of a potential exposure-specific epigenetic memory. Together, our results revealed wide-spread epigenetic alterations associated with p53 mutation that influence cellular response to sodium arsenite exposure, which may constate an important epigenetic mechanism by which tumour promoting agents synergize with driver mutations in cancer promotion.

G-Quadruplex Structures as Epigenetic Regulatory Elements in Priming of Defense Genes upon Short-Term Trichoderma atroviride Inoculation in Maize.

Symbiosis establishment between Trichoderma atroviride and plant roots triggers the priming of defense responses, among other effects. Currently, there is no clear evidence regarding the molecular mechanisms that allow the plant to remain alert to future stimulus, either by pathogen attack or any other abiotic stress. Epigenetic modifications have emerged as a strategy to explain the increased defense response of plants in a priming state conferred by Trichoderma. Recently, various non-canonical structures of nucleic acids, especially G-quadruplex structures (G-quadruplexes or G4s), have been identified as potential targets during the establishment or maintenance of plant signals. In the present study, we developed a screening test for the identification of putative G4-forming sequences (PQSs) in previously identified Z. mays priming genes. Bioinformatic analysis revealed the presence of PQSs in the promoter region of five essential genes playing a critical role in priming in maize. Biophysical and spectroscopy studies showed the formation of G4s by these PQSs in vitro, and ChIP assays demonstrate their formation in vivo. Therefore, G4 formation could play a role as an epigenetic regulatory mechanism involved in the long-lasting primed state in maize plants.

Dissecting the temporal genetic networks programming soybean embryo development from embryonic morphogenesis to post-germination

Key messageDesiccation-stage transcription factors perform similar functions, with early ones focused on desiccation tolerance and later ones on development. Gene networks governing late embryo development diverge between soybean and Arabidopsis.To understand gene activities programming seed embryo development, we profiled the soybean embryo transcriptome across embryonic morphogenesis through post-germination. Transcriptomic landscapes across embryo development feature highly prevalent transcripts, categorized into early and late groups, with shared and distinct functions. During the mid-storage reserve accumulation stage, the upregulated genes are enriched with regulatory tasks at both the transcriptional and chromatin levels, including DNA methylation and chromatin remodeling. The epigenetic-related functions also dominate in the upregulated genes during germination, involving core histone variants and histone chaperones. Gene network analysis reveals both stage-specific modules and modules active across multiple stages. The desiccation-associated gene module integrates diverse transcription factors (TFs) that are sequentially active during different desiccation stages, transitioning from abiotic stress functions early on to developmental functions later. Two TFs, active during the early and mid-desiccation stages were functionally assessed in Arabidopsis overexpression lines to uncover their potential roles in desiccation processes. Interestingly, nearly half of the Arabidopsis orthologs of soybean TFs active in the desiccation-associated module are inactive during Arabidopsis desiccation. Our results reveal that chromatin and transcriptional regulation coordinate during mid-storage reserve accumulation, while distinct epigenetic mechanisms drive germination. Additionally, gene modules either perform stage-specific functions or are required across multiple stages, and gene networks during late embryogenesis diverge between soybean and Arabidopsis. Our studies provide new information on the biological processes and gene networks underlying development from embryonic morphogenesis to post-germination.

Maternal Malnutrition in Mice Impairs Nephrogenesis by Disrupting DNA Methylation of Regulatory Regions.

Maternal caloric restriction during pregnancy significantly impacts kidney development, influencing susceptibility to chronic kidney disease in adulthood. This study explores DNA methylation changes in nephron progenitor cells resulting from caloric restriction and their implications for kidney health. Global DNA hypomethylation is observed in nephron progenitors from caloric-restricted embryos, with specific genomic regions displaying distinct methylation patterns, including hypomethylation and hypermethylation. Differentially methylated regions exhibit enhanced chromatin accessibility, indicating biological relevance. Hypomethylated regions are enriched for genes associated with developmental processes, reflecting changes in gene expression and highlighting their functional relevance in kidney development. The study also reveals that supplementing methionine, an essential amino acid, restores disrupted DNA methylation patterns, particularly in enhancer regions, emphasizing methionine's critical role in regulating nephron progenitor cell epigenetics and ensuring proper kidney development. The intricate relationship between maternal nutrition, dynamic DNA methylation, and kidney development is highlighted, emphasizing the enduring impact of early-life nutritional challenges on kidney function. This research elucidates epigenetic mechanisms as mediators for the lasting effects of maternal caloric restriction on kidney health. The study contributes valuable insights into the origins of chronic kidney diseases during early developmental stages, offering potential interventions to mitigate adverse outcomes.

Methylomic signature of current cannabis use in two first-episode psychosis cohorts.

The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = > 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure.

Hsa_circ_0002473 inhibits GH3 cell proliferation and GH secretion as a competitive endogenous RNA for has-miR-4645-3p.

Growth hormone deficiency (GHD) diagnosis still lacks a gold standard or ideal diagnostic marker. Unlike other epigenetic mechanisms, non-coding RNAs regulate post-transcriptional levels. The information on non-coding RNAs in the field of GHD is limited. Therefore, this study aimed to explore the role of hsa_circ_0002473 as a competitive endogenous RNA for has-miR-4645-3p in attenuating the inhibitory effect of has-miR-4645-3p on SSTR2. In this study, we screened three significantly expressed circular RNAs (circRNAs) in five children with GHD, and selected the highest expressed hsa_circ_0002473 as the study object, and screened has-miR-4645-3p, which is the most likely to bind to hsa_circ_0002473, according to the microRNA (miRNA)-circRNA regulatory network, to study the role and mechanism of has-miR-4645-3p as a competitive endogenous RNA of has-miR-4645-3p on GH3 cells. Somatostatin receptor 2 (SSTR2) inhibits GH3 cell proliferation, and miRNA binding to SSTR2 inhibits the latter expression. Both bioinformatics and dual-luciferase reporter analyses showed targeting relationships between hsa_circ_0002473 and has-miR-4645-3p and between has-miR-4645-3p and SSTR2. We constructed the hsa_circ_0002473/has-miR-4645-3p axis and transfected it into GH3 cells and found that overexpression of hsa_circ_0002473 inhibited the proliferation and growth hormone (GH) secretion of GH3 cells, and that hsa-miR-4645-3p promoted the proliferation and GH secretion of GH3 cells by targeting SSTR2. Co-culture revealed that the inhibitory effect of hsa_circ_0002473 was reversed by has-miR-4645-3p. In conclusion, our findings suggest that hsa_circ_0002473 can act as a competitive endogenous RNA for has-miR-4645-3p to regulate GH3 cell proliferation and secretion by targeting SSTR2.

The impact of climate change-related disasters on mental health and epigenetics: a narrative review

Climate change has contributed to an increase in the frequency and intensity of natural disasters such as droughts, wildfires, hurricanes, and floods, leading to both immediate physical harm and long-term mental health consequences. Survivors often experience psychological distress, including anxiety, depression, and post-traumatic stress disorder (PTSD), as a result of these traumatic events. This narrative review explores the intersection of climate change-related disasters, mental health outcomes, and epigenetic modifications. Specifically, we summarize recent findings on how environmental stressors influence both mental health and epigenetic changes, such as DNA methylation. Emerging evidence suggests that epigenetic mechanisms, particularly DNA methylation, could mediate the effects of climate change-related stress on mental health, potentially contributing to the onset of mental disorders like depression, panic disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. We also discuss other epigenetic mechanisms, such as histone modifications and non-coding RNAs, and emphasize the importance of longitudinal studies to capture the dynamic nature of epigenetic changes over time. Finally, we propose future research directions to deepen our understanding of the complex relationships between climate change-related disasters, mental health outcomes, and epigenetic mechanisms, which will pave the way for more effective mental health interventions and policy integration.

CHH hypermethylation contributes to the early ripening of grapes revealed by DNA methylome landscape of “Kyoho” and its bud mutant

Abstract DNA methylation is a stable epigenetic mark that plays a crucial role in plant life processes. However, the specific functions of DNA methylation in grape berry development remain largely unknown. In this study, we performed whole-genome bisulfite sequencing on “Kyoho” grape and its early-ripening bud mutant “Fengzao” at different developmental stages. Our results revealed that transposons (TEs) and gene flanking regions exhibited high levels of methylation, particularly in “Fengzao”, attributed to CHH site methylation. Interestingly, the methylation patterns in these two cultivars showed distinct dynamics during berry development. While methylation levels of genes and TEs increased gradually in “Kyoho” throughout berry development, “Fengzao” did not display consistent changes. Notably, “Fengzao” exhibited higher methylation levels in promoters compared to “Kyoho”, suggesting that hypermethylation of promoters may contribute to its early ripening phenotype. Integration of methylome and transcriptome data highlighted differentially methylated genes (DMGs) and expressed genes (DEGs) associated with secondary metabolite biosynthesis, with 38 genes identified as potential candidates involved in grape berry development. Furthermore, the study identified a jasmonate-induced oxygenase gene (JOX1) as a negative regulator of ripening in Arabidopsis and grapes, indicating that hypermethylation of JOX1 may play a role in the early ripening of “Fengzao”. Overall, our findings provide insights into the distinct DNA methylation patterns during grape berry development, shedding light on the epigenetic regulatory mechanisms underlying the early-ripening bud mutant.

Species-specific satellite DNA composition dictates de novo formation of PRC1-mediated pericentric heterochromatin.

Pericentromeres are heterochromatic regions adjacent to centromeres that ensure accurate chromosome segregation. Despite their conserved function, they are composed of rapidly evolving A/T-rich satellite DNA. This paradoxical observation is partially resolved by epigenetic mechanisms that maintain heterochromatin, independent of specific DNA sequences. However, it is unclear how satellite DNA sequence variation impacts de novo formation of pericentric heterochromatin, which is initially absent from paternal chromosomes in the zygote. Here we show that satellite variation has functional consequences for zygotic heterochromatin formation, recruitment of the Chromosome Passenger Complex (CPC), and interactions with spindle microtubules. In M. musculus zygotes, Polycomb Repressive Complex 1 (PRC1) is recruited to pericentric satellites by its AT-hook domain, which binds runs of A/T nucleotides, to generate H2AK119ub1 (H2Aub) heterochromatin. By fertilizing M. musculus eggs with sperm from other mouse species, we show that species-specific satellite sequences differ in their ability to recruit PRC1 and form H2Aub. This satellite-DNA mediated increase in PRC1 heterochromatin leads to reduced CPC recruitment and increased microtubule forces on kinetochores. Our results provide a direct link between satellite DNA composition and pericentromere function in the zygote, when epigenetic pathways maintaining pericentromere heterochromatin are absent.

The Protective Effect against Lung Injury of Phytosome Containing the Extract of Purple Waxy Corn Tassel in an Animal Model of PM2.5-Induced Lung Inflammation.

Lung inflammation caused by fine particulate matter (PM), particularly PM2.5, poses a significant public health challenge, with oxidative stress and inflammation playing central roles in its pathophysiology. This study evaluates the protective effects of phytosome-encapsulated extract of purple waxy corn tassel (PPT) against PM2.5-induced lung inflammation. Male Wistar rats received PPT at doses of 100, 200, and 400 mg/kg BW for 21 days prior to exposure and continued to receive the same doses for 27 days during PM2.5 exposure. Significant reductions in inflammatory markers, including cyclooxygenase-2 (COX-II), various interleukins (IL-1β, IL-6, IL-8), tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa B (NF-κB), were observed, indicating that PPT effectively regulates the inflammatory response. Additionally, PPT improved oxidative stress markers by reducing malondialdehyde (MDA) levels and enhancing antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), thereby restoring lung antioxidant defenses. Notably, the study revealed that PPT modulates epigenetic mechanisms, as evidenced by decreased histone deacetylase (HDAC) activity and upregulation of sirtuins in lung tissue. These epigenetic modifications likely contribute to the reduction in inflammation and oxidative stress, suggesting a multifaceted protective role of PPT that involves both direct biochemical pathways and epigenetic regulation. The interplay between reduced inflammatory signaling, enhanced antioxidant capacity, and epigenetic modulation underscores PPT's potential as a therapeutic agent for managing respiratory inflammation-related diseases and its promise for the development of future functional food products.

Precision Population Cancer Medicine in Brain Tumors: A Potential Roadmap to Improve Outcomes and Strategize the Steps to Bring Interdisciplinary Interventions.

Brain tumors, a significant health burden,rank as the second leading cause of cancer among adolescents and young adults and the eighth most common cancer in older adults. Despitetreatment advances, outcomesfor many brain tumor types,especiallyglioblastoma multiforme (GBM), remain poor. Precision population cancer medicine (PPCM) offerspromising avenues for improving outcomes in brain tumor management.This comprehensive reviewdelves intothe current landscape of brain tumor diagnosis and treatment,with a primary focus onthe potential of PPCM toenhancecare. The reviewexploresseveral key areas where PPCM approaches show promise. In genetics and molecular biology, the genetic heterogeneity of brain tumors poses challengesandopportunities for targeted therapies. Understanding genetic patterns canguidetreatment strategies and improve prognostication. Epigenetic modificationsarecrucialin brain tumor development and progression. Deoxyribonucleic acid(DNA) methylation patterns, particularly of theO6-methylguanine-DNA methyltransferase (MGMT) gene promoter, serve asessentialbiomarkers for treatment response and prognosis in GBM. Targeting epigenetic mechanisms could lead to novel therapeutic approaches. Non-invasive liquid biopsy techniques show potential for diagnosis, monitoring, and prognostication in brain tumors. Analysis of circulating tumor DNA and microRNAs may provide valuable information about tumor characteristics and treatment response. Advanced imaging techniques, including radiomics and radiogenomics, combined with artificial intelligence (AI) algorithms, are enhancing tumor detection, characterization, and treatment planning. These technologies can contribute to more personalized treatment approaches.In addition, emergingnanotherapeutic platforms, which involve the use of nanoparticles to deliver drugs directly to tumors,and theranostic approaches, which combine therapy and diagnostics in a single platform,offer new possibilities for targeted drug delivery and real-time treatment monitoring in brain tumors. The review also addresses socioeconomic and demographic factors influencing brain tumor incidence and outcomes. It highlightsthe starkdisparities in care access and survival rates among different racial and ethnic groups, emphasizing theurgentneed for PPCM strategies to address these inequities. Challenges in implementing PPCM for brain tumors include the blood-brain barrier, which limits drug delivery, and the need for more extensive clinical trials to validate new approaches. The authors stress the importance of interdisciplinary collaboration and data sharing to advance the field, making the audience feel united and part of a larger team. While PPCM holds great promise, the review emphasizes that it should complement, not replace, population-level interventions and standard-of-care treatments. The authors advocate for a balanced approach that leverages cutting-edge personalized strategies while ensuring broad access to effective treatments. In conclusion, PPCM represents a powerful tool in the fight against brain tumors, offering the potential for more targeted, effective, and less toxic treatments. However, realizing its full potential will require ongoing research, clinical validation, and policy interactionsto address disparities in care access.

Preliminary study of the role of histone deacetylase (HDAC) in steroid-induced avascular necrosis of the femoral head induced by BMSC adipogenic differentiation

Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH.Graphical abstract

DNA methylation drives hematopoietic stem cell aging phenotypes after proliferative stress.

Aging of hematopoietic stem cells (HSCs) is implicated in various aging phenotypes, including immune dysfunction, anemia, and malignancies. The role of HSC proliferation in driving these aging phenotypes, particularly under stress conditions, remains unclear. Therefore, we induced forced replications of HSCs in vivo by a cyclical treatment with low-dose fluorouracil (5FU) and examined the impact on HSC aging. Our findings show that proliferative stress induces several aging phenotypes, including altered leukocyte counts, decreased lymphoid progenitors, accumulation of HSCs with high expression of Slamf1, and reduced reconstitution potential, without affecting stem cell self-renewal capacity. The divisional history of HSCs was imprinted in the DNA methylome, consistent with functional decline. Specifically, DNA methylation changes included global hypermethylation in non-coding regions and similar frequencies of hypo- and hyper-methylation at promoter regions, particularly affecting genes targeted by the PRC2 complex. Importantly, initial forced replication promoted DNA damage repair accumulated with age, but continuous proliferative stress led to the accumulation of double-strand breaks, independent of functional decline. Overall, our results suggest that HSC proliferation can drive some aging phenotypes primarily through epigenetic mechanisms, including DNA methylation changes.